CN103079557A - Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses - Google Patents

Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses Download PDF

Info

Publication number
CN103079557A
CN103079557A CN2011800153054A CN201180015305A CN103079557A CN 103079557 A CN103079557 A CN 103079557A CN 2011800153054 A CN2011800153054 A CN 2011800153054A CN 201180015305 A CN201180015305 A CN 201180015305A CN 103079557 A CN103079557 A CN 103079557A
Authority
CN
China
Prior art keywords
mercaptan
sulfydryl
chemical compound
bis
antibiotic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2011800153054A
Other languages
Chinese (zh)
Inventor
B·H·J·贝克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Microbion Corp
Original Assignee
Microbion Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2010/023108 external-priority patent/WO2010091124A2/en
Application filed by Microbion Corp filed Critical Microbion Corp
Priority to CN201710523562.8A priority Critical patent/CN107308186A/en
Publication of CN103079557A publication Critical patent/CN103079557A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
    • A01N55/02—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur containing metal atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/29—Antimony or bismuth compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural 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

Be used for comprising the biomedical applications for the treatment of of bacterial biof iotalm and the bismuth-mercaptan of other purposes as antibacterial
The cross reference of related application
The application requires the PCT application No.PCT/US2010/023108 that submitted on February 3rd, 2010 and the U.S. Provisional Application No.61/373 that submitted on August 12nd, 2010,188 rights and interests, described application respectively by reference integral body incorporate this paper into.
Background of invention
Technical field
Disclosure working of an invention scheme relates to compositions and the method that is used for the treatment of infected by microbes.Especially, the present embodiment relates to for epithelial tissue (be included in wound for example chronic wounds and acute wounds in), and the treatment of (comprising in the treatment of bacterial biof iotalm and other condition of illness) improvement that control antibacterial infects in clinical, individual health care and other situation.
The description of association area
Promote skin wound healing and respond to the adverse effect that usually can be subjected to various external factor with anti-microbial infection and/or the combination that promotes healing or keep systemic a series of collaborative cell and interaction of molecules, for example opportunistic infection and hospital infection (for example, can increase the clinical protocol of infection risk), antibiotic part or general use that (it can affect Growth of Cells, the migration or other function and can screen the antibiotic resistance microorganism), wound dressing changes frequently, expose wound to the open air with healing acceleration, the use of temporary artificial structure's supporter substrate or timbering material, for debridement and/or repeatedly perform the operation to excise and infect or possible demand and/or its factor of slough.
Therefore wound healing remains huge challenge in the world clinicist.Current treatment for the intractable wound is impracticable and invalid, often needs Repeated Operation with closure of wound.For example,
Figure BDA00002178874500011
(Inc. can be by Ethicon for becaplermin, Ortho-McNeil Pharmaceutical, and Inc. obtains, the recombinant platelet derivative growth factor) enumerated a kind of for the treatment of chronic wounds that minority can use, but produces costliness and Clinical practicability is limited.
Chronic and acute wounds and wound biomembrane
When organize between the inner cell or tissue between seriality for example be subject to, physics, machinery, biology, pathology and/or chemical force (for example, burn, skin infection, stab, gunslinging or shell wound, skin ulcer, radiation poisoning, malignant tumor, gangrene, autoimmune disease, immunodeficiency, breathing damage (such as by sucking or infecting), gastrointestinal damage (such as ingesting or infect by harmful), circulation and blood disorderly (comprising coagulation defect)) or produce wound during the destruction of other traumatic injury etc.
Yet, " cluster " of the germ contamination of limited level or wound may not necessarily hinder the process of wound healing in the wound, but can cause acute wounds or chronic wounds or have the wound of bacterial biof iotalm with the antibacterial that the quantity that is enough to overwhelm the host immune defence exists, for example bacterial growth produces the wound infection of infringement to the host.Bryant and Nix, Acute and Chronic Wounds:Current Management Concepts, 2006 Mosby (Elsevier), NY; Baronoski, Wound Care Essentials:Practical Principles (second edition) 2007 Lippincott, Williams and Wilkins, Philadelphia, PA).For example, acute wounds for example can be caused by damage, wound, surgical operation or other reason usually do not have potential healthy defective (health deficit) and quickly-healing, but sometimes can not heal rapidly owing to there is infection; Described in acute wounds and formed bacterial biof iotalm (for example, WO/2007/061942) fast.Can promote forfeiture that the other factor of chronic wounds development comprises activeness (for example, it causes putting on the pressure that continues of wound location), sensation or intellectual deficiency, wound location not accessible (for example, at respiratory tract or gastrointestinal tract) and circulation defective.Can pass through the clinical sign of skin rubefaction, edema, suppuration and/or bad smell, perhaps the standard of other relevant clinical acceptance detects the infection at the chronic wounds position.
In higher organism (include but not limited to people and other mammals) when host's immune system oneself by wound location (for example, acute wounds) antibacterial infects institute and overwhelms, when producing bacterial invasion and further histoclastic permissive condition, the acute wounds that can not suitably heal can occur thus, and chronic wounds thus can be developed.Usually, chronic wounds is healing in three months, and is not to diminish but along with antibacterial is infiltrated development and wound that trend increases.When beginning impaired (neuropathy) along with near the nerve the wound development, for the patient, the chronic wounds very pain and frightening that can become.These wounds have influence on 4,000,000 Americans every year and treatment cost spends about 9,000,000,000 dollars.Got involved individual great majority above 60 years old.
Chronic wounds can result from acute wounds also so can comprise in some cases, for example, gunslinging or shell fragment wound, burn, stab, venous ulcer, pressure ulcer, diabetic ulcer, radiation poisoning, malignant tumor, skin infection, gangrene, surgical incision, the diabetic ulcer of foot, decubital ulcer, venous leg ulcers, that infect and/or contain the biomembranous surgical incision that do not heal, Pyoderma gangrenosum, trauma wounds, acute arterial function is incomplete, necrotizing fasciitis, osteomyelitis (infection of bone) and rasdiation damage, for example wound of osteoradionecrosis and soft tissue radium necrosis or other type.For example, venous ulcer mainly betides lower limb, by poor circulation (for example, ischemia), venous valve malfunction or physics wound (for example, repeatability damage) and causing repeatedly.Pressure ulcer can occur when being applied to wound site or near local pressure greater than blood pressure, for example thus poor circulation, paralysis and/or decubital ulcer can promote chronic wounds or make its deterioration.Diabetic ulcer can betide in the individuality of suffering from diabetes, for example, wherein uncontrolled hyperglycemia can promote when extreme sensory deprivation, cause repeatability damage and/or the individual treatment of ignoring damage of part.May make clinical onset and chronic wounds result complicated or other have the factor of other impact to comprise that experimenter's immune state is (such as, impaired immune system on (for example HIV-AIDS), the radiotherapy or on the pharmacology on immunosuppressant, the pathology; Age; Stress); Biomembranous generation and progress in skin aging (comprising that photochemistry is aging) and the wound.In respiratory tract and/or gastrointestinal tract in the situation of epithelial tissue, unapproachability, seal, be difficult to produce the local microenvironment that epithelial surface cleaning fluid power or development be conducive to microbial survival and can cause clinical complication.
The damage that wound is relevant may follow organ dysfunction forfeiture or impaired, shock, hemorrhage and/or thrombosis, cell death (for example, necrosis and/or apoptosis), stress and/or infected by microbes.These events arbitrary or whole (particularly infecting) can postpone or stop effective process of tissue reparation related in the wound healing.Therefore, importantly remove debility from wound location as early as possible in suffering the individuality of wound and organize, this process is called as debridement, and removes any foreign body from wound location in addition, also is called wound clean.
Serious wound, acute wounds, chronic wounds, burn and ulcer may be benefited from the cell wound dressing.Several artificial skin products can be used for non-healing of wound or burn, for example:
Figure BDA00002178874500031
(Norvartis),
Figure BDA00002178874500032
(Advance Tissue Science),
Figure BDA00002178874500033
Dermal Regeneration
Figure BDA00002178874500034
(from Integra Life Sciences Technology) and
Figure BDA00002178874500035
Yet these products are not that the problem of invading profit and wound expansion for solving the antibacterial tissue designs.
Regrettably, systemic antibiotics is invalid for treatment chronic wounds, and generally is not used, unless there is acute bacterial infection.Present method comprises uses or uses 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 fastbacteria (for example methicillin resistance staphylococcus aureus ((Staphylococcus aureus) or MRSA) time uses the antibacterial particular importance that may become.Many widely used antibacterial are arranged, and the bacterial flora or the subgroup that still produce may not replied these reagent, perhaps any other at present available treatment are not replied.In addition, many antibacterial may be toxicity resisting effectively that the antibacterial that produces infects under the required concentration host cell, so these antibacterial are unaccommodated.This problem may attempt removing in the situation about infecting outstanding especially from self-faced, described self-faced comprises interior epithelial surface, for example respiratory tract (for example, air flue, nasopharynx larynx passage, trachea, lung, bronchus, bronchioles, alveolar etc.) or gastrointestinal tract (for example, oral cavity, esophagus, stomach, intestinal, rectum, anus etc.) or other epithelial surface.
Problematic especially is to be made of bacterial biof iotalm (the antibacterial tissue of being familiar with recently) to infect, free whereby unicellular (" swimming ") antibacterial is gathered into organized many cells groups (biomembrane (biofilm)) by intercellular adhesion, and described many cells group has significantly different behavioral pattern, gene expression and to the sensitivity of the surrounding material that comprises antibiotic.Biomembrane can adopt the biophylaxis mechanism of not finding in planktonic bacteria, described mechanism can protect biomembrane group to avoid antibiotic and host immune response.Established biomembrane can stop the organization healing process.
Common microorgranic contaminant comprises staphylococcus aureus (it comprises MRSA (methicillin resistance staphylococcus aureus)), enterococcus, escherichia coli, Pseudomonas aeruginosa, streptococcus and Acinetobacter baumannii under lasting and potential harmful infection.These microorganisms show a bit in the non-nutritive ability of clinical surface survival several months.Shown staphylococcus aureus around the dry glass survival, and at blood stasis and 3 to 6 months (Domenico etc., 1999 Infect.Immun.67:664-669) of cotton fiber survival.Shown escherichia coli and Pseudomonas aeruginosa on blood stasis and cotton fiber than staphylococcus aureus survival longer time (as previously mentioned).
Microbial biofilm is with relevant with the obvious resistance that increases of antibiotic to disinfectant.When being attached to the surface, antibacterial and/or fungus 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, they are to the resistance of immune system.In case forming, biomembrane is very difficult to eradicate, so the prevention biofilm formation is very important clinical priority principle.Recently research shows that open wound can be polluted fast by biomembrane.These microbial biofilms are considered to postpone wound healing, and probably the generation with serious wound infection is relevant.
For example, the at present guideline of the military wound of nursing (military wound) regulation brute force and fully flushing and debridement (Blankenship CL, Guidelines for care of open combat casualty wounds, Fleet Operations and Support.U.S.Bureau ofMedicine and Surgery).Although it is important should getting involved in early days, it is not enough to the generation of prevention infection.After debridement, need to take other treatment step to promote healing, to reduce the biological load of microorganism, form wound infection and the biomembranous probability of wound thereby reduce.
Because the complexity of military trauma wound, the probability of infection is very large, particularly considers the introducing of exotic and other environmental contaminants.Both have served as the important sources of potentially pathogenic microorganism military affairs and clinical setting (comprising the people in these two kinds of environment), particularly for those people that suffer open wound and/or complicated wound.Acute and chronic wounds (comprising surgical wound and military wound) has damaged body and has mainly defendd and barrier to anti-infective; Skin.Therefore, wound makes internal body (moistening and nutrient environment) be exposed to opportunistic infection and pathogenic infection.Many infection, particularly persistence wound infection during these infect may be relevant with biofilm formation, shown it is this situation (James etc., 2008) such as chronic wounds.The infection of wound consists of one of common cause of nosocomial infection in the hospital, and the wound that produces in military and the natural disaster environment is to microbial contamination especially sensitivity.Military wound usually is extensive and deep because usually relevant with tissue injury and be easy to infect, and can introduce allochthon and disturb local blood supply, can follow fracture and have a fever, and can cause suffering a shock and immune defence impaired.
Skin framework and wound healing
Complete functional skin and other epithelial tissue are (for example, the general non-blood vessel epithelial surface that between microorganism and its external environment condition, forms barrier, such as exist in those and respiratory tract and gastrointestinal lining form, the glandular tissue etc. that exist in the skin those) keep for the health of people and other animal and to survive be important.Skin is people and other high organ that waits maximum in the vertebrates (for example mammal), defends environmental injury by its barrier function, mechanical strength and impermeability.As important environmental interface, skin provides the body covering of protectiveness, and physiology's balance is maintained.
The skin framework is known.In brief, covered by horny layer as the epidermis of skin outer layer, horny layer is dead epidermis Skin Cell (for example keratinocyte) and the protective layer of extracellular connective tissue albumen.Along with epidermis is substituted by the novel substance of upwards releasing from lower surface granular cell, spine cell and basal cell layer, epidermis stands the continuous process that comes off, wherein continuous cell division and albumen synthesize generation new Skin Cell and skin protein (for example, keratin, collagen).Corium is positioned under the epidermis, by connective tissue protein (for example be, collagen, elastin laminin etc.) the position of dermal fibroblast processing, described connective tissue protein is gathered into extracellular matrix and filamentary structure, this filamentary structure is given skin flexibility, intensity and elasticity.Also there are nerve, blood vessel, smooth muscle cell, hair follicle and sebaceous gland in the corium.
As the first line of defence of health, skin is the main target of following clinical infringement (physics, machinery, chemistry and the biology (for example xenobiotic, autoimmune) that for example can change skin texture and function are attacked).Skin also is considered to the important component part of microorganism immune defence.Can find to have migration and resident leukocyte (for example, lymphocyte, macrophage, mastocyte) and epidermis dendron shape (Langerhans) cell of potential antigen presentation activity in the skin, the protection of their Promote immunities.The potential harmful ultraviolet of pigment melanocyte Cell uptake (UV) radiation in the basal layer.Skin destroys as the experimenter brings the risk of not expecting, comprises and opportunistic infection, incomplete or improper organization reinvents, cicatrization, mobility are impaired, pain and/or other complication are relevant those risks.The same with skin, other epithelial surface (for example, respiratory tract, gastrointestinal tract and gland lining (glandular lining)) has definite structure attribute when health, so that infection or other destruction can be brought serious health risk.
Skin impaired or that destroy can be derived from for example wound, for example incised wound, scratch, abrade, stab, burn (comprising chemical burn), infection, extreme temperature, otch (for example, operative incision), wound and other damage.Therefore, under these environment and like environment, obviously expect by effective skin repair of wound healing.
Although skin natural surface after being permitted eurypalynous damage reveals significant self-repairing capability, but still there are many situations that wherein skin healing can not occur fast enough and/or wherein unsuitable tissue repair mechanism causes not exclusively reinventing skin, as a result, not exclusively reinvent skin and may lack integrity, barrier, mechanical strength, elasticity, flexibility or the character of other expectation of damaged skin not.Therefore, skin wound healing for example brings this type of related challenge in the chronic wounds environment.
Wound healing occured with three dynamic and overlapping stages, started from the formation of fibrin clot.Grumeleuse provides make-up shielding and has attracted cell to enter the somatomedin bank of wound.The provisional extracellular matrix (ECM) that it is also invaded as cell during repairing.Forming overlapping with grumeleuse is inflammatory phase, it is characterized by phagocyte and neutrophilic granulocyte and invades profit in wound, and fragment and the antibacterial of cleaning wound discharge somatomedin simultaneously, amplify the immediate union reaction.The process of recovering exposed region begins at the proliferation period of healing, and is driven by immunocyte secretion and the chemotactic factor, cytokine and the protease that are gathered in the grumeleuse.Stimulate angle albuminous cell propagation and migration, form the new epithelial layer that covers wound, and the wound blood vessel is sent oxygen, nutrient and inflammatory cell to wound area.The phase of reinventing is the last stage of wound repair, and undertaken by myofibroblast, myofibroblast promotes connective tissue to shrink, increase wound intensity, and the ECM of formation of deposits cicatrix (Martin, P.Wound Healing-Aiming for Perfect Skin Regeneration.Science 1997; 4:75-80).
The class antibacterial of bismuth mercaptan-(BT)
Many have an antimicrobial, particularly the natural product of antibacterial properties (for example antibiotic) and synthesis of chemicals are known in the art, and characterized by chemical constitution and anti-microbial effect at least in part, described anti-microbial effect 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 antibacterial 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 chemical compound) such as antibiotic, disinfectant, antibacterial, the factor that comprises the choice and operation that affects such composition for example comprises sterilization or antibacterial character, valid density and to the risk of toxicity of host tissue.
Bismuth, V family metal is the element (class is silvery) with anti-microbial properties.Bismuth self may not have therapeutical effect and may show some unsuitable character, therefore replaces, and can usually send to use with chelating agent, carrier and/or other vehicle, and modal example is Pepto
Figure BDA00002178874500071
Wherein bismuth and subsalicylate combination (sequestration).Research before determined, some contain mercaptan-(SH, sulfydryl) chemical compound for example the combination of dithioglycol and bismuth exemplary bismuth mercaptan (BT) chemical compound is provided, compare with present other available bismuth preparation, improved the antimicrobial efficacy of bismuth.There are many mercaptan compounds that can be used for producing BTs (to be disclosed in such as Domenico etc., 2001 Antimicrob.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 chemical compound: MRSA (methicillin resistance staphylococcus aureus), MRSE (methicillin resistance staphylococcus epidermidis (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 faecals), enterobacter cloacae (Enterobacter cloacae), Salmonella typhimurium (Salmonella typhimurium), proteus vulgaris (Proteus vulgaris), Yersinia enterocolitica (Yersinia enterocolitica), vibrio cholera (Vibrio cholera) 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 fungus.Proved BT reduce Pathogenicity of Bacteria, suppress or kill and wound broad ectrum antibiotic resistant microorganism (Gram-positive and Gram-negative), prevention biofilm formation, prevention septic shock, treatment septicemia and increase to before to it effect that shows the antibiotic antimicrobial susceptibility of resistance (referring to for example, Domenico etc., 2001 Agents Chemother.45:1417-1421; Domenico etc., 2000 Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.In Antimicrob.Agents ﹠amp; Chemother.3:79-85; Domenico etc., 1997Antimicrob.Agents Chemother.41 (8): 1697-1703; Domenico etc., the 1999 J Antimicrob.Chemother.44:601-605 such as 1999Infect.Immun.67:664-669:Huang; Veloira etc., 2003 J 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 chemical compound, but effectively selecting the suitable BT chemical compound for the specific indication that catches still is the target that is difficult to realize, 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, wherein external BT effect may be not always BT effect in the predictor, and wherein may not can predict BT effect for microbiologic population's (for example being organized into biomembranous antibacterial) for the BT effect of (unicellular) micropopulation that swims.In addition, the restriction of the aspects such as dissolubility, tissue permeability, bioavailability, bio distribution may hinder safe and effective ability of sending clinical benefit in some BT chemical compounds.Disclosure invention embodiment has solved these other associated advantages need to and be provided.
Summary of the invention
Open and do not expect bound by theory first such as this paper, according to some embodiment as herein described, bismuth-mercaptan (BT) chemical compound can be used for the treatment of that various clinical catches and condition of illness and the antibacterial that is used for personal health, also reduce simultaneously the expense that this type for the treatment of of infection produces, comprise those expenses that realize by at least part of prevention by the BTs mediation or prevention of saving.
In addition, as described herein, in certain embodiments, relate to being used for the treatment of and (for example contain bacterial biof iotalm or the antibacterial relevant with biofilm formation, can form or other promotes biomembranous antibacterial) tissue and/or the preparation of the expection on surface, described preparation comprises one or more BT chemical compounds and one or more Antibiotique compositions, wherein according to non-limiting theory, provide so far not antibiotic (the comprising the antibiont film) of prediction effect of said preparation based on present disclosure BT chemical compound and the antibiotic compositions of suitably selecting, and/or be used for prevention, the effective medical needle of preventing and/or treating property is to the not potentiation of prediction of the infected by microbes that comprises the infection that contains bacterial biof iotalm.
The present invention also provides first and comprises the basically new bismuth-composition of mercaptans of monodispersed microparticle suspending liquid, and synthetic and using method.
According to certain embodiments of the present invention as herein described, a kind of bismuth-composition of mercaptans is provided thus, it comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, basically all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m, and wherein said BT chemical compound comprises bismuth or bismuth salt and contains the chemical compound of mercaptan.Another embodiment provides bismuth-composition of mercaptans, comprise a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, basically all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m, and form by the method that may further comprise the steps: (a) obtain the condition of essentially no solid precipitation and mix under the time being enough to: (i) comprise bismuth salt (containing at least bismuth of 50mM concentration) and do not contain hydrophilic, the acidic aqueous solution of polarity or organic solubilized agent is enough to obtain to comprise by volume at least about 5% with (ii), 10%, 15%, 20%, the ethanol of the amount of the mixture of 25% or 30% ethanol; (b) under the condition that is enough to form the precipitation that comprises the microgranule that contains described BT chemical compound and time, add the alcoholic solution that comprises the chemical compound that contains mercaptan in the mixture of (a) obtaining reaction solution, the wherein said chemical compound that contains mercaptan in described reaction solution with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 exist.In certain embodiments, described bismuth salt is Bi (NO 3) 3In certain embodiments, described acidic aqueous solution comprises by weight at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth.In certain embodiments, described acidic aqueous solution comprises by weight at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid.In certain embodiments, the described chemical compound that contains mercaptan comprises that one or more are selected from the material by the following group that forms: 1,2-dithioglycol, 2,3-dimercaptopropanol, BAL, PTO, 1,4-Dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propanol, 1,4-Dithioerythritol, alpha-lipoic acid and dithiothreitol, DTT.
A kind of method for the preparation of bismuth-composition of mercaptans is provided in another embodiment, described bismuth-composition of mercaptans comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, basically all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m, said method comprising the steps of: (a) in the condition of the solution that is enough to obtain to be substantially free of solid precipitation with mix under the time: (i) comprise bismuth salt (containing at least bismuth of 50mM concentration) and do not contain hydrophilic, the acidic aqueous solution of polarity or organic solubilized agent is enough to obtain to comprise by volume about 5% with (ii), 10%, 15%, 20%, the ethanol of the amount of the mixture of 25% or 30% ethanol; (b) under the condition that is enough to form the precipitation that comprises the microgranule that contains described BT chemical compound and time, add the alcoholic solution that comprises the chemical compound that contains mercaptan in the mixture of (a) obtaining reaction solution, the wherein said chemical compound that contains mercaptan in described reaction solution with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 exist.In certain embodiments, described method comprises that also the described precipitation of recovery is to remove impurity.In certain embodiments, described bismuth salt is Bi (NO 3) 3In certain embodiments, described acidic aqueous solution comprises by weight at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth.In certain embodiments, described acidic aqueous solution comprises by weight at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid.In certain embodiments, the described chemical compound that contains mercaptan comprises that one or more are selected from the material by the following group that forms: 1,2-dithioglycol, 2,3-dimercaptopropanol, BAL, PTO, 1,4-Dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propanol, 1,4-Dithioerythritol, alpha-lipoic acid, dithiothreitol, DTT, methanthiol (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]); coenzyme A; thioctamide; glutathion; cysteine; cystine; 2 mercapto ethanol; dithiothreitol, DTT; 1,4-Dithioerythritol; the 2-sulfydryl indole; T-5398; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); the functionalized golden nanometer particle of (11-sulfydryl undecyl) four (ethylene glycol); 1; 1 '; 4 '; 1 " terphenyl-4-mercaptan; 1; 11-hendecane two mercaptan; 1; 16-hexadecane two mercaptan; 1; 2-dithioglycol (technical grade); 1; the 3-dimercaptopropane; 1; the 4-benzene dimethanethiol; 1; the 4-succinimide mercaptans; 1; 4-succinimide mercaptans diacetate esters; 1; the 5-pentane disulfide thioalcohol; 1; the 6-ethanthiol; 1; hot two mercaptan of 8-; 1; 9-mercaptan in the ninth of the ten Heavenly Stems two; diamantane (obsolete) 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 the golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propanol; 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; 11-bromo-1-hendecane 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; the 3-succinimide mercaptans; the 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; 3; 3; 4; 4; 5; 5; 6; 6; 6-nine fluoro-1-hexyl mercaptans (pure); 3-(dimethoxy-methyl silicyl)-1-propanethiol; 3-chloro-1-propanethiol; 3-sulfydryl-1-propanol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionic acid amide.; the 3-mercaptopropionic acid; the silica gel that 3-sulfydryl propyl group is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4; 4 '-two (mercapto methyl) biphenyl; 4; 4 '-dimercapto stilbene; 4-(6-sulfydryl hexyloxy) 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-capryl alcohol; the 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; xenyl-4,4 '-two 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 golden nanometer particle, the average M of PEG two mercaptan of spicy thioalcohol n8,000, PEG two mercaptan molar average molecular weight 1,500, PEG two mercaptan molar average molecular weight 3,400, S-(11-bromo-n-11 base) thiacetate, S-(4-cyano group butyl) thiacetate, phenylmercaptan., 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 "-two mercaptan, uncle's lauryl mercaptan and uncle's nonyl mercaptan.
A kind of protection self-faced is provided in another embodiment; comprise for example epithelial tissue surface opposing bacterial pathogens of biological tissue surface; the method of one or more in fungal pathogens and the viral pathogen; comprise that the BT compositions that makes described epithelial tissue surface and effective dose contacts being enough to satisfy with under the condition of lower one or more and time: (i) prevent described surface by described antibacterial; fungus or viral pathogen infect; (ii) suppress described antibacterial; cell viability or the Growth of Cells of basically all cells that swim of fungus or viral pathogen; (iii) suppress by described antibacterial; the biofilm formation of fungus or viral pathogen; (iv) suppress described antibacterial; biomembrane vigor or the biofilm development of the biomembranous cell of basically form of ownership of fungus or viral pathogen; wherein said BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically.In certain embodiments, at least a in following of described bacterial pathogens: (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), mycobacterium tuberculosis, 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, Yersinia enterocolitica, vibrio cholera, shigella flexneri, vancomycin resistance enterococcus (Enterococcus) (VRE), Burkholderia cepacia complex (Burkholderia cepacia complex), soil Lafranchise Salmonella (Francisella tularensis), anthrax bacillus (Bacillus anthracis), yersinia pestis (Yersinia pestis), Pseudomonas aeruginosa (Pseudomonas aeruginosa), vancomycin resistance enterococcus, streptococcus pneumoniae, the penicillin resistance streptococcus pneumoniae, 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 bacterial pathogens shows antibiotic resistance.In certain embodiments, described bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, nafcillin (naficilin), gentamycin, ampicillin, chloromycetin, doxycycline and tobramycin.
In certain embodiments, described self-faced comprises surface, mouth/cheek chamber.In other embodiments, self-faced comprises biological surface, for example BJM, ligament or tendon.
In certain embodiments, described surface comprises that epithelial tissue surface, described epithelial tissue comprise and is selected from following tissue: epidermis, corium, respiratory tract, gastrointestinal tract and gland lining.
In certain embodiments, contact procedure is carried out one or many.In certain embodiments, at least one contact procedure comprises spraying, washes, floods and smears the one in the described self-faced.In certain embodiments, at least one contact procedure comprises the one in suction, picked-up and the dentilave.In certain embodiments, at least one contact procedure comprise by be selected from part, intraperitoneal, oral, parenteral, intravenous, intra-arterial, transdermal, Sublingual, subcutaneous, intramuscular, approach through cheek, intranasal, in suction, ophthalmic, atrium, in the ventricle, in subcutaneous, the fat, in intraarticular and the sheath uses.In certain embodiments, described BT compositions comprises and is selected from by in the BT chemical compound of the following group that forms one or more: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and Bis-EDT/2-hydroxyl-1-propanethiol.
In certain embodiments, described bacterial pathogens shows antibiotic resistance.In some other embodiment, said method also comprises the step that contacts with described BT compositions with described surface simultaneously or successively and with any order, described self-faced is contacted with collaborative antibiotic and/or with the enhancement antibiotic.In certain embodiments, described collaborative and/or enhancement antibiotic comprises and is selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics and Aminopenicillin antibiotic.In certain embodiments, described collaborative and/or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, arbekacin, gentamycin, 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 (for example overcoming antibiotic resistance at the self-faced that has antibiotic resistance bacterium pathogen, for the anti-at least a bacterial pathogens that the antibacterial of resisting identical bacteria culture is had the known antibiotic at least a antibacterial action of antibacterial action, this pathogen to antibiotic sensitive is provided) method, its be included in be enough to satisfy following one or more condition and under the time, make described surface simultaneously or successively and with (1) at least a bismuth-mercaptan (BT) compositions of any order and effective dose and (2) at least a by and/or can contact with at least a antibiotic that at least a BT compositions synergism strengthens: (i) prevent surperficially to be infected by described bacterial pathogens, (ii) cell viability or the Growth of Cells of basically all cells that swim of the described bacterial pathogens of inhibition, (iii) inhibition is by the biofilm formation of described bacterial pathogens, (iv) biomembrane vigor or the biofilm development of the biomembranous cell of basically form of ownership of the described bacterial pathogens of inhibition, wherein said BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically; And overcome antibiotic resistance on the epithelial tissue surface thus.In certain embodiments, at least a in following of described bacterial pathogens: (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), mycobacterium tuberculosis, 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, Yersinia enterocolitica, vibrio cholera, shigella flexneri, vancomycin resistance enterococcus (Enterococcus) (VRE), Burkholderia cepacia complex (Burkholderia cepacia complex), soil Lafranchise Salmonella (Francisella tularensis), anthrax bacillus (Bacillus anthracis), yersinia pestis (Yersinia pestis), Pseudomonas aeruginosa (Pseudomonas aeruginosa), vancomycin resistance enterococcus, streptococcus pneumoniae, the penicillin resistance streptococcus pneumoniae, escherichia coli, Burkholderia cepacia, bite burkholderia (Bukholderia multivorans) more, smegmatis mycobacterium (Mycobacterium smegmatis) and the Acinetobacter baumannii (bacterial pathogens of (Acinetobacter baumannii).
In certain embodiments, described bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, nafcillin, gentamycin, ampicillin, chloromycetin, doxycycline, tobramycin, clindamycin and Gatifloxacin.
In certain embodiments, described self-faced comprises surface, mouth/cheek chamber.In other embodiments, self-faced comprises biological surface, for example BJM, ligament or tendon.
In certain embodiments, described surface comprises the tissue that is selected from the group that is comprised of epidermis, corium, respiratory tract, gastrointestinal tract and gland lining.In certain embodiments, contact procedure is carried out one or many.In certain embodiments, at least one contact procedure comprises spraying, washes, floods and smears the one in the described self-faced.In certain embodiments, at least one contact procedure comprises the one in suction, picked-up and the dentilave.In certain embodiments, at least one contact procedure comprise by be selected from part, intraperitoneal, oral, parenteral, intravenous, intra-arterial, transdermal, Sublingual, subcutaneous, intramuscular, approach through cheek, intranasal, in suction, ophthalmic, atrium, in the ventricle, in subcutaneous, the fat, in intraarticular and the sheath uses.In certain embodiments, described BT compositions comprises and is selected from the following BT chemical compound one or more: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, described collaborative and/or enhancement antibiotic comprises and is selected from following antibiotic: clindamycin, Gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics and Aminopenicillin antibiotic.In certain embodiments, described collaborative and/or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
Turn to another embodiment that a kind of antimicrobial composition is provided, it comprises (a) at least a BT chemical compound; (b) at least a by and/or can with the synergistic Antibiotique composition of described BT chemical compound; (c) pharmaceutically acceptable excipient or carrier comprise the local carrier that uses.In certain embodiments, described BT chemical compound is selected from: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, described BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically.In certain embodiments, described BT chemical compound is selected from BisEDT and BisBAL.In certain embodiments, described Antibiotique composition comprises and is selected from following antibiotic: methicillin, vancomycin, nafcillin, gentamycin, ampicillin, chloromycetin, doxycycline, tobramycin, clindamycin, Gatifloxacin and aminoglycoside antibiotics.In certain embodiments, described aminoglycoside antibiotics is selected from: amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.In certain embodiments, described aminoglycoside antibiotics is amikacin.
A kind of method of supporting or containing the self-faced of bacterial biof iotalm that is used for the treatment of is provided in some other embodiment, comprise (a) with on the described surface or in antibacterial infect be accredited as comprise one of following: (i) gram positive bacteria, (ii) gram negative bacteria, and (iii) comprise (i) and (ii) both; (b) comprise the preparation of one or more bismuth mercaptan (BT) compositionss to described surface applied, wherein (i) comprises gram positive bacteria if described antibacterial infects, then described preparation comprise at least a BT chemical compound for the treatment of effective dose and at least a be the antibiotic of rifamycin, (ii) if infecting, described antibacterial comprises gram negative bacteria, then described preparation comprises at least a BT chemical compound and the amikacin for the treatment of effective dose, (iii) if infecting, described antibacterial comprises gram positive bacteria and gram negative bacteria, then described preparation comprises one or more BT chemical compounds for the treatment of effective dose, rifamycin and amikacin, thus and treat described surface.
In certain embodiments, biomembrane comprises one or more antibiotic resistance bacterium.In certain embodiments, treating described surface comprises with lower at least a: (i) eradicate described bacterial biof iotalm, (ii) reduce described bacterial biof iotalm, and (iii) weaken the growth of described bacterial biof iotalm.In certain embodiments, described BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 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 listed in that mention in this description and/or the request for data table, comprise U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248 incorporate this paper in this mode integral body by reference, as each incorporates separately this paper into.In case of necessity, aspect of the present invention and embodiment can be modified to adopt the concept of various patents, patent application and patent announcement, so that other embodiment to be provided.
The summary of several figure of accompanying drawing
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, imipenum (imipenem) 10 * MIC; CEF, cefepime 10 * MIC; CIP, ciprofloxacin 100 * MIC; Cpd 2B, chemical compound 2B (Bis-BAL, 1:1.5).(MIC; Minimum inhibitory concentration, for example, the least concentration of prevention bacterial growth).
Fig. 2 shown at 10% tryptic soy agar and 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 rifampicin, RIF 100 * MIC; Daptomycin, DAP 320 * MIC; Minocycline, MIN 100 * MIC; The ampicillin, AMC 10 * MIC; Vancomycin, VAN 10 * MIC; Cpd 2B, chemical compound 2B (Bis-BAL, 1:1.5), Cpd 8-2, chemical compound 8-2 (Bis-Pyr/BDT (1: 1/0.5).
Fig. 3 has shown that to be exposed to the scratch in time of biomembranous keratinocyte closed.(*) significantly be different from contrast (P＜0.001).
Fig. 4 A and 4B have shown the inferior inhibition BisEDT that reverses several antibiotic antibiotic resistances.Shown the antibiotic effect that is with or without BisEDT (0.05 μ g/ml) on MRSA (the 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=gentamycin, CZ=cephamycin, FEP=cefepime, IPM=imipenum, SAM=ampicillin/sulbactam, LVX=levofloxacin.
Fig. 5 has shown that BisEDT and antibiotic are to the effect of biofilm formation.With staphylococcus epidermidis at the 48h that in the polystyrene board of TSB+2% glucose, grows under 37 ℃.Gatifloxacin (GF), clindamycin (CM), minocycline (MC), gentamycin (GM), vancomycin (VM), cefazolin (CZ), nafcillin (NC) and rifampicin (RP).The 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 that BisEDT and antibiotic are to the grow effect of 48h of staphylococcus epidermidis in 37 ℃ TSB+2% glucose.The result is expressed as the mean change (n=3) that MIC (dilution step) increases along with BisEDT.Referring to the legend that defines for antibiotic among Fig. 5.
Fig. 7 is presented at after the three kinds of BT preparations, Bis-EDT, MB-11 that contain or do not contain the cefazolin antibiotic therapy and the MB-8-2 treatment, from the block diagram of the average staphylococcus aureus level that detects on the bone of the compound fracture in the live body rat model and hardware (hardware) sample.The standard error of average 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 the group 2.
Detailed Description Of The Invention
Specific embodiments disclosed herein is based on following surprising discovery: some bismuth-mercaptan provided herein (BT) chemical compound (comprise in certain embodiments and have about 0.4 μ m to the BT microgranule of about 5 μ m volume mean diameters) but not some other BT chemical compound (even providing as microgranule) shows strong antibiotic (antiseptic) for specific bacteria, antibiotic (antibacterial) and/or antibiont film activity, described antibacterial comprise the antibacterial relevant with many clinically severe infections (comprising the infection that can contain bacterial biof iotalm).
Beat all is that not all BT chemical compound as one man effectively resists this bacterioid in measurable mode, but depends on that the target bacteria strain shows different effects.Particularly, as described herein, find that some BT chemical compound (preferably include and have about 0.4 μ m to the BT microgranule of about 5 μ m volume mean diameters) shows higher effect to gram negative bacteria, and find that some other BT chemical compound (preferably include and have about 0.4 μ m to the BT microgranule of about 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 antibacterial infects the processing of (comprising that bacterial biof iotalm infects).
In addition, such as institute's more detailed description hereinafter, the surprising advantage that is provided by novel bismuth-mercaptan (BT) compositions is provided in some aspect of the present invention as herein described, as described herein, described bismuth-mercaptan (BT) compositions can be made into to comprise a plurality of preparations that basically singly disperse the BT microgranule of (for example having about 0.4 μ m to the volume mean diameter of about 5 μ m) with regard to granularity.At some in these and the related embodiment, particles B T is provided as for example component of multilamellar phosphocholine-cholesterol liposome or other multilamellar or unilamellar liposome vesicle of lipid vesicle or liposome.
Also disclosed such 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 do not have therapeutical effect can by with these antibiotic one or more with BT chemical compounds of selecting, while or sequential therapeutic infect (for example by directly applying to infection site for example on the self-faced or in the self-faced) and by remarkable enhancing (for example, with statistically significantly mode increase).In inscrutable mode before the disclosure, some BT chemical 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.As hereinafter in greater detail the not prediction character of this type of combination proved by following observation post: although some BT/ antibiotic composition synergism or demonstrate the enhancing of some antibacterial of antagonism, some other BT/ antibiotic composition is failed to show collaborative or is strengthened antibiotic and/or the antibiont film activity.
According to these and related embodiment, antibiotic and BT chemical compound can simultaneously or be used successively and with any order, 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 compositions of one or more BT chemical compounds do not show measurable (for example, adduction only) activity, but to work in coordination with or to strengthen the effect of (super adduction) mode beyong contemplationly, as selected antibiotic, the function of selected BT chemical compound and the special target bacteria of identifying.
For example, as example explanation and unrestricted, in the environment of the self-faced 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 chemical compound disclosed herein and particular B T chemical compound or both may be for specific bacteria bacterial strain or the limited antibacterial actions of strain performance when using separately, but the combination of described Antibiotique composition and described BT chemical compound is brought into play strong antibacterial action for identical bacterial isolates or strain, this acts on the intensity greater than (having significance,statistical) the simple adduction of every kind of compound effects when 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 potentiation (for example, 0.5＜FICI≤1.0).Therefore, not that any antibiotic can be worked in coordination with or strengthen to any BT chemical compound with any antibiotic, and not being that any antibiotic can be collaborative with any BT chemical compound, or strengthening any BT chemical compound, generally is uncertain so that 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 chemical compound, described antibacterial action is included in specific environment, self-faced as herein described for example, and also comprise in some cases for the biomembranous antibacterial action that is 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 a BT compositions synergism (FICI＜0.5) that comprises at least a BT chemical compound provided herein, wherein this concertedness is shown as detectable effect, there is antibiotic in its intensity greater than (that is, in the mode with respect to the statistically significant of suitable collating condition) and does not have the BT chemical compound and/or have the BT chemical compound and detectable effect when not having antibiotic.Similarly, some BT-antibiotic composition shows enhancing (0.5＜FICI≤1.0), wherein but this enhancing is shown as detection effect, there is not the BT chemical compound in its intensity greater than there is antibiotic in (that is, in the mode with respect to suitable collating condition statistically significant) and/or has the BT chemical compound and detectable effect when 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 basically all cells that swim of anti-bacteria pathogen, (iii) biofilm formation of anti-bacteria pathogen, (iv) basically biomembrane vigor or the biofilm development of all biomembrane form cells of anti-bacteria pathogen, but the present invention is not intention so to be limited, so that in the embodiment of other expection, antibiotic-BT concertedness can be shown as one or more detectable effects, described detectable effect can comprise clinically significant parameter of change (for example increase of statistically significant or minimizing) one or more other, for example bacterial pathogens is to resistance or the sensitivity level of one or more antibiotic or other medicines or chemical agent, bacterial pathogens is to one or more chemistry, physics or mechanical condition are (for example, pH, ionic strength, temperature, pressure) resistance or sensitivity level, and/or bacterial pathogens is to one or more biological agents (for example, virus, another kind of antibacterial, the biological activity polynucleotide, immunocyte or immunocyte product be antibody for example, cytokine, chemotactic factor, 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 ﹠amp; Sons, Hoboken, NJ; Schwalbe etc., Antimicrobial Susceptibility Testing Protocols, 2007, CRC Press, Boca Raton, FL), purpose is to determine antibiotic-BT concertedness or enhancement, exists during the simple adduction of the effect of observing when the component that the effect that this concertedness or enhancement such as this paper are provided at antibiotic collaborative or that strengthen-BT combination surpasses combination does not exist.
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 or leaf, 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 Chemotherapy 52:1).Concertedness can also usual definition be the minimizing of antibiotic concentration 〉=4 times, perhaps alternatively, uses the FIC (FIC) of describing such as (1998 Antimicrob.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 compositions) effect that produces, wherein the effect of combination greater than the mode of statistically significant (for example, with) if the effect the when concentration of the second medicine is replaced by the first medicine.
Therefore, as described herein and in some preferred embodiment, BT and antibiotic combination should be understood to when the collaborative (Odds, 2003) of observing when being less than or equal to 0.5 FICI value.Also as described herein, in some other preferred embodiment and according to non-limiting theory, disclose some BT-antibiotic compositions and can show FICI value between 0.5 and 1.0, it represents this synergitic high potential, and can observe the FICI value with at least a BT and at least a antibiotic non-optium concentration of the antimicrobial efficacy that shows independent or the common cooperation that strengthens.This acts on this paper also can claim " enhancing " antibacterial activity or " enhancing " BT activity.
When exist following both the time, can detect the antibiotic of enhancing and/or BT is active according to some embodiment:.(i) at least a BT, its concentration to given target microorganism (for example is lower than (in the statistically significant mode) BT, given bacteria culture or bacterial strain) characteristic minimum inhibitory concentration (MIC), (ii) at least a antibiotic, its concentration are lower than (in the statistically significant mode) characteristic IC 50(the concentration that suppresses 50% micropopulation bulk-growth; For example, Soothill etc., 137) and/or be lower than antibiotic to the biomembrane of given target microorganism prevention concentration (BPC) 1992 J Antimicrob Chemother 29 (2):, if cause the BT-antibiotic composition with respect to (for example using arbitrary antimicrobial in same concentrations, BT or antibiotic) and lack other antimicrobial (for example, antibiotic or BT) with (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, have " enhancing " antibiotic and/or BT activity greater than 0.5 o'clock.
The technical staff should understand based on the disclosure, in certain embodiments, it is active to measure antibiotic and/or BT 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., 2005 Medical Mycology 43:133-152).Be used for to measure collaborative or the antibiotic that strengthens and/or the illustrative method of BT activity are described in thus, such as Meletiadis etc., the list of references that 2005 Medical Mycology 43:133-152 and this paper quote (also referring to, Meletiadis etc., 2002Rev Med Microbiol 13:101-117; White etc., 1996Antimicrob Agents Chemother 40:1914-1918; Mouton etc., 1999 Antimicrob Agents Chemother 43:2473-2478).
One or more antibiotic that some other embodiment expection is as described herein and the particular composition of one or more BT chemical compounds, it in specific infection (for example, the biomembrane that is formed by gram negative bacteria or gram positive bacteria) can show the effect of collaborative or enhancing in the interior therapeutic, even wherein BT chemical compound and antibiotic do not show predictable (for example, adduction only) activity in vivo, and on the contrary with working in coordination with or enhancing (for example, super adduction of not predicting; Or the effect when two or more this combinations of substances exist of giving is greater than (for example, in the statistically significant mode) if the effect that obtains when the concentration of the second reagent is replaced by the first reagent place) mode, as the function of selected antibiotic, selected BT chemical compound and one or more special target bacteria strains that comprise infection of identifying.Therefore should understand, according to these and relevant embodiment, FICI or FBCI value (it is by external mensuration) may be difficult for obtaining in the situation in some body, and opposite with BT-antibiotic concertedness or potentiation, but may measure in the mode that be given by the quantification metrics that infects.
For example, in one embodiment, for example in such as embodiment 11 described bodies in the critical defect model of rat (Rattus norvegicus) femur of open fracture, with antibiotic therapy or independent BT Compound Phase ratio, the count of bacteria that statistically significant is observed in treatment behind the BT-antibiotic combinations reduces, and is the indication of concertedness or potentiation.Can use method well known to those skilled in the art to measure significance,statistical.In some other embodiment, in this body inner model or other body inner model, observe after being used for BT-antibiotic combinations injury in treating viewed count of bacteria and consider that antibiotic therapy or independent BT chemical compound are that the index of concertedness or potentiation is compared and is reduced by at least 5%, 10%, 20%, 30%, 40% or 50%.
The exemplary sign of other of In vivo infection can be according to developing for the methodology that quantitatively infects the establishment of severity, for example, various wounds well known by persons skilled in the art get subsystem measure (referring to, for example, the Europe wound is managed the subsystem that gets 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 gets subsystem and comprises ASEPSIS (Wilson AP, J Hosp Infect 1995; 29 (2): 81-86; Wilson etc., Lancet 1986; 1:311-13), Southampton's wound opinion rating (Bailey IS, Karran SE, Toyn K etc.BMJ 1992;304:469-71)。Also referring to, Horan TC, Gaynes P, Martone WJ etc., 1992 Infect Control Hosp Epidemiol 1992; 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 clinicist also can be measured when BT chemical compound and/or antibiotic exist or do not exist.Therefore, based on present disclosure, the technical staff should be easily understood that be used to determining whether that BT compositions-antibiotic combination changes the whole bag of tricks (for example, with respect to enhancing or the reduction of suitable contrast in the statistically significant mode) of body internal injury healing.
Consider these and related embodiment, this paper with effective dose (for example provides, treat in certain embodiments effective dose) treat the whole bag of tricks of the self-faced (for example providing or comprise the surface of bacterial biof iotalm) of infected by microbes such as compositions provided herein or preparation, described compositions or preparation comprise one or more BT chemical compounds, and randomly 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 now expection of some antibiotic is used for the treatment of the infection of given type, is wherein thought invalid to the infection of same type by those skilled in the art before this antibiotic.
Some embodiment thus severity comprises one or more as the compositions of the BT chemical compound of antibacterial.Antibacterial is the material that kills and wounds microorganism or prophylaxis of microbial growth, usually can be applicable to living tissue, this differentiates (Goodman and Gilman ' s " The Pharmacological Basis of Therapeutics " with 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 or leaf).The common example of antibacterial is ethanol and iodine tincture.Antibacterial comprises the antibacterial that kills and wounds microorganism (for example microbial pathogens).
The compositions of one or more BT chemical compounds and one or more Antibiotique compositions (the concertedness antibiotic and/or the enhancement antibiotic that for example, provide such as this paper) is provided in some embodiment expection as herein described.Antibiotic is known in the art and generally includes the medicine of the chemical compound preparation 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 in the microorganism comprises this medicine when local the application.In the embodiment disclosed herein is that wherein antibiotic can belong to those of one of following type: aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, glycopeptide antibiotics, lincosamide class (for example, clindamycin), penicillinase resistance penicillin and Aminopenicillin.Therefore antibiotic can comprise; but be not limited to penicillin; piperacillin; cefuroxime; cefotaxime; cefepime; imipenum; aztreonam; streptomycin; tobramycin; tetracycline; minocycline; ciprofloxacin; levofloxacin; erythromycin; Linezolid; fosfomycin; capreomycin; isoniazid; Ansamycin (ansamycin); carbacephem; Monobactam; nitrofuran; penicillin; quinolinones; sulfonamide; clofazimine; dapsone; capreomycin; cycloserine; ethambutol; ethionamide; isoniazid; pyrazinamide; rifampicin (Rifampicin); rifampicin (Rifampin); rifabutin; rifapentine; streptomycin; arsphenamine; chloromycetin; fosfomycin; fusidic acid; Linezolid; metronidazole; mupirocin; dull and stereotyped mycin; quinupristin; dalfopristin; rifaximin; thiamphenicol; tinidazole; aminoglycoside; beta-lactam; penicillin; cephamycin; carbapenem; fluoroquinolone; the ketone lactone; Lincoln's (acyl) amine; macrolide oxazolidone; streptogramine (stretogramin); sulfanilamide; tetracycline; glycylcycline; the methicillin; vancomycin; nafcillin; gentamycin; the ampicillin; chloromycetin; doxycycline; tobramycin; amikacin; arbekacin; gentamycin; 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 catalog 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), 2007 Lippincott, Williams and Wilkins, Philadelphia, PA:Hauser, AL, Antibiotic Basics for Clinicians, 2007Lippincott, Williams and Wilkins, Philadelphia, PA).
An exemplary class antibiotic that uses with one or more BT chemical compounds in some embodiment disclosed herein is aminoglycoside antibiotics, it is summarized the RS in Edson, Terrell CL.Theaminoglycosides.Mayo Clin Proc.1999 May; 74 (5): 519-28.Such antibiotic reduces Bacterioprotein biosynthesis and bacteria growing inhibiting by combination and inactivation bacterial ribosome subunit.Except this type of antibacterial character, aminoglycoside also shows bactericidal action by the cell wall that destroys in the gram negative bacteria.
Aminoglycoside antibiotics comprises gentamycin, 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 gentamycin tolerant bacteria bacterial strain, usually in intravenous or intramuscular administration, this can cause patient's pain.In addition, the toxicity relevant with aminoglycoside antibiotics (for example amikacin) 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, gastrointestinal tract/gastral one or more positions of some embodiment expection disclosed herein.Some other embodiment it is also contemplated that compositions as herein described and method as the purposes of disinfectant, and disinfectant refers to kill and wound microorganism on the xenobiotic external surface or stops the preparation of its growth.
Also such as other local description of this paper, the BT chemical compound can be the compositions that comprises bismuth or bismuth salt and contain mercaptan (for example-SH or sulfydryl) chemical compound, it comprises those (comprising its preparation method): Domenico etc. that describe in the following, 1997 Antimicrob.Agent.Chemother.41 (8): 1697-1703, Domenico etc., 2001 Antimicob.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 the BT chemical compound that contains the chemical compound of mercaptan.The chemical compound that contains mercaptan can contain 1,2,3,4,5,6 or more mercaptan (group for example-SH).In preferred embodiments, the BT chemical compound comprises by ionic bonding and/or as the bismuth of co-ordination complex with the chemical compound association that contains mercaptan, and in some of the other embodiments, bismuth can associate with the chemical compound that contains mercaptan by the covalent bond that for example may reside in the organo-metallic compound.Yet it is the BT chemical compound of organo-metallic compound that the embodiment of some expection is clearly got rid of, and for example wherein finds the chemical compound of bismuth and organic moiety covalent bonding.
Exemplary BT compound exhibits is in table 1:
Table 1
Exemplary BT chemical compound *
Figure BDA00002178874500231
Figure BDA00002178874500241
The BT chemical compound that is used for some disclosure embodiment can be according to fixed method preparation (for example U.S.RE37.793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248; Domenico etc., 1997Antimicrob.Agent.Chemother.41 (8): 1697-1703, Domenico etc., 2001Antimicob.Agent.Chemother.45 (5): 1417-1421), and in some other embodiment, the BT chemical 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 chemical compound with especially for obtaining the basically synthetic method of the BT chemical compound of monodispersed particulate form, wherein contain concentration and be 50mM at least, at least 100mM, at least 150mM, at least 200mM, at least 250mM, at least 300mM, at least 350mM, at least 400mM, at least 500mM, at least 600mM, at least 700mM, at least 800mM, at least 900mM or at least 1M the dissolving bismuth and do not contain hydrophilic, the acid bismuth aqueous solution of polarity or organic solubilized agent mixes with ethanol and obtains the first alcoholic solution, this first alcoholic solution and the second alcoholic solution that comprises the chemical compound that contains mercaptan the condition that is enough to form the precipitation that comprises the microgranule that contains the BT chemical compound and time (for example, the concentration that as described herein and those skilled in the art will appreciate that based on present disclosure, solvent strength, temperature, pH, mix and/or the condition such as pressure) lower reaction and obtain reaction solution, the wherein said chemical compound that contains mercaptan with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 be present in the reaction solution.
Therefore, exemplary BT comprises chemical compound 1B-1, Bis-EDT (bismuth-1，2-ethandithiol, reactant 1:1); Chemical compound 1B-2, Bis-EDT (1:1.5); Chemical compound 1B-3, Bis-EDT (1:1.5); Chemical compound 1C, Bis-EDT (solubility Bi preparation, 1: 1.5); Chemical compound 2A, and Bis-Bal (the anti-lewisite agent of bismuth-Britain (British anti-Lewisite) (bismuth-dimercaptopropanol, BAL, bismuth-2,3-dimercaptopropanol, BAL), 1:1); Chemical compound 2B, Bis-BAL (1:1.5); Chemical compound 3A Bis-Pyr (bismuth-PTO, 1:1.5); Chemical compound 3B Bis-Pyr (1:3); Chemical compound 4, and Bis-Ery (bismuth-1,4-Dithioerythritol, 1:1.5); Chemical compound 5, Bis-Tol (bismuth-3,4-dimercapto toluene, 1: 1.5); Chemical compound 6, Bis-BDT (bismuth-2,3-succinimide mercaptans, 1: 1.5); Chemical compound 7, Bis-PDT (bismuth-1,3-dimercaptopropane, 11.5); Chemical compound 8-1Bis-Pyr/BDT (1:1/1); Chemical compound 8-2, Bis-Pyr/BDT (1: 1/0.5); Chemical compound 9, the Bis-2-hydroxyl, propanethiol (bismuth-1-sulfydryl-2-propanol, 1:3); Chemical compound 10, Bis-Pyr/Bal (1:1/0.5); Chemical compound 11, Bis-Pyr/EDT (1:1/0.5); Chemical compound 12Bis-Pyr/Tol (1:1/0.5); Chemical compound 13, Bis-Pyr/PDT (1:1/0.5); Chemical compound 14Bis-Pyr/Ery (1:1/0.5); Chemical 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 chemical compound of the present disclosure may expect to produce the compositions that comprises the BT chemical compound, wherein this compositions has the character of one or more expectations, comprise easy large-scale production, raising product purity, uniformity or concordance (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 to comprise the acidic liquid aqueous solution (aqueous solution of nitric acid that for example comprises bismuth nitrate) of bismuth in some preferred embodiment.
In specific embodiments, have been found that the BT chemical compound for preparing first according to method as herein described shows the favourable uniformity with regard to it with regard to monodispersed microparticle suspending liquid occurs basically, according to some at present preferred embodiment, each microgranule has about 0.4 μ m to the volume mean diameter (VMD) of about 5 μ m.Measuring of granularity can be called as volume mean diameter (VMD), mass median diameter (MMD) or mass median aerodynamic diameter (MMAD).Can for example characterize by bump (MMD and MMAD) or by laser (VMD) and carry out these measurements.For liquid particle, if keep environmental condition (for example standard humidity), then VMD, MMD may be identical with MMAD.Yet if humidity is not held, MMD and MMAD measured value will be less than VMD, and this is because the dehydration in the bump measuring process.For the purpose of describing, VMD, MMD and MMAD measurement are considered under standard conditions, so that the description of 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 basically suspension of the monodispersed BT of containing microgranule.The BT deposition can be for example optimized in generation with clear and definite BT granularity of limited geometric standard deviation (GSD), and to the accessibility of the expection target site in the self-faced or on the self-faced, and/or the experimenter is to the toleration of the BT microgranule used.The VMD of limited GSD restriction expection or the granule amount outside the MMAD size range.
Liquid or the aerosol suspension of the microgranule that contains one or more BT chemical compounds disclosed herein with about 0.5 micron extremely about 5 microns VMD are provided in one embodiment.In another embodiment, provide have about 0.7 micron to about 4.0 microns VMD or liquid or the aerosol suspension of MMAD.In another embodiment, provide have about 1.0 microns to about 3.0 microns VMD or liquid or the aerosol suspension of MMAD.In some other preferred embodiment, provide comprise one or more about 0.1 to about 5.0 microns VMD about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8 or about 0.9 micron to about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5 or the liquid suspension of about 8.0 microns BT chemical compound microgranule, described microgranule comprises the BT chemical compound of 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 compositions of BT chemical compound that " basically " all microgranules wherein have the particulate form of the volume mean diameter (VMD) in the prescribed limit (for example about 0.4 μ m is 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 have those compositionss of the VMD in the described size range.
Provide according to these and relevant character of the BT compositions of synthetic method as herein described preparation and to have surpassed the before advantage of the novelty of the BTs of description, comprise lower cost and easily produce, and can allow uniformity in its compositions that characterizes in the mode that is conducive to according to the one or more rules compliance in medicine, preparation and the cosmetic standard.
In addition or alternatively, basically monodispersed BT microgranule as herein described can advantageously be produced and do not needed micronization, namely, need not the processing of the grinding of costliness and effort or supercritical fluid or be generally used for producing other device of microgranule and program (for example, the 2008 Adv.Drug Deliv.Rev.60 (3) such as Martin: 339; Moribe etc., 2008 Adv.Drug Deliv.Rev.60 (3): 328; Cape etc., 2008Pharm.Res.25 (9): 1967; 2004 Pharm.Dev.Technol.9 such as Rasenack (1): 1-13).Therefore, the present embodiment provides basically the uniformly beneficial effect of microparticle formulation, that include but not limited to strengthen and uniform solubilize character basically, the administration form (for example oral, suction or Dermatology/skin wound localized forms) that is fit to expection, the bioavailability of increase and other beneficial property.
BT chemical compound microparticle suspending liquid can be used as aqueous formulation, as the suspension in aqueous solvent and the organic solvent (comprising the halogenated hydrocarbons propellant) or solution, use as dry powder or with other form that hereinafter describes in detail, for example, comprise and contain the known wetting agent of preparation technique personnel, surfactant, mineral oil or other composition or additive to keep the preparation of the single microgranule in the suspension.Aqueous formulation can atomize by liquid dispenser, adopts for example waterpower or ultrasonic atomizatio.System based on propellant can utilize suitable pressurization allotter.Dry powder can utilize the dry powder dispersal device that can effectively disperse to contain the BT microgranule.The granularity of expection and distribution can obtain by selecting appropriate device.
Also as mentioned above, the method for preparing bismuth-mercaptan (BT) compositions of the microgranule that comprises a plurality of BT of comprising chemical compounds also is provided according to some embodiment this paper, basically all this microgranules have about 0.1 to about 8 microns, and in some preferred embodiment about 0.4 micron to about 5 microns volume mean diameter (VMD).
Generally speaking, described method comprises the steps: that (a) obtains to be substantially free of the condition of solid precipitation and to mix under the time being enough to: (i) comprise bismuth salt (containing at least bismuth of 50mM concentration) and do not contain the acidic aqueous solution of hydrophilic, polarity or organic solubilized agent, be enough to obtain to comprise by volume about 5%, 10%, 15%, 20%, 25% or 30% and the ethanol of the amount of the mixture of preferred about 25% ethanol with (ii); (b) under the condition that is enough to form the precipitation that comprises the microgranule that contains described BT chemical compound and time, add the alcoholic solution that comprises the chemical compound that contains mercaptan in the mixture of (a) obtaining reaction solution, the wherein said chemical compound that contains mercaptan in described reaction solution with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 exist.
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, 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 the acidic aqueous solution.In certain embodiments, acidic aqueous solution comprises by weight at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth.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 by weight 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.
The chemical compound that contains mercaptan can be any chemical compound that contains mercaptan as herein described, and can comprise in certain embodiments with lower one or more: 1,2-dithioglycol, 2,3-dimercaptopropanol, BAL, PTO, 1,4-Dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propanol, 1,4-Dithioerythritol and dithiothreitol, DTT.Other exemplary chemical compound that contains mercaptan comprises alpha-lipoic acid, methanthiol (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]); coenzyme A; thioctamide; glutathion; cysteine; cystine; 2 mercapto ethanol; dithiothreitol, DTT; 1,4-Dithioerythritol; the 2-sulfydryl indole; T-5398 and can be available from Sigma-Aldhch (St.Louis; MO) following mercaptan compound any: (11-mercaptan undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); the functionalized nanometer gold of (11-sulfydryl undecyl) four (ethylene glycol); 1; 1 '; 4 '; 1 " terphenyl-4-mercaptan; 1; 11 – hendecanes, two mercaptan; 1; 16-hexadecane two mercaptan; 1; 2-dithioglycol (technical grade); 1; the 3-dimercaptopropane; 1; the 4-benzene dimethanethiol; 1; the 4-succinimide mercaptans; 1; 4-succinimide mercaptans diacetate esters; 1; 5-pentane two mercaptan; 1; the 6-ethanthiol; 1; hot two mercaptan of 8-; 1; 9-mercaptan in the ninth of the ten Heavenly Stems two; diamantane (obsolete) 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 the golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propanol; 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; 11-bromo-1-hendecane 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; the 3-succinimide mercaptans; the 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; 3; 3; 4; 4; 5; 5; 6; 6; 6-nine fluoro-1-hexyl mercaptans (pure); 3-(dimethoxy-methyl silicyl)-1-propane diol; 3-chloro-1-propanethiol; 3-sulfydryl-1-propanol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionic acid amide.; the 3-mercaptopropionic acid; the silica gel that 3-sulfydryl propyl group is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4; 4 '-two (mercapto methyl) biphenyl; 4; 4 '-the dimercapto stilbene; 4-(6-sulfydryl hexyloxy) 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-capryl alcohol; the 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; xenyl-4,4 '-two 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 TMACID 11, NanoThinks TMACID16, NanoThinks TMALCO 11, NanoThinks TMTHIO8, functionalized nanoparticle, the average M of PEG two mercaptan of spicy thioalcohol n8,000, PEG two mercaptan mean molecule quantities 1,500, PEG two mercaptan mean molecule quantities 3,400, S-(11-bromo-n-11 base) thiacetate, S-(4-cyano group butyl) thiacetate, phenylmercaptan., 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 " two mercaptan, uncle's lauryl mercaptan and uncle's nonyl mercaptan.
Exemplary reaction condition described herein (comprising temperature, pH, response time, use stirring or the program of stirring to dissolve solute and to be used for control and washing precipitation) also adopts technology well known in the art.
The method of the production BT chemical 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 about 0.4 to about 5 microns in some preferred embodiment, and generally is about 0.1 micron to about 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 with measure at least about 0.5% to about 5% (w/w) and preferably less than the nitric acid of 5% (w/w) and do not contain in the acidic aqueous solution of hydrophilic, polarity or organic solubilized agent.
In view of the technology of generally acknowledging is instructed: bismuth is water-fast (for example U.S.RE37793) when 50 μ M, bismuth in water unstable (for example, Kuvshinova etc., 2009 Russ.JInorg.Chem 54 (11): 1816), and bismuth even unstable in salpeter solution, unless have hydrophilic, polarity or organic solubilized agent, just in this point, the inventive method provides advantage astonishing and beyong contemplation.For example, in the clearly description of all BT preparation methoies (such as Domenico etc., 1997 Antimicrob.Agents.Chemother.41:1697; U.S.6,380,248; U.S.RE37793; U.S.6,248,371), hydrophilic solubilizing agent propylene glycol is that the dissolving bismuth nitrate is 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 chemical compound.
On the contrary, according to present disclosure, the dissolving bismuth does not need aqueous, polarity or organic solubilized agent, and accident has obtained higher concentration.Hydrophilic, polarity or organic solubilized agent comprise propylene glycol (PG) and ethylene glycol (EG), and can comprise any of many known solubilizing agents, comprise polar solvent, for example glycerol and mannitol and other material of epoxy hexane and dimethyl sulfoxide (DMSO), polyhydric alcohol (comprise for example PG and EG, also comprise Polyethylene Glycol (PEG), polypropylene glycol (PPG), tetramethylolmethane etc.), polyhydroxy-alcohol for example.The miscible Organic substance of the water of other high polarity comprises dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and NMP (METHYLPYRROLIDONE).
Therefore, it will be understood by those skilled in the art that can be such as (the 1995 Liebigs Ann.241 for example of the system that uses Catalan etc. according to solvent polarity/polarizability (SPP) scale value; Also referring to Catalan, 2001 Handbook of Solvents, Wypych (editor), Andrew Publ., NY, and the list of references wherein quoted) selective solvent comprises those of hydrophilic, 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-propanol has 0.848 SPP value.Described and be used for based on 2-N, N-dimethyl-7-nitrofluorene/right ultraviolet measurement of 2-fluoro-7-nitrofluorene probe/homomorphism is measured the method (Catalan etc., 1995) of solvent SPP value.
Based on the solubility properties of particular B T compositions, 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 Godfrey 1972 Chem.Technol.2:359) can easily be determined with reference to present disclosure by those skilled in the art, although as mentioned above, according to some preferred embodiment of synthetic method step as herein described, do not need hydrophilic, 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 describing the solubility parameter of solvent that the bismuth salt comprise bismuth dissolves therein or 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 compositions 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 expecting that wherein more the situation of hydrophilic environments is preferred.
As limiting examples, the BisEDT that has with structure shown in the following formula I can prepare according to following reaction scheme:
Figure BDA00002178874500301
In brief, and as nonrestrictive illustrative example, can be in room temperature under agitation to the 5%HNO of excessive (11.4L) 3Aqueous solution slowly adds the acid bismuth aqueous solution of 0.331L (about 0.575 mole), for example Bi (NOs) 3Solution (for example, 43%Bi (NOs) 3(w/w), 5% nitric acid (w/w), 52% water (w/w) can be available from Shepherd Chemical Co., Cincinnati, OH), slowly add subsequently dehydrated alcohol (4L).Can add 72.19mL (0.863 mole) 1，2-ethandithiol, then stir and prepared separately for example alcoholic solution (1.56L) of 1，2-ethandithiol [～0.55M] of mercaptan compound in 5 minutes to the 1.5L dehydrated alcohol by using the 60mL syringe.1，2-ethandithiol (CAS 540-63-6) and other mercaptan compound can be available from for example Sigma-Aldrich, St.Louis, MO.Then the alcoholic solution of mercaptan compound can slowly be added into Bi (NO 3) 3/ HNO 3Aqueous solution stirs and spends the night to form reaction solution.According to some preferred embodiment, the chemical compound that contains mercaptan can be present in the reaction solution to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.The product sedimentation that makes formation is the precipitation that comprises microgranule described herein, then by filter collecting precipitation and successively with ethanol, water and washing with acetone to obtain the BisEDT of yellow amorphous powder solid, shaped.Crude product can under agitation be dissolved in dehydrated alcohol again, then filters also successively with washing with alcohol several times, with washing with acetone several times subsequently.Powder after the washing can grind in 1M NaOH (500mL), filter, and successively water, ethanol and washing with acetone so that the particles B isEDT of purification to be provided.
According to non-limiting theory, the bismuth anti-bacteria produces the ability of Extracellular Polymers matter (EPS) (for example antibacterial exopolysaccharide), and this inhibition causes biofilm formation to reduce.Think that antibacterial employing glue sample EPS is used for the biomembrane adhesion.According to infecting character, biofilm formation and EPS processing can promote bacterial disease originality, for example disturb wound healing.Yet independent bismuth is as getting involved agent without therapeutical effect, but usually as complex for example the part of BT use.Therefore, bismuth-mercaptan (BTs) is to comprise the chemical compound that produces by bismuth and mercaptan compound chelating and a based composition that shows the antimicrobial therapy effect of the bismuth that significantly improves.BTs shows significant infection, antibiont film and immunoregulation effect.Bismuth-mercaptan effectively resists the spectrum microorganism, and not affected by antibiotic resistance.BTs is with the concentration prevention biofilm formation of significantly low (inferior suppress), prevents many pathogen features of common wound pathogens with same inferior inhibition level, can prevent septic shock in animal model, and can with many antibiotic synergisms.
As described herein, this concertedness of the antibacterial action when one or more specify BT and one or more to specify the Antibiotique composition combination 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, can comprise amikacin, ampicillin, cefazolin, cefepime, chloromycetin, ciprofloxacin, clindamycin (or other lincoln amides antibiotics), daptomycin with the synergistic antibiotic of some BTs
Figure BDA00002178874500311
Doxycycline, Gatifloxacin, gentamycin, imipenum (imipenim), levofloxacin, Linezolid
Figure BDA00002178874500312
In minocycline, nafcillin, paromomycin, rifampicin, Sulfamethoxazole, tobramycin and the vancomycin one or more.In vitro study shows, for example, separately poor to gentamycin, cefazolin, cefepime, Sulfamethoxazole, imipenum or levofloxacin sensitivity or in these antibiotic any one shown significant sensitivity when insensitive MRSA is exposed to antibiotic in the presence of BT compd B isEDT at all.Therefore, some embodiment of this paper expection is clearly expected and can be comprised that wherein BT chemical compound and one or more are selected from amikacin, ampicillin, cefazolin, cefepime, chloromycetin, ciprofloxacin, clindamycin (or other lincoln amides antibiotics), daptomycin Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid
Figure BDA00002178874500322
The compositions of the antibiotic combination of minocycline, nafcillin, paromomycin, rifampicin, 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, chloromycetin, ciprofloxacin, clindamycin (or other lincoln amides antibiotics), daptomycin
Figure BDA00002178874500323
Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid The antibiotic BT chemical compound of minocycline, nafcillin, paromomycin, rifampicin, Sulfamethoxazole, tobramycin and vancomycin and compositions and/or the method for one or more antibiotic combinations.Notice that in this environment, gentamycin and tobramycin belong to aminoglycoside antibiotics.Also have Domenico etc., 2001 Agents Chemother.45:1417-1421 from what the embodiment of some expection was clearly got rid of; Domenico etc., 2000 Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.In Antimicrob.Agents ﹠amp; Chemother.3:79-85; Domenico etc., 1997 Antimicrob.Agents Chemother.41 (8): 1697-1703; Domenico etc., the 1999 J Antimicrob.Chemother.44:601-605 such as 1999 Infect.Immun.67:664-669:Huang; Veloira etc., 2003 J Antimicrob.Chemother.52:915-919; Wu etc., 2002 Am J Respir Cell Mol Biol.26:731-738; Halwani etc., 2008 Int.J Pharmaceut.358:278; Halwani etc., some compositions and the method described among 2009 Int.J.Pharmaceut.373:141-146 wherein it should be noted that during these openly and do not instruct absolutely or hint as disclosed herein monodispersity particles B T compositions.
Therefore as described herein, in some preferred embodiment, provide with comprising particles B T as herein described and in some other embodiment, randomly also comprising compositions and the method that the antibiotic compositions of concertedness and/or enhancement is treated the experimenter.Various equivalent modifications will be appreciated that suitable clinical setting and the situation that wherein may need this treatment based on the disclosure, its standard is definite at medical domain, especially comprises such as surgery, battle surgery, dermatological, Wound medicine, presbyatrics, cardioangiology, metabolic disease (such as diabetes, obesity etc.), infection and inflammation (being included in for example epithelial layer of glandular tissue of respiratory tract or gastrointestinal tract or other epithelial tissue surface) medical speciality and the son specialty relevant with other.
It is therefore to be understood that such as this paper to disclose with known in the art that in certain embodiments expection promotes skin tissue recovering (or other tissue repair, for example epithelial tissue, bone, joint, tendon or ligament repair).In certain embodiments, promote skin histology or other epithelial tissue reparation can comprise stimulation or disinthibite to be selected from one or more following cell wound repair activity: (i) epithelial cell (for example, keratinocyte) or dermal fibroblast migration, (ii) epithelial cell (for example, keratinocyte) or dermal fibroblast growth, (iii) the downward modulation epithelial cell (for example, keratinocyte) or the dermal fibroblast collagenase, gelatinase or matrix metal proteinase activity, (iv) dermal fibroblast extracellular matrix protein deposition, and (v) induce or strengthen the corium blood vessel and occur.For the identification of being described with the methodology that characterizes this type of cell wound repair activity, so that the compositions that wound tissue disclosed herein repairing accelerant chemical compound for example comprises BT agent as herein described can be based on present disclosure easily and need not undo experimentation and determine to the effect of these and related activity.For example, herein disclosed is the compositions and the method that relate to the wound repair model of generally acknowledging in the field, described model is based on keratinocyte wound closure after the scratch.
The preferred compositions that is used for the treatment of the antibacterial infection on the self-faced or in the self-faced of using according to embodiment as herein described can comprise the compositions that comprises in certain embodiments bismuth-mercaptan as herein described (BT) chemical compound, and in some difference but also comprise other chemical compound known in the art, for example compositions of one or more Antibiotique compositions as herein described in the related embodiment.BT chemical compound and their method of preparation are open at this paper, and are disclosed in such as (1997 Antimicrob.Agent.Chemother.41 (8): 1697-1703 such as Domenico; 2001 Antimicrob.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 chemical compound is to contain and those of the bismuth of the compound ions bonding that contains mercaptan or ligand complex or bismuth salt, for example comprise the compositions with the bismuth of sulfur-containing compound chelating, and some other preferred BT chemical compound is to contain and those of the bismuth of the chemical compound covalent bonding that contains mercaptan or bismuth salt.Preferred basically monodispersed particles B T compositions as described herein also.The effort of not infecting according to treatment antibacterial before, also not according to before the sign of any chemical compound (as the purposes that has in promoting self-faced therapeutic combination as herein described and method) of describing first of this paper in other environment, can predict and use the inventive method of this compounds will have beneficial effect as herein described.
According to preferred embodiment, the method that is used for the treatment of self-faced is provided thus, comprise at least a particles B T chemical compound as herein described of described surface applied.In certain embodiments, described method also comprises simultaneously or uses at least a Antibiotique composition successively and with any order, wherein can be concertedness antibiotic as herein described in some preferred embodiment, and can be enhancement antibiotic as herein described in some other preferred embodiment.Described Antibiotique composition can be aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics 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), 2007 Lippincott, Williams and Wilkins, Philadelphia, PA; And Hauser, AL, Antibiotic Basics for Clinicians, 2007 Lippincott, Williams and Wilkins, Philadelphia, PA.
As described herein, some embodiment is derived from following discovery beyong contemplation: infect for the antibacterial that comprises gram positive bacteria, preferably treat effective preparation and can comprise BT chemical compound (BisEDT for example, bismuth: 1，2-ethandithiol; BisPyr, bismuth: PTO; BisEDT/Pyr, bismuth: 1，2-ethandithiol/PTO) and rifamycin or BT chemical compound and daptomycin ( Cubist Pharmaceuticals, Lexington, MA) or BT chemical compound and Linezolid (
Figure BDA00002178874500342
Pfizer, Inc., NY, NY) or BT chemical compound (for example, BisEDT, bismuth: 1，2-ethandithiol; BisPyr, bismuth: PTO; BisEDT/Pyr, 1，2-ethandithiol/PTO) and ampicillin, cefazolin, cefepime, chloromycetin, clindamycin (or another kind of lincoln amides antibiotics), daptomycin bismuth: Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid
Figure BDA00002178874500344
One or more of nafcillin, paromomycin, rifampicin, Sulfamethoxazole, tobramycin and vancomycin.
Also as described herein, some embodiment is derived from following discovery beyong contemplation: infect for the antibacterial that comprises gram negative bacteria, preferably treat effective preparation and can comprise BT chemical compound and amikacin.Some related embodiment expection is treated the infection that comprises gram negative bacteria with BT chemical compound and another kind of antibiotic (for example another kind of aminoglycoside antibiotics), and described another kind of aminoglycoside antibiotics is not gentamycin or tobramycin in certain embodiments.Therefore in view of these embodiments, other relevant embodiment expection is according to the known methodology of medical microbial those skilled in the art, identify in the self-faced or lip-deep one or more bacterial communities or subgroup by Gram-positive or the gram-negative standard known, as a step selecting to be included in the suitable Antibiotique composition in the preparation of using according to the inventive method.
Compositions as herein described and method (for example can be applicable in the diversity of settings microorganism, antibacterial, virus, yeast, mycete and other fungus, microorganism parasite etc.) processing, it is usually by using chemical compound as herein described (for example, separately or with one or more particles B Ts of one or more concertednesses disclosed herein and/or enhancement antibiotic combinations) or be applied to microorganism site (for example being present in the microorganism on the self-faced or in the self-faced) and finish.This self-faced includes but not limited to the mammalian tissues (epithelial cell that for example, comprises skin, scalp, gastrointestinal tract gland lining, oral cavity etc.; Endotheliocyte, cell and tissue film such as peritoneal membrane, pericardium, pleura, periosteum, meninges and sarcolemma etc.; Cornea, sclera, mucosa etc.; And other mammalian tissues such as tooth, bone, joint, tendon, ligament, muscle, heart, lung, kidney,liver,spleen, gallbladder, pancreas, bladder, nerve etc.).
Microgranule antimicrobial as herein described can be used for suppressing growth of microorganism, reduces infected by microbes, reduces biomembrane, pre-bacteriological protection is to biomembranous conversion, prevention or stops infected by microbes and other purposes as herein described.These reagent also can be used for multiple anti-viral uses, comprise that prevention or prevention are by the viral infection of herpes coe virus (for example cytomegalovirus, herpes simplex virus type 1 and herpes simplex virus type 2) and/or by other Viral infection.In this respect, described reagent can be used for prevention or stops by various viruses (for example, single strand RNA virus, single-stranded DNA viruses, rous sarcoma virus (RSV), hepatitis A virus, hepatitis 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 Viruses (HIV), human papilloma virus (HPV) and human T cells lymphoma virus (HTLV)) viral infection.
Other inside or the outside pharmaceutical use of antimicrobial as herein described comprise, but for example yeast and fungal infection be (for example to be not limited to treatment or pre-bacteriological protection infection, tuberculosis, fungal infection, Candida (for example, Candida albicans, Candida glabrata, Candida parapsilosis, Oidium tropicale and Dublin candidiasis) or Cryptococcus or other fungus), Helicobacter pylori infection and peptic ulcer.In one embodiment, usually antibacterial is not caused death but its dosage that still enough reduces protectiveness polysaccharide layer (it will resist innate immune reaction in addition) uses described dose.Therefore this technology is believed to be helpful in the degree that the antibacterial of eradicating immune-mediated in the situation of not damaging human symbiotic microorganism (for example, normal intestinal flora etc.) infects the possible situation of antibiotic of applying.
Unrestricted by explanation, the embodiment of some expection is now described.
In certain embodiments, the particles B T chemical compound as herein described compositions of particles B T chemical compound (or comprise) can be used for control biofilm development, disrupting biofilm or reduce at least a or multiple antibiont membrane combination of biofilm biomass.Understand such as this area, selected sensitivity (interspecies quorum sensing) is relevant with biofilm formation between kind.Strengthen the LuxS-Dependent or plant between selected sensitive signal Cucumber (referring to, for example, U.S. Patent No. 7,427,408) help to control biomembranous growth and/or propagation.Exemplary material comprises, for example, perhaps combination or independent N-(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 chemical compound and at least a antibiont membrane be used for to destroy and stop bacterial biof iotalm and be used for the treatment of periodontal disease (referring to, for example, U.S. Patent No. 6,726,898).
Comprise the compositions of microgranule bismuth-mercaptan and be used for oral hygiene and the purposes that is used for the treatment of oral inflammation and infection.In another embodiment, the compositions preparation that will comprise particles B T chemical compound is used for oral use, and can be used for preventing or reduce the growth of microorganism in the oral cavity and be used for preventing and/or treating infected by microbes and the inflammation in oral cavity.Therefore, these compositionss are for prevention or treatment (that is, the probability that occurs or recur is grown, reduced in reduction or inhibition) dental plaque, halitosis, periodontal disease, gingivitis and other oral cavity infection.The oral cavity composition that comprises particles B T chemical compound also can be used for the biofilm development that exists on prevention and/or control (that is, slow down, postpone, suppress) oral surfaces, particularly tooth or the gingiva, disrupting biofilm or reduce biomembranous amount.
Residual, the bad oral hygiene of food particle and bad oral cavity health and improperly artificial tooth cleaning can impel between the tooth, around the gingiva and the growth of microorganism on the tongue.The growth of microorganism that continues and the existence of dental caries can cause halitosis, dental plaque (that is the biomembrane that, is formed by the field planting of microorganism), gingivitis and inflammation.When lacking suitable mouth care (for example, brush teeth, dental floss tooth-cleaning), can then cause more serious infection, for example periodontal disease and jaw infect.
Good oral hygiene is not only for oral health, but also is important for the prevention of some chronic condition of illness.Bacterial growth in the control oral cavity can help to reduce the heart disease risk, keep infection and inflammation risk in memory and other position of reduction health.The risk that serious gingiva problem appears in diabetics is higher, and can help to control blood glucose by the risk that keeps good oral health to reduce gingivitis.The anemia of pregnant woman perhaps more may suffer from gingivitis, and some studies show that between gum disease among the anemia of pregnant woman and premature labor, the low birth weight infant relation.
Antibacterial is the main pathogens of periodontal disease.Can find to surpass 500 kinds of bacterial isolateses (Kroes etc., Proc.Natl.Acad.Sci.USA 96:14547-52 (1999)) in the dental plaque.Antibacterial 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 and the current antibiotic that is used for the treatment of this infection do not kill all attack organisms usually.The propagation that can cause the antibacterium strain to the use of the invalid material of some bacteria culture.In addition, these materials can cause the side effect that makes the people unhappy, for example allergy, inflammation and tooth discoloration.
Dental plaque is the biomembrane that is adhered to securely dental surface, restoration and prosthetic device.The biomembranous main method of control in the oral cavity is by mechanical cleaning (that is, brush teeth, dental floss tooth-cleaning etc.).In not carrying out initial two days of such cleaning, dental surface is mainly the facultative coccus of the Grain-positive institute field planting of streptococcus strain.Antibacterial secretion helps that antibacterial anchored to the surface and the antibacterial that adheres to is provided the outer rete malpighii of born of the same parents of protection.Microcolony forms in case the antibacterial that dental surface is attached covers.Biomembrane is the cell division by the antibacterial that adheres to mainly, but not by novel bacteria adhere to grow.The doubling time that antibacterial forms speckle is fast in developing in early days, and slower in more ripe biomembrane.
The copolymerization collection appears when bacterial clump adheres to the antibacterial that has been attached to thin film subsequently.The result of copolymerization collection is the compound set that forms different bacterium connected to one another.After the original state plaque formation several days, gingival margin becomes inflammation and enlargement.The gingival sulcus that inflammation can cause deepening produces.Biomembrane is expanded to this gum lower area and is flouring in this protection of the environment, causes phagocytosis Biofilm formation under the ripe gum.Gingivitis just appears until become the biomembrane that comprises gram-negative anaerobic bacteria by a kind of biomembrane that mainly is comprised of gram positive bacteria.In gingival sulcus, begin to form gingiva lower bacteria microcolony (mainly being formed by gram-negative anaerobic bacteria) between 3 and 12 weeks after gum edge plaque formation begins.
Shielded Bacterial microcolony has resistance to antibiotic (systemic administration), antibacterial or disinfectant (local application) and immune defence usually in biomembrane.For example, the antibiotic dosage that kills the free bacterium that swims need to increase nearly 1,500 times to kill the biomembrane antibacterial.Under this high concentration, these antibacterial also trend towards to the patient toxic (referring to, for example, Coghlan 1996, New Scientist 2045:32-6; Elder etc., 1995, Eye 9:102-9).
Making great efforts frequently, physical removal bacterial plaque biomembrane is the most effective means of eliminating and control bacterial plaque.Yet, the subgingival plaque in the recess can not by brush teeth, dental floss or oral cavity clean to reach.Therefore, often by dentist or dentist carry out root surface under the gum periodontal to remove be the key component of prevention and treatment periodontitis.
In certain embodiments, particles B T chemical compound can join in the oral hygiene composition, for example, but be not limited to toothpaste, mouthwash (being the oral rinse agent), buccal cavity gel, dentifrice, mouthspray (comprising the spraying that disperses 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 chemical compound can join in the main oral hygiene composition by the use of dental care industry, and it comprises for example fluoride liquids therapeutic agent, Cleasing compositions, buffer compositions, oral rinse agent and dental floss.The present embodiment expection replaces described antibacterial with the oral hygiene composition preparation in this area with particles B T chemical compound as herein described, so that advantage disclosed herein to be provided, it comprises following scope: the enhancing of antimicrobial acivity, dissolubility and bioavailability, antibiont membrane interaction, non-toxicity, antibiotic effect and other character as herein described.
Particles B T chemical compound also can be by coming particles B T compound administration for prevention or treatment dental caries and/or inflammation (that is, reducing respectively the probability that occurs or recur dental caries and/or inflammation) in dental surface.The compositions that comprises particles B T chemical compound can the mucus adhesive composite, described compositions is applied to dental surface and/or gingiva or oral mucosa, and it can be to adhere to the surface or to send the active component of effective dose pharmaceutically to any form on required surface to a certain extent.Also particles B T chemical compound can be formulated as by the compositions that is applied to the oral cavity and slowly discharge.For example, compositions can be gel (for example, hydrogel, mercaptides polymer (thiomer), aeroge or organogel) or liquid.Organogel can comprise organic solvent, thioctic acid, vegetable oil or mineral oil.This gel or liquid apply preparation can inside or applications to amalgam, complex or other repairing composition.Slowly release composition can be sent pharmaceutically the particles B T chemical compound 1,2,3,4,5,6,7 of effective dose (week) day or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.Said composition can be prepared with many methods known in the art by those skilled in the art.
As described herein, in some other embodiment, provide the antimicrobial compositions that comprises particles B T chemical compound and one or more other Antimicrobe compounds or antimicrobial to be used for oral use.As described herein, useful especially is to comprise and have the compositions of second antimicrobial agent enhancing or the Synergistic antimicrobial effect when working as combined administration.For example, when being used with the antimicrobial of chelated iron, particles B T chemical compound can be observed the anti-microbial effect of enhancing.In other particular, with particles B T chemical compound and antiinflammatory, chemical compound, micromolecule or macromole (for example peptide or polypeptide) preparation.
Any particles B T chemical compound preparation as herein described can be used for oral use.In certain embodiments, can use the particles B T chemical compound with hydrophobic mercaptan (for example, the sulfo-chlorophenol) preparation, and it shows the ability that adhere to tooth and oral cavity tissue larger than the BT chemical compound of hydrophobic difference.BT chemical 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 chemical compound can comprise in addition one or more active component 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.Because chemistry and the physical property of sodium bicarbonate, it has widely uses, and comprises cleaning, deodorization and buffering.Sodium bicarbonate chemically in and stink, but not shelter or adsorb them.Sodium bicarbonate can with particles B T compound combination, perhaps as mixture of powders or dissolving or be suspended in dentifrice as herein described, gel, paste and the liquid any.In other embodiments, particles B T chemical compound can with help to keep required alkaline pH and also have cleaning and other alkali metal hydrogencarbonate of deodorization character or carbonate material (for example, potassium bicarbonate or calcium carbonate) make up.
The oral hygiene composition that comprises particles B T chemical compound can comprise one or more following compositions in addition. Anti- Microorganism agent: for example, chlorhexidine; The Sanguinaria canadensis extract; Metronidazole; Quaternary ammonium compound (for example cetylpyridinium chloride); Biguanide (for example, chlorhexidine gluconate, hexetidine, octenidine, alexidine); Halogenated bisphenol chemical compound (for example, 2,2 ' di-2-ethylhexylphosphine oxide (4-chloro-6-bromophenol) or other phenol antimicrobial compound; The alkyl hydroxy benzoate; The cation antimicrobial peptide; Aminoglycoside; Quinolinones; Lincoln's amide; Penicillin; Cephamycin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii Briq. (Coleus forskohlii) quintessence oil; Silver or collargol antibacterial; Antibacterial based on stannum or copper; Manuka (Manuka) oil; Skin Sa grass (oregano); Herba thymi vulgaris; Herba Rosmarini Officinalis; Or other herb extracts; And grapefruit seed extract. Antiinflammatory or anti- Oxidant: for example, ibuprofen, flurbiprofen, aspirin, indomethacin, Aloe (aloe vera), Rhizoma Curcumae Longae, Olive leaf P.E, Flos Caryophylli, pantothenylol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, Rhizoma Zingiberis Recens, Semen Vitis viniferae etc. The dental 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 agent (Plaque buffer): for example, urea, calcium lactate, calcium glycerophosphate and polyacrylic acid strontium class. Vitamin: for example, vitamin A, C and E. Plant extract Desensitizer: for example, potassium citrate, potassium chloride, Soluble tartar., potassium bicarbonate, potassium oxalate, potassium nitrate and strontium salt. Anticalculus agent: such as alkali metal pyrophosphate salts, the polymer that contains hypophosphites, Organophosphonate and phosphocitrate etc. Biomolecule: for example, bacteriocin, phage, antibody, enzyme etc. Flavoring agent: for example, thin He and Oleum menthae, Fructus Foeniculi, Cortex Cinnamomi etc. Protein material: for example, collagen. Anticorrosion Agent Opacifier Coloring agent PH adjusting agent Sweeting agent 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 (referring to, for example, U.S. Patent No. 6,485,711). Abrasive material particles: for example, the microgranule abrasive material of silicon dioxide, aluminium oxide, calcium carbonate, dicalcium phosphate, calcium pyrophosphate, hydroxyapatite, trimetaphosphate, insoluble hexametaphosphate, cohesion, Chalk, fine grinding natural whiting etc. Humidizer: for example, glycerol, Sorbitol, propylene glycol, xylitol, lactose etc. Sticking Mixture and thickening agent: for example, sodium carboxymethyl cellulose, hydroxyethyl-cellulose ( ), Xanthan gum, Radix Acaciae senegalis, (for example, polyacrylate and C974P BufferGel are for example for synthetic polymer
Figure BDA00002178874500392
).Enhanced activity composition for example antimicrobial is sent Polymerizable compoundThe pH of buffering oral care composition and ionic strength Buffer and salt Depigmenting agent: for example, per-compound (for example, peroxide diphosphonic acid potassium). Rise The bubble system: for example, the sodium bicarbonate/citric acid system. Color change systemIn specific embodiments, grinding agent is silicon dioxide or fine grinding natural whiting.
Preparation can further comprise humidizer (for example, glycerol or Sorbitol), surfactant, binding agent and/or flavoring agent with the oral hygiene composition that comprises particles B T chemical compound as toothpaste.Toothpaste also can comprise sweeting agent, brightening agent, antiseptic and antimicrobial.Toothpaste reaches the pH of other compositions that is used for oral use usually between pH 5.5 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 chemical compound.Dentifrice composition as herein described can comprise one or more in Chalk, Tri-Compress, Sorbitol, water, hydrated alumina, precipitated silica, sodium lauryl sulphate, sodium carboxymethyl cellulose, flavoring agent, sorbitan monooleate, saccharin sodium, tetrasodium pyrophosphate, methyl butex, the propyl parabene.For example can adopt one or more coloring agent, FD﹠amp if need; C is blue.Other composition that is fit to that can be contained in the 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 chemical compound, alkaline buffer (for example, potassium bicarbonate), alcohol, sweetener component and fragrance system.The fragrance system also can have with lower more than one: essence, humidizer, surfactant, sweeting agent and coloring 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, comprise particles B T oral hygiene composition 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, UK Patent Application No.GB 1557163, U.S. Patent No. 6,488,912).As described herein, particles B T also can with one or more other antimicrobial combination, to such an extent as to described compositions has additive effect or cooperative effect when making up with particles B T.
In yet another embodiment, oral hygiene composition as herein described can further comprise at least a or multiple antibiont membrane for control biofilm development, disrupting biofilm or minimizing biofilm biomass.Such as in this area understanding, selected sensitivity (interspecies quorum sensing) is relevant with biofilm formation between kind.Can strengthen the LuxS Dependent or plant between selected sensitive signal (interspecies quorum sensing signal) (referring to, for example, U.S. Patent No. 7,427,408) some reagent help to control biomembranous growth and/or propagation.For example, exemplary agents comprises or N-that make up 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 chemical compound and at least a antibiont membrane be used for to destroy and stop bacterial biof iotalm and be used for the treatment of periodontal disease (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 chemical compound of the amount of antibacterial action in time that dental floss tooth-cleaning is required.As described herein, particles B T chemical compound can remain on the oral surfaces (for example tooth, amalgam, complex, mucosa, gingiva).Smear, gargle wash, particles B T chemical compound for example can continue to remain on tooth and the gingiva so that antibiont film and the antiinflammatory action of prolongation to be provided behind the dental floss tooth-cleaning.
In other embodiments, particles B T chemical compound slowly discharges from mucus-binder polymer or other reagent of helping particles B T chemical compound to keep somewhere on mucosa and dental surface.Particles B T chemical compound can be added to stable, viscosity and/or mucus binding agent water composition, described water composition also can be used for preventing and treating mucosa 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 chemical compound further comprises the olive oil that can strengthen plaque removal.Olive oil is being used for oral hygiene, for example the use in the product of toothpaste, mouthwash, spray, oral inhaler or Chewing gum can help to eliminate or reduce the quantity of the antibacterial that exists in (minimizing) bacterial plaque and/or elimination or reduction (minimizing) oral cavity, thus, reach and (for example reduce odontopathy, aging, the periodontal disease of tooth) 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 chemical compound can further comprise the mucosa disinfectant preparation that is applied topically to the oral cavity.Oral hygiene composition can further comprise for the useful aqueous unguentum (aqueous slurry) of cleaning tongue and 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 chemical compound can further comprise at least a formation (dental caries) for prevention (that is, reducing possibility occurrence) cavity or reduce the Herba Menthae agent (mint) of cavity number.A kind of being called
Figure BDA00002178874500411
This type of Herba Menthae 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 Herba Menthae agent in the oral hygiene composition that comprises particles B T chemical compound therefore can improve pH and strengthen particles B T chemical compound to the adhesion of oral surfaces.
The compositions preparation that comprises microgranule bismuth-mercaptan is used for plastic surgery's purposes.In specific embodiments, provide with the compositions that comprises particles B T chemical compound and prevent and/or treat because plastic surgery's formality (for example, plastic surgery operations, plastic treatment, arthroplasty (comprising two step arthroplasties), orthodontic treatment) infected by microbes that causes and the method for inflammation.Therefore the described compositions that comprises particles B T chemical compound as herein described can be used for preventing and/or treating (namely, reduce or suppress its growth, reduce the probability of its generation or recurrence) infected by microbes of skeleton and supporting construction (that is, BJM, ligament, tendon) osteomyelitis for example.The compositions that comprises particles B T chemical compound as herein described also can be used for prevention and/or control (that is, slow down, postpone, suppress) biofilm development, the biomembranous amount that exists on disrupting biofilm or minimizing intraarticular or bone, ligament, tendon or the tooth surface.
The compositions that comprises particles B T chemical compound for plastic surgery's purposes as herein described can further comprise one or more other Antimicrobe compound or materials.As described herein, useful especially is to comprise to have particles B T chemical compound enhancing or the Synergistic antimicrobial effect and the compositions of second antimicrobial agent when combined administration.By other embodiment, when being used with the antimicrobial of chelated iron, particles B T chemical compound can be observed the anti-microbial effect of enhancing.In other particular, with particles B T chemical compound and antiinflammatory, chemical compound, micromolecule or macromole (for example peptide or polypeptide) preparation.
Comprise particles B T chemical compound compositions can with at least a have when the combined administration strengthen or other antimicrobial of Synergistic antimicrobial effect (, greater than summation action) (that is, and second, third, the 4th, wait antimicrobial) combination.For example, when using with the antimicrobial of ferrum chelating, particles B T chemical compound can be observed the anti-microbial effect of enhancing.In specific embodiments, comprise particles B T chemical compound compositions can be selected from following at least a other antimicrobial and/or antiinflammatory the combination: Antimicrobial: for example, chlorhexidine; The Sanguinaria canadensis extract; Metronidazole; Quaternary ammonium compound (for example cetylpyridinium chloride); Biguanide (for example, chlorhexidine gluconate, hexetidine, octenidine, alexidine); Halogenated bisphenol chemical compound (for example, 2,2 ' di-2-ethylhexylphosphine oxide (4-chloro-6-bromophenol) or other phenol antimicrobial compound; The alkyl hydroxy benzoate; The cation antimicrobial peptide; Aminoglycoside; Quinolinones; Lincoln's amide; Penicillin; Cephamycin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii Briq. (Coleus forskohlii) quintessence oil; Silver or collargol antibacterial; Antibacterial based on stannum or copper; Manuka (Manuka) oil; Skin Sa grass (oregano); Herba thymi vulgaris; Herba Rosmarini Officinalis; Or other herb extracts; And grapefruit seed extract. Antiinflammatory or antioxidant: for example, ibuprofen, flurbiprofen, aspirin, indomethacin, Aloe, Rhizoma Curcumae Longae, Olive leaf P.E, Flos Caryophylli, pantothenylol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, Rhizoma Zingiberis Recens, Semen Vitis viniferae etc.In specific embodiments, the compositions that comprises particles B T chemical compound can further comprise and is selected from following antibiotic: clindamycin, vancomycin, daptomycin, cefazolin, gentamycin, tobramycin, metronidazole, cefaclor, ciprofloxacin or other antimicrobial be quaternary ammonium compound (for example, benzalkonium chloride, cetylpyridinium chloride), antimicrobial zeolite, alkali metal hydroxide or alkaline earth oxide for example.Described compositions optionally comprises one or more pharmaceutically suitable carrier (that is, excipient), surfactant, buffer, diluent and salt as herein described, and depigmenting agent.Therefore, these some disclosed embodiment expections relevant with this paper are contained in the method for this product and present disclosed particles B T compositions, described BT compositions can comprise one or more particles B T, and described BT compositions also optionally further comprises for example collaborative or enhancing antibiotic as herein described of antibiotic.
The biology of particles B Ts, biomedicine and other purposes.Some other embodiment is expected the purposes of particles B Ts as herein described, no matter still use different V family metals for example antimony (Sb) or arsenic (As) replacement bismuth BTs partly as independent BTs, and/or this BT of conduct as described herein and one or more antibiotic combinations, the BT of oral nutritional formulation shows antimicrobial acivity collaborative or that strengthen.
According to non-limiting theory, particles B Ts and other component be included in this preparation can be in certain embodiments with promote BT and randomly antibiotic and/or other nutrition composition cause obstruction or retardance by the nutrition of the micropopulation bulk absorption in the digestive tract to the mode of the bioavailability increase in Host Digestion road, described other component is vitamin, mineral, aminoacid, Hydrocarbon (comprising sugar, fatty acid, oil, nutrient for plants, tea, medical herbs or herb extracts and/or other nutriment or food) for example.In some other embodiment, be contained in specific vitamin, mineral, aminoacid, Hydrocarbon (comprising sugar, fatty acid, oil, nutrient for plants, tea, medical herbs or herb extracts and/or other nutriment or food) in oral microparticles BT (or AsT or SbT) preparation by change, can reduce (for example, with respect to suitable contrast in the statistically significant mode) BT and optional antibiotic and/or other nutrition composition to the bioavailability in Host Digestion road.
For example, when the infection of pathologic gastrointestinal (GI) road existed, the particles B T preparation that can expect to use the intestinal absorption that hinders the BT chemical compound was so that it keeps bioavailability in the GI road, with the anti-microbial effect of performance for pathogen infection.Those skilled in the art should know a large amount of vitamin, mineral, aminoacid, Hydrocarbon (comprising carbohydrate, fatty acid, oil, nutrient for plants, tea, medical herbs and/or herb extracts), they promote or stop GI road Absorption of nourishment plain, thereby the preparation that uses particles B T of the present disclosure (or AsT or SbT) to exist for the preparation of the GI road that strengthens or reduce one or more components (for example, particles B T chemical compound, antibiotic or one or more specific nutritions element).
Some other embodiment expection provided herein is included in for oral delivery particles B T chemical compound disclosed herein reducing the compositions (for example in accepting the patient of colostomy) of feces or digestive gas stink, and is included in for local delivery to reduce and there is other compositions of relevant oxter, foot or other body odor in local antibacterial.Many skins and GI road micropopulation (comprise and swimming and the biomembrane antibacterial) are to low concentration particles B T chemical compound as herein described (comprising this BT chemical compound when existing with enhancing as herein described or concertedness antibiotic) sensitivity.
Therefore, the particles B T preparation of some embodiment expection oral delivery and local delivery, in order to reduce the antibacterial of (for example, with respect to suitable contrast in the statistically significant mode) GI field planting or skin field planting in the mode that reduces or alleviate the problem of the stink of not expecting.Oral cavity and topical pharmaceutical formulation are below described, so that these provide the advantage relevant with this microparticle formulation of BT, for example compatible bioavailability and dissolution properties and hypotoxicity with related embodiment; The other factors that can affect the selection of antimicrobial compositions is described in other place of this paper, and can be referring to for example U.S.6, in 582,719.
Exemplary BT compd B isEDT is employed (the 1mg/mL DMSO solution of 50 μ L) to human trial experimenter's underarm region and shows and offset body odor two to three days.Be applied to the mixture of BisEDT in Pulvis Talci that the people tests experimenter's foot and substantially reduced foot odor.The laboratory mice that continues twice of every day five days oral 1mg/kg BisEDT that feed shows the reduction of faecal microbiota several 90%.Relevant embodiment is also expected any stink (is for example contained thiol solution, fish oil is trout oil for example) common useful deodorizer, it comprises the particles B T preparation as described herein of being made by excessive bismuth, and can be used as the stink quencher and add to and contain in the thiol solution.The gained mixture is kept the microbial resistance of particles B T.Other application of expection comprises solvent for example oil or the butter of other biological origin, for example, cannabis oil, tea tree oil, shea butter (Shea butter), Semen Lini oil, fish oil, and in certain embodiments expection for example can have independently or the antiinflammatory of working in coordination with and/or the oil that reduces pain and/or other useful physiological action.
Pharmaceutical composition and using
Some embodiment also relates to the pharmaceutical composition that comprises particles B T chemical compound disclosed herein; Can further comprise one or more antibiotic in some such embodiment Chinese medicine compositions, for example the antibiotic of as described herein and BT compound exhibits concertedness or potentiation.In one embodiment, as disclosed herein, when being applied to animal, preferred mammal most preferably is provided at the compositions that comprises one or more such particles B T chemical compounds in pharmaceutically acceptable carrier, excipient or the diluent with therapeutic dose during human patients.
Can carry out using of particles B T chemical compound or its pharmaceutically acceptable salt (purified form or in suitable pharmaceutical composition) via accept method of application as the material of similar purposes any.Pharmaceutical composition can prepare by combination particles B T chemical compound and suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into the preparation of solid, semisolid, liquid or gas form, for example tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, gel, microspheres agent and spray.That the typical route of administration of this pharmaceutical composition includes, but not limited to is oral, local, transdermal, suction, parenteral, Sublingual, rectum, vagina and intranasal.Comprise subcutaneous injection, intravenous, intramuscular, breastbone inner injection or infusion techniques as term parenteral used herein.The compounding pharmaceutical compositions is so that but the active component that comprises is biological utilisation when compositions is applied to the patient herein.The compositions that will be applied to experimenter or patient is taked the form of one or more dosage units, and wherein for example, tablet can be single dosage unit, and can hold a plurality of dosage units with the container of the chemical compound of spray form.The existing method for preparing this dosage form is known, or will be apparent to those skilled in the art; For example, referring to The Science and Practice of Pharmacy, the 20 edition (Philadelphia College of Pharmacy and Science, 2000).In any case will comprise the chemical compound that is used for the treatment of target disease or condition of illness for the treatment of effective dose according to the instruction of this paper compositions to be administered, or its pharmaceutically acceptable salt.
The useful pharmaceutical composition of this paper also comprises pharmaceutically acceptable carrier (comprising any suitable diluent or excipient), they comprise itself does not induce any medicament that the harmful antibody of the individuality of accepting compositions is produced, and it can be used in the situation of excessive toxicity not having.Pharmaceutically acceptable carrier includes but not limited to, liquid, such as water, saline, glycerol and ethanol etc.The detailed discussion of pharmaceutically acceptable carrier, diluent and other excipient is referring to REMINGTON ' S PHARMACEUTICAL SCIENCES (Mack Pub.Co., N.J. current edition).
Pharmaceutical composition can be solid or liquid form.In one aspect, carrier is microgranule, thereby makes compositions be for example tablet or powder form.When compositions during for for example oral syrup, injectable liquids or spray (they are useful in for example sucking and using), carrier can be liquid.
When being used for when Orally administered, pharmaceutical composition is preferably solid or liquid form, and wherein semisolid, semiliquid, suspension and gel form are included in the form of solid that this paper considers or liquid.
As Orally administered solid composite, pharmaceutical composition can be formulated as the forms such as powder, granule, tablet agent, pill, capsule, elata chewing gum agent, wafer (wafer).This solid composite will comprise one or more inert diluents or edible carrier usually.In addition, can have in following one or more: binding agent is carboxymethyl cellulose, ethyl cellulose, microcrystalline Cellulose, Tragacanth or gelatin for example; Excipient is starch, lactose or dextrin for example; Disintegrating agent such as alginic acid, sodium alginate, Primogel, corn starch etc.; Lubricant is magnesium stearate or Sterotex for example; Fluidizer is silica sol for example; Sweeting agent is Mel, sucrose or glucide for example; Flavoring agent is Herba Menthae, methyl salicylate or orange flavor for example; And coloring agent.
When pharmaceutical composition be capsule for example, during the form of gelatine capsule, except the material of the above-mentioned type, it can comprise liquid-carrier for example Polyethylene Glycol or oil.
Pharmaceutical composition can be liquid form, for example elixir, syrup, solution, emulsion or suspension.As two kinds of examples, liquid can be used for Orally administered or is used for passing through injected delivery.When being used for when Orally administered, except this chemical compound, preferred compositions also comprises one or more sweeting agents, antiseptic, dyestuff/coloring agent and fumet.Compositions being used for using by injection can comprise one or more surfactants, antiseptic, wetting agent, dispersant, suspending agent, buffer agent, stabilizing agent and isotonic agent.
Composition of liquid medicine, no matter they are solution, suspension or other similar type, all can comprise in the following adjuvant one or more: sterile diluent is water for injection, saline solution (preferred normal saline), Ringer's mixture, isotonic sodium chloride for example; Fixed oil is synthetic monoglyceride or dialycerides (it can be used as solvent or suspension media), Polyethylene Glycol, glycerol, propylene glycol or other solvent for example; Antibacterial is benzyl alcohol or methyl butex for example; Antioxidant is ascorbic acid or sodium sulfite for example; Chelating agen is ethylenediaminetetraacetic acid for example; Buffer is for example sodium chloride or glucose of acetate, citrate or phosphate and material that be used for to adjust tension force for example.Parenteral formulation can be packaged in ampoule, disposable syringe or the multiple dose vials of being made by glass or plastics.Normal saline is preferred adjuvant.Injectable composition is preferably aseptic.
Be used for Orally administered parenteral or Orally administered composition of liquid medicine and should comprise an amount of particles B T chemical compound in order to obtain suitable dosage.Usually, this amount is at least 0.01% of particles B T chemical compound in compositions.When being used for when Orally administered, this amount can composition weight 0.1 and 70% between change.Preferred combination of oral medication is included in the BT chemical compound between about 4% and about 50%.Preferably, will be prepared as the parenteral dosage unit according to pharmaceutical composition of the present invention and preparation and before dilution, comprise by weight 0.01 to 10% particles B T chemical compound.
Pharmaceutical composition can be used for local application, carrier can suitably comprise solution, emulsion, ointment or gel-type vehicle in this case.Substrate, for example can comprise in following one or more: vaseline, lanoline, Polyethylene Glycol, Cera Flava, mineral oil, shea butter, tea tree oil, Semen Lini oil, cannabis oil or comprise knownly having other vegetable oil or vegetable oil, the trout oil of antiinflammatory and/or pain relieving or other beneficial effect or comprise known other fish oil with antiinflammatory and/or pain relieving or other beneficial effect, diluent for example water and alcohol, and emulsifying agent and stabilizing agent.Thickening agent can be present in the pharmaceutical composition of local application.If be used for transdermal administration, then compositions can comprise percutaneous plaster or iontophoresis device.Topical formulations can comprise from the particles B T chemical compound of about 0.1 to about 10%w/v (weight per unit volume) concentration.
Pharmaceutical composition can be used for the form rectal administration with for example suppository (it will melt and discharge medicine at internal rectum).The compositions of rectal administration can comprise oleaginous base as suitable nonirritant excipient.This substrate includes but not limited to lanoline, cocoa butter and Polyethylene Glycol.
Pharmaceutical composition can comprise the various materials of the physical form of adjusting solid or liquid dosage unit.For example, compositions can be included near the material that forms the coating shell of active component.The material of formation coating shell is generally inertia, and can be selected from for example sugar, Lac and other enteric coating agent.Alternatively, active component can be encapsulated in the gelatine capsule.
Thereby the pharmaceutical composition of solid or liquid form can comprise the material that is bonded to particles B T chemical compound and assists described chemical compound to send.The material that is fit to that can play this effect comprises monoclonal or polyclonal antibody, protein or liposome.Yet some expection embodiment has clearly been got rid of liposome in pharmaceutical composition.
Pharmaceutical composition can form by can be used as the measurement unit that aerosol uses.The term aerosol is used for representing many systems, and scope is from the system of colloidal nature to the system that is comprised of pressurized package.Send and to pass through liquid gas or Compressed Gas, perhaps by distributing the pumping system that is fit to of active component.The aerosol of particles B T chemical compound can be single-phase, two-phase or three-phase system are sent, with delivering active ingredients.Sending of aerosol comprises necessary container, activator, valve, sub-container etc., and they can form test kit together.Those skilled in the art need not undo experimentation can determine preferred aerosol.
Pharmaceutical composition can prepare by the methodology that pharmaceutical field is known.For example, expection can prepare by chemical compound of the present invention and sterile distilled water are made up to form solution as the pharmaceutical composition that is applied by injection.Can add surfactant to promote the formation of homogeneous solution or suspension.Surfactant is and the chemical compound of chemical compound noncovalent interaction of the present invention to promote that chemical compound dissolves or evenly suspends in the aqueous delivery system.
Particles B T chemical compound as herein described or its pharmaceutically acceptable salt are used with the treatment effective dose, and described treatment effective dose will change according to many factors, comprise the activity of the particular compound of employing; The metabolic stability of chemical compound and action time length; Experimenter's age, body weight, health status, sex and diet; Mode of administration and time; Discharge rate; Drug regimen; The severity of specified disease or condition of illness; And through subject experimenter.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).
Effective dosage ranges provided herein is not restrictive, and represents preferred dosage range.Yet most preferred dosage will be formulated according to individual subjects, this be various equivalent modifications be appreciated that and determine (referring to, for example, the editors such as Berkowet, The Merck Manual, the 16th edition, Merck and Co., Rahway, N.J., 1992; The editors such as Goodmanetna, Goodman and Cilman ' 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 al. 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 multiple dose or single dose through the time for every kind.Generally speaking, treatment can be begun by the smaller dose that is lower than the chemical compound optimal dose.After this, dosage is increased by a small margin, until be issued to optimum efficiency at described environment.Diagnostic medicine chemical compound or compositions can be separately or with using for pathology or for other diagnosis and/or the medicament of other pathology symptom.The receiver that uses of particles B T chemical compound and/or compositions can be any vertebrates, for example mammal.In the mammal, preferred receiver is the mammal of Primates (comprising people, ape and monkey), Artiodactyla (comprising horse, goat, cow, sheep, pig), Rodentia (comprising mice, rat, rabbit and hamster) and Carnivora (comprising cat and dog).In bird, preferred receiver is turkey, chicken and with other member of purpose.Most preferred receiver is the people.
For topical application, preferably to target zones for example, what skin surface, mucosa etc. was used effective dose contains particles B T pharmaceutical composition.This amount will be used about 0.0001mg to the scope of about 1gBT chemical compound each usually, and this depends on zone to be treated; Whether purposes is diagnostic agent, preventive or therapeutic agent; The severity of symptom and the local vectorial character that adopts.Preferred topical formulations is ointment, and wherein every cc ointment base uses about active component of 0.001 to about 50mg.Pharmaceutical composition can be formulated as transdermal composition or transdermal delivery device (" paster ").Such composition comprises for example backing, reactive compound bank, controlling diaphragm, liner and contact adhesive.This type of transdermal patch can be used for providing continuous impulse, and sending of required chemical compound of the present invention perhaps is provided when requiring.
By adopting program known in the art, can prepare particles B T compositions in order to provide the active component that is applied to after the patient fast, continues or postpones to discharge.Controlled release-drug delivery system comprise osmotic pump system and dissolution system, it contains polymer-coated bank or drug-polymer matrix formulations.The example of controlled release system is referring to U.S. Patent No. 3,845, and 770 and 4,326,525 and P.J.Kuzma etc., Regional Anesthesia 22 (6): 543-551 (1997), it all incorporates this paper by reference into.
Also particles B T compositions can be sent for part, whole body and the nose therapeutic treatment to brain by the intranasal drug delivery system.The known controlled particle of those skilled in the art is disperseed (CPD) TMSend part and systemic medication effectively to provide by targeting olfactory region and nasal sinuses for technology, traditional nose spray bottle, inhaler or aerosol apparatus.
The invention still further relates in certain embodiments and be suitable for vagina inner shell or the nuclear pharmaceuticals delivery apparatus used to woman or jenny.Described device can be comprised of the active medicine component in the polymeric matrix, is surrounded by shell, and can discharge chemical compound with the pattern of zero level basically based on every day, is similar to the device that is used for applications of testosterone described in the WO98/50016.
The current method that is used for ocular delivery comprises local application (eye drop), subconjunctival injection, periocular injections, intravitreal injection, Srgery grafting and iontophoresis (carry ionized drugs to enter and pass bodily tissue with a small amount of electric current).Those skilled in the art will make up optimal excipient and chemical compound is used for safe and efficient ophthalmic.
Optimal approach depends on character and the severity of condition of illness to be treated.Those skilled in the art also be familiar with to determine methods of use for topical application (oral, intravenous injection spray, suction, subcutaneous, rectum etc.), dosage form, suitable drug excipient and other material relevant with the experimenter who chemical compound is delivered to needs.
Compositions as herein described and method also can be used for treating acute and chronic wounds and wound biomembrane, it comprises for example as burn cream, the topical formulations that comprises those existing wounds as herein described as treatment, be used for the preventing chronic wound, be used for the treatment of the MRSA skin infection, and be used for other relevant indication that should be understood that according to present disclosure with the technical staff disclosed herein.
According to some embodiment as described herein, compositions as herein described and method comprise staphylococcus aureus (S.aureus) to it limiting examples with antibacterial of beneficial effect, MRSA (methicillin resistance staphylococcus aureus), staphylococcus epidermidis, MRSE (methicillin resistance staphylococcus epidermidis), mycobacterium tuberculosis, 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, Yersinia enterocolitica, vibrio cholera, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, anthrax bacillus, yersinia pestis, Pseudomonas aeruginosa, responsive and the vancomycin resistance enterococcus of vancomycin (enterococcus faecalis (E.faecalis) for example, enterococcus faecalis (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 faecalis (Enterococcus faecium), micrococcus scarlatinae (Streptococcus pyogenes), streptococcus agalactiae (Streptococcus agalactiae), anthrax bacillus, Klebsiella Pneumoniae, proteus mirabilis (Proteus mirabilis), proteus vulgaris, Yersinia enterocolitica (Yersinia enterocolytica), have a liking for maltose Stenotrophomonas (Stenotrophomonas maltophilia), streptococcus pneumoniae, the penicillin resistance streptococcus pneumoniae, Burkholderia cepacia, bite burkholderia (Bukholderia multivorans) more, smegmatis mycobacterium (Mycobacterium smegmatis) and enterobacter cloacae (E.cloacae).
Unless opposite indication is arranged, the enforcement of certain embodiments of the present invention will be adopted the conventional method of microbiology, molecular biology, biochemistry, cytobiology, virusology 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 Coning: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.Gai 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 has requirement in addition, 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 description mentions that to " embodiment " or " a kind of embodiment " or " aspect " specific features, structure or characteristics that expression is 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 description and refer to identical embodiment.And concrete feature, structure or characteristics can be combined in one or more embodiments in any suitable manner.
Some embodiment relates to acute or chronic wounds or the biomembranous method of wound, compositions and the test kit that is used for the treatment of the experimenter, it can comprise the skin tissue recovering that promotes the experimenter, and one or more cell wound repair that perhaps change cell or a plurality of cells are active.Cell refers generally to individual cells, and a plurality of cell refers to surpass a cell.Cell can consist of tissue, organ or whole microorganism.And one or more cells can be positioned at body, external or stripped.Keep the conventional program that cell, tissue and organ culture are those skilled in the art, condition of culture and culture medium can easily determine (referring to, Freshney for example, Culture of Animal Cells:A Manual of Basic Technique, Wiley-Liss the 5th edition. (2005); Davis, Basic Cell Culture, Oxford University Press the 2nd edition. (2002)).
As disclosed herein, some embodiment relates to acute or chronic wounds or the biomembranous method of wound that is used for the treatment of the experimenter, comprise to the compositions of experimenter's administering therapeutic effective dose, described compositions (for example comprises the BT chemical compound for these class methods as herein described, provide with a plurality of basically monodispersed particulate form), and randomly in some other embodiment, also comprise the Antibiotique composition for these class methods as herein described, BT chemical compound for example, other chemical compound of proposing of BisEDT or BisBAL or this paper table 1 for example, perhaps any other BT agent is such as with those of lower description: (1997 Antimicrob.Agent.Chemother.41:1697 such as Domenico; 2001 Antimicrob.Agent.Chemother.45:1421) and/or U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248 and/or according to those of method preparation disclosed herein.Some other embodiment relates to and comprises that the method that any self-faced is contacted with the compositions that comprises one or more particles B T chemical compound described herein, this contact procedure can comprise in making the BT compositions and self-faced contacting one or more of direct application, coating, dipping, cleaning, spraying, coating or other.
To the experimenter for example the step of applying of people or other mammalian subject can be undertaken by any mode known in the art, for example local (comprise by directly being applied to skin or any epithelial tissue surface, comprise this type of surface that exists in glandular tissue or respiratory tract and/or the gastrointestinal tract), intravaginal, intraperitoneal, oral, parenteral, intravenous, intra-arterial, transdermal, Sublingual, subcutaneous, intramuscular, through cheek, intranasal, in suction, ophthalmic, subcutaneous, fat, in intraarticular or the sheath.
In preferred embodiments, use and can carry out the part, wherein the local drug excipient that uses or carrier are described herein and be known in the art.
As mentioned above, the topical formulations that some invention embodiment as herein described relates to described BT chemical compound (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, chloromycetin, ciprofloxacin, clindamycin (or another kind of lincoln amides antibiotics), daptomycin
Figure BDA00002178874500511
Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid Minocycline, nafcillin, paromomycin, rifampicin, Sulfamethoxazole, tobramycin and vancomycin; Or carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics and/or Aminopenicillin antibiotic and/or aminoglycoside antibiotics, for example amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin or apramycin and/or lipopeptide antibiotics daptomycin for example
Figure BDA00002178874500513
The Huo oxazolidinone antibiotics is Linezolid for example
Figure BDA00002178874500514
As disclosed herein, when the part is applied to animal, preferred mammal, optimum is chosen, and in particularly preferred embodiments, have acute or chronic wounds or contain might relate to biomembranous antibacterial and (for example infects, wherein may there be the antibacterial that can promote biofilm formation, but not yet detect biomembrane) or contain the people that antibacterial infects the wound of biological example film or the existence of other antibacterial, these and related preparations can be included in pharmaceutically acceptable carrier, the BT chemical compound of the therapeutic dose in excipient or the diluent (with choosing any one kind of them or Multiple Classes of Antibiotics).
BT chemical compound as herein described or its pharmaceutically acceptable salt carry out with pure form or with any of local application pattern of agent that the local application of suitable pharmaceutical composition can be by the similar effectiveness accepted.In preferred embodiments, the topical application of compositions or use comprise make compositions (for example topical formulations) with through subject experimenter's skin and/or another kind of epithelial tissue surface (for example, respiratory tract, gastrointestinal tract and/or glandular epithelium layer) directly contact, this can be at one or more local skins or the skin that extensively distributes and/or position, other epithelial tissue surface, and this acute or chronic wounds position that can generally instigate topical formulations and complete horny layer or epidermis to center on contacts, but not necessarily so restriction; For example, some embodiment is expected topical formulations topical application as herein described or be applied to injured, scraping or impaired skin or the experimenter's that stands to perform the operation skin, so that the contact of topical formulations can occur in not only horny layer or epidermis, also occur in skin granulocyte, spine cell and/or basal cell layer and/or corium or lower covering weave, for example, may follow the wound repair of some type or wound healing or other skin histology to reinvent.
Therefore, in some preferred embodiment, this type of skin tissue recovering can comprise dermal wounds healing, for example prevention or alleviate in acute chronic wounds or the biomembrane wound or as another example in prevention or alleviate in the skin wound cracking or may exist acute or improve, accelerate when chronic wounds and/or skin wound cracking or strengthen otherwise that this may expect in the skin wound healing.Expection is locally applied to respiratory tract, some other embodiment on the epithelial tissue surface that exists in gastrointestinal tract and/or the gland lining can comprise similarly by suitable approach known in the art uses topical formulations to send topical formulations provided herein to respiratory tract (air flue for example, nasopharynx larynx path, trachea, lung, bronchus, bronchioles, alveolar etc.) and/or gastrointestinal tract (oral cavity for example, esophagus, stomach, intestinal, rectum, anus etc.) one or more epithelial tissue surface and/or other epithelial surface of existing in.
According to the embodiment of some expection, local application can comprise and directly is applied to open wound.For example, open fracture or other open wound can comprise skin breakdown, and this can make other following tissue so that the mode that they are subject to infected by microbes is exposed to external environment condition.This situation is common in the military wound of the acute traumatic of some type, comprises for example III type (severe) open fracture.According to these and relevant embodiment, local application can make BT compositions as herein described and this type of damaged skin and/or another epithelial surface and/or other organize for example connective tissue (comprising muscle, ligament, tendon), bone, loop organization for example blood vessel, related neural tissue and any other organ that may be exposed to this open wound directly contact.The example that may expose and therefore consider other tissue of this direct contact comprises kidney, bladder, liver, pancreas and may so detrimentally be exposed to any other tissue or the organ of the opportunistic infection relevant with open wound.
Topical formulations (for example pharmaceutical composition) can be by the described BT chemical compound of combination (for example, comprise U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and/or U.S.6,380, the chemical compound of describing in 248, and/or according to the chemical compound of present disclosure preparation, particles B T suspension as herein described for example), and in some related embodiment by independent one or more required antibiotic of combination (aminoglycoside antibiotics for example, amikacin for example) or with the BT chemical compound, with suitable pharmaceutically acceptable carrier, diluent or excipient make up together for topical formulations and prepare, and can be mixed with solid, semi-solid, gel, colloid, the preparation of suspension or liquid or other topical application form, for example powder, granule, ointment, solution, lotion, the gel base, paste, plaster, varnish, bioadhesive polymer, microsphere suspensoid and aerosol spray.
The pharmaceutical composition of these and related embodiment be formulated to allow the active component that wherein contains and in particularly preferred embodiment separately or with simultaneously or successively and one or more antibiotic of using with any order (for example, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics and Aminopenicillin antibiotic or aminoglycoside antibiotics, for example amikacin or rifamycin) but the BT chemical compound as herein described of combination the preparation that contains BT chemical compound and/or antibiotic composition be locally applied to the acute or chronic wounds of experimenter and optional be biological utilisation when being applied to surrounding skin, described experimenter is for example mammal (comprising the people), and in some preferred embodiment, have acute or chronic wounds or be in the people patient of the increase risk (for example, obesity and/or diabetic individual) with acute or chronic wounds or wound biomembrane or wound cracking.Some embodiment expection local application BT chemical compound and antibiotic disclosed herein, comprising can be simultaneously or successively and using with any order, but the present invention is not intention so to be limited, and clearly expects in other embodiments the BT compound administration approach different with respect to antibiotic route of administration.Therefore, antibiotic can be used by oral, intravenous or any other route of administration as herein described, and the BT chemical compound can be used by the approach that is independent of the antibiotic administration approach.As nonrestrictive illustrative example, the BT chemical compound can carry out local application such as this paper with providing, and antibiotic can be simultaneously or successively (and with any order) use for example oral, intravenous, transdermal, subcutaneous, intramuscular and/or by any other route of administration by different approaches.
The antibacterial of topical formulations delivery treatments effective dose as herein described or Wound-healing agent (with antibiotic randomly) be to wound location, for example to Skin Cell dermal fibroblast for example.Preferred preparation can contact by spraying, wash, flood and/or smearing with the position of expecting, the position of described expectation is local wound position, chronic wounds, epithelial tissue surface or other expection site of administration for example; Therefore, this type of preparation can show the permeability of preparing to enter skin, this can determine according to any one of many known methods of the percutaneous permeability for the testing drug compositions known in the art (referring to for example, Wagner etc., 2002 J.Invest.Dermatol.118:540, and the list of references of wherein quoting; Bronaugh etc., 1985 J.Pharm.Sci.74:64; Bosman etc., 1998 J.Pharm.Biomed.Anal.17:493-499; Bosman etc., 1996 J.Pharm Biomed Anal.199614:1015-23; Bonferoni etc., 1999 Pharm.Dev.Technol.4:45-53; Frantz, Instrumentation and methodology in vitro skin diffusion cells in methodology for skin absorption.In:Methods for Skin Absorption (Kemppainen and Reifenrath edit), CRC Press, Florida, 1990, the 35-59 pages or leaves; Tojo, Design and calibration of in vitro permeation apparatus.In:Transdermal Controlled Systemic Medications (Chien YW, Ed), Marcel Dekker, New York, 1987,127-158; Barry, Methods for studying percutaneous absorption.In:Dermatological Formulations:Percutaneous absorption, Marcel Dekker, New York, 1983,234-295).
The preparation that will be applied to the compositions of experimenter or patient skin and comprise this compositions can be taked the form of one or more dosage units in certain embodiments, wherein for example liquid filling capsule or ampoule can contain single dosage unit, and the container of the topical formulations as herein described of aerosol form can contain a plurality of dosage units.The practical methods for preparing this type of dosage form is known, perhaps is apparent for those skilled in the art; For example referring to The Science and Practice of Pharmacy, the 20th edition (Philadelphia College of Pharmacy and Science, 2000).According to this instruction, compositions to be administered or preparation under any circumstance will contain antibacterial provided herein and/or the wound healing for the treatment of effective dose and promote chemical compound (for example BT chemical compound) or its pharmaceutically acceptable salt.
As mentioned above, this local preparation can adopt any of various ways, and comprises such as ointment, lotion, solution, spray, gel, ointment, paste etc., and/or can be prepared as and contain liposome, micelle and/or microsphere.Referring to for example U.S. Patent No. 7,205,003.For example, know such as pharmaceutical preparation and cosmeceutical formulation art, ointment is oil-in-water or water in oil viscous liquid or semi-solid Emulsion.Ointment substrate can be washed, and contains oil phase, emulsifying agent and water.Oil phase also is called " interior " phase, and generally for example spermol or octadecanol consist of by vaseline and aliphatic alcohol.Water usually but must surpass the volume of oil phase, and generally contains humidizer.Emulsifying agent in the ointment preparation generally is nonionic, anion, cation or amphoteric surfactant.
Lotion is preferred for delivery of cosmetic, is without the preparation of friction applications to skin surface, and normally liquid or semi-liquid preparations, and wherein solids (comprising active component) are present in water or the pure substrate.Lotion is solid suspension normally, and preferably includes the liquid oiliness Emulsion of oil-in-water type.Lotion is the preferred formulation that this paper is used for the treatment of larger body region, because use easily more fluid composition.Generally preferably, the insoluble matter in the lotion is in small, broken bits.Lotion contains suspending agent usually to produce better dispersion and the chemical compound that is used for concentrating and keeping activating agent and contact skin, described suspending agent such as methylcellulose, sodium carboxymethyl cellulose etc.
Solution is by one or more chemical substances (solute) are dissolved in liquid so that the material of dissolving is scattered in the homogeneous mixture for preparing in the solvent.Solution can contain other pharmaceutically acceptable and/or cosmeceutical learns upper acceptable chemicals with buffering, stable or preserve solute.The common example of the solvent that uses during preparation solution has ethanol, water, propylene glycol or any other pharmaceutically acceptable and/or upper acceptable vehicle of cosmeceutical.
Gel is system semi-solid, the suspension type.Single-phase gels contains the organic macromolecule that basically is uniformly distributed in the carrier liquid, and described carrier liquid is aqueous normally, but also preferably contains pure and mild optional oil.Preferably " organic macromolecule " is gellant, 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 BDA00002178874500551
Trade mark obtains.In certain embodiments can also preferred hydrophilic polymer, for example poly(ethylene oxide), Pluronic F68 and polyvinyl alcohol; Cellulosic polymer, for example hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, hydroxypropylmethyl cellulose phthalate and methylcellulose; Natural gum, for example Tragacanth and xanthan gum; Sodium alginate; And gelatin.In order to prepare even gel, can add dispersant for example ethanol or glycerol, perhaps gellant can make up to disperse by grinding, mechanical mixture or stirring or its.
As known in the art, ointment is semi-solid 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 vehicle, 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 or leaf explain that 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 emulsifying ointment base also is called the absorbability ointment base, contains seldom water or not moisture, and comprises for example Oxystearin sulfate (hydroxystearin sulfate), anhydrous lanolin 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 spermol, glyceryl monostearate, lanoline and stearic acid.Preferred Fend A-2 substrate 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 the suitable substrate.According to medium property, the paste that paste is divided into fatty paste or is made by the single-phase water gel.Substrate in the fat paste generally is vaseline or hydrophilic petrolatum etc.The paste of being made by the single-phase water gel generally adds carboxymethyl cellulose etc. as substrate.
Preparation can also be used liposome, micelle and microsphere preparation.Liposome is to have the microsphere folliculus that one (monolayer) or a plurality of (multilamellars) comprises the lipid wall of double-layer of lipoid, and in this environment, can seal and/or adsorb one or more components of topical formulations as herein described to its lipid film surface, described component is antibiotic, wound healing/skin histology/epithelial tissue repairing accelerant chemical compound (for example particles B T chemical compound is optional with one or more 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 to obtain easily.For example, N[1,2,3-, two oleyl oxygen bases) propyl group]-N, N, N-triethyl ammonium (DOTMA) liposome can trade name
Figure BDA00002178874500561
(GIBCO BRL, Grand Island, N.Y.) obtains.Similarly, anion and neutral fat plastid also obtain from for example Avanti Polar Lipids (Birmingham, AL) easily, perhaps can easily use the material preparation of easy acquisition.This material comprises phosphatidylcholine, 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.
Micelle known in the art be to comprise being arranged so that its polar head-group forms outside spherical shell the hydrophobicity hydrocarbon chain towards the surfactant molecule of ball center's (formation core).Micelle is containing concentrated surfactant so that form in the aqueous solution of the natural generation of micelle.The surfactant that is used to form micelle includes but not limited to potassium laurate, perfluorooctane sulfonate, decane sodium sulfonate, dodecane sulfonic acid sodium, sodium lauryl sulfate, docusate sodium, DTAB, Dodecyl trimethyl ammonium chloride, Tetradecyl Trimethyl Ammonium Bromide, tetradecyl trimethyl ammonium chloride, lauryl ammonium chloride, PEG-8 lauryl ether, Polyethylene Glycol-12 lauryl ether, nonoxinol 10 and nonoxinol 30.
Similarly, microsphere can add in the topical formulations as herein described.The same with liposome and micelle, microsphere has been sealed one or more components of preparation of the present invention basically.They generally but not necessarily by lipid, preferred charged lipids for example phospholipid 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 the topical formulations.For example, solvent (alcohol that comprises relative a small amount of) can be used for some formulation components of solubilising.For some topical formulations or after the skin injury of especially severe is for example performed the operation after acute or chronic wounds or the operation in the situation of dermal wounds cracking, may be desirably in and comprise the dermal osmosis accelerator that makes an addition in the preparation in the topical formulations.The example of suitable promoter includes but not limited to ether, and for example diethylene glycol monoethyl ether (can
Figure BDA00002178874500562
Through being purchased acquisition) and diethylene glycol monomethyl ether; Surfactant for example sodium laurate, sodium lauryl sulfate, cetyl trimethyl ammonium bromide, benzalkonium chloride,
Figure BDA00002178874500563
(231,182,184),
Figure BDA00002178874500564
(20,40,60,80) and lecithin (United States Patent (USP) the 4th, 783, No. 450); Alcohol, such as ethanol, propanol, capryl alcohol, benzylalcohol etc.; Polyethylene Glycol and ester thereof, for example polyethylene glycol monolaurate (PEGML; Referring to for example, U.S. Patent No. 4,568,343); Amide and other nitrogen-containing compound, for example urea, dimethyl acetylamide (DMA), dimethyl formamide (DMF), 2-Pyrrolidone, 1-Methyl-2-Pyrrolidone, ethanolamine, diethanolamine and triethanolamine; Terpene; Alkyl ketone; And organic acid, particularly citric acid and succinic acid.Can also use
Figure BDA00002178874500571
And sulfoxide, for example DMSO and C 10MSO, but more not preferred.
Most preferred dermal osmosis accelerator is commonly referred to as those lipotropy secondary accelerators (coenhancer) of " plasticising (plasticizing) " promoter, that is, have the molecular weight of about 150 to 1000 dalton's scopes, less than about 1wt%, preferably less than about 0.5wt% and most preferably less than the promoter of the water solubility of about 0.2wt%.The Hildebrand solubility parameter scope about 2.5 of plasticising promoter is to about 10, preferable range about 5 to about 10.Preferred lipotropy promoter is fatty ester, aliphatic alcohol and aliphatic ether.Example concrete and most preferred fatty acid ester comprises methyl laurate, ethyl oleate, PGML, propylene glycol dilaurate, glyceryl monolaurate, glycerin mono-fatty acid ester, n-capric acid isopropyl ester and octyl dodecyl myristate.Aliphatic alcohol comprises for example octadecanol and oleyl alcohol, and aliphatic ether comprises wherein glycol or triol, preferred C 2-C 4The chemical compound that alkane glycol or triol are replaced by one or two aliphatic ether substituent group.Other dermal osmosis accelerator is that the localized drug delivery those skilled in the art are known, and/or is described in the pertinent literature.Edit referring to for example Percutaneous Penetration Enhancers.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, spice, antiseptic, softening agent, pigment, dyestuff, humidizer, propellant and sunscreen with and to exist can be that beauty treatment is upper, medically or other material classification of other side needs.The representative instance of optional additive of preparation that is included in certain embodiments of the present invention is as follows: antiseptic, for example sorbate; Solvent, for example isopropyl alcohol and propylene glycol; Astringent, for example methanol and ethanol; Softening agent, for example polyalkylene methyl glucosamine; Humidizer, for example glycerol; Emulsifying agent, for example tristerin, PEG-100 stearate, polyglycereol-3 hydroxyl lauryl ether and polysorbate 60; Sorbitol and other polyhydroxy-alcohol be Polyethylene Glycol for example; Sunscreen, for example octyl methoxycinnamate (can be used as Parsol MCX through being purchased acquisition) and Uvinul BMBM (can trade name Parsol 1789 obtain); Antioxidant, for example ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), betatocopherol, Gamma-Tocopherol, Delta-Tocopherol, ε-tocopherol, ζ 1-tocopherol, ζ 2-tocopherol, η-tocopherol and retinol (vitamin A); Quintessence oil, ceramide, essential fatty acid, mineral oil, wetting agent and other surfactant for example can be available from BASF's (Mt.Olive, NJ)
Figure BDA00002178874500572
The hydrophilic polymer of series, vegetable oil are (for example, the liquid fraction of soybean oil, Petiolus Trachycarpi oil, shea butter, sunflower oil), animal oil (for example, perhydro-squalene), mineral oil, artificial oil, silicone oil or wax are (for example, cyclomethicone and simethicone), fluorinated oil (generally being PFPE), aliphatic alcohol (for example, spermol) and wax (for example, Cera Flava, Brazil wax and paraffin); The dermal sensation regulator; And thickening agent and structural agent (structurants), for example expansive clay and crosslinked carboxyl polyalkylene (carboxypolyalkylene) can Trade mark is through being purchased acquisition.
Other additive comprises benefit materials, and for example conditioning skin (particularly upper layers of skin in the horny layer) also reduces those materials that keep the skin softness and/or protect skin by postponing its water content.This conditioner and humidizer comprise for example pyrrolidine carboxylic acid and aminoacid; Organic antimicrobial, for example 2,4,4 '-three chloro-2-dihydroxy diphenyl ether (triclosan) and benzoic acid; Antiinflammatory, for example aspirin and glycyrrhetinic acid; Antiseborrheic, for example tretinoin; Vasodilation, for example nicotinic acid; Melanogenesis inhibitor, for example kojic acid; And composition thereof.The cosmeceutical 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 tocopherol, for example above-mentioned those, and the upper acceptable salt of retinol (vitamin A) and/or its beauty treatment, ester, amide or other derivant.Other cosmetics agent comprises those that can improve oxygen supply in the skin histology, for example described in WO 94/00098 and the WO 94/00109.Can also comprise sunscreen.
Other embodiment can comprise healing material non-carcinogenic, non-stimulation of multiple promotion certain embodiments of the present invention preparation for treating.This type of healing material can comprise nutrient, mineral, vitamin, electrolyte, enzyme, medical herbs, plant extract, Mel, body of gland or animal extracts, maybe can be added into preparation to promote the safe treatment agent of corium healing.The amount of these various additives is the conventional amounts used of cosmetic field, and scope is for example from about 0.01% to about 20% of topical formulations gross weight.
The preparation of certain embodiments of the present invention can also comprise conventional additives, such as opacifier, aromatic, coloring agent, gellant, thickening agent, 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 mycete of microorganism.The antimicrobial that is fit to is selected from methyl ester and propyl ester (for example, methyl butex and propyl ester), sodium benzoate, sorbic acid, miaow urea (imidurea) and the combination thereof of P-hydroxybenzoic acid usually.Said preparation can also contain abirritant additive, so that the minimizing possibility of skin irritation or skin injury or elimination, described skin irritation or skin injury are acute by anti-infection property to be administered or chronic wounds healing and promote the skin tissue recovering chemical compound to cause, or caused by other component of compositions.The abirritant additive that is fit to for example comprises: alpha-tocopherol; Oxidase inhibitor, particularly phenyl alcohol, for example 2-phenyl-1-ethanol; Glycerol; Salicylate; Ascorbate; Ionophore, for example monensin; Amphipathic amine; Ammonium chloride; N-acetylcystein; Capsaicin; And chloroquine.If abirritant additive exists, the effective concentration of abirritate or skin injury adding topical formulations usually accounts for the about 20wt% of being no more than of preparation, more generally is no more than about 5wt%.
Except antibiotic/wound healing/antibiont film/promotion skin tissue recovering chemical compound (for example, the BT chemical compound, be preferably basically uniform microgranule provided herein, choose wantonly and one or more collaborative antibiotic combinations as herein described) in addition, topical formulations can also contain other pharmacologically active agents of one or more suitable local applications for the treatment of effective dose.This material can comprise the asymmetric stratiform aggregation that is comprised of phospholipid and oxygen load fluorocarbon or fluorocarbon mixture, it can improve the oxygen supply of skin histology, for example described in international patent publications No.WO 94/00098 and the WO 94/00109.
Can add this local preparation and therefore the pharmacologically active agents that is fit to of topical application can include but not limited to following: improve or eradicate material painted or non-staining senile plaque, cutin and wrinkle; Antimicrobial; Antibacterial; Pruritus and drying retarder; Antiinflammatory; Local anesthetic and analgesics; 17-hydroxy-11-dehydrocorticosterone; Retinoid (for example, tretinoin); Vitamin; Hormone and antimetabolite.Some examples of local pharmacologically active agents comprise acyclovir, amphotericin, chlorhexidine, clotrimazole, ketoconazole, econazole, miconazole, metronidazole, minocycline, nystatin, neomycin, kanamycin, phenytoin, p-aminobenzoate, octyl methoxycinnamate, ethylhexyl salicylate, oxybenzone, dioxybenzone, tocopherol, tocopherol acetas, selenium sulfide (selenium sulfide), pyrithione zinc (zinc pyrithione), diphenhydramine, pramocaine (pramoxine), lignocaine, procaine, erythromycin, tetracycline, clindamycin, crotamiton, hydroquinone and monomethyl thereof and benzylic ether, naproxen, ibuprofen, sodium cromoglicate, tretinoin, retinol, retinyl palmitate, retinol acetate, coal tar, griseofulvin, estradiol, hydrocortisone, hydrocortisone 21-acetas, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, Progesterone, betamethasone valerate, betamethasone dipropionate, triamcinolone acetonide, fluocinonide, clobetasol propionate, minoxidil, dipyridamole, diphenyl hydantoin, benzoyl peroxide and 5-fluorouracil.Also as mentioned above, some embodiment is expected at and adds antibiotic in the preparation, for example carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics, Aminopenicillin antibiotic or aminoglycoside antibiotics, for example amikacin.
The upper acceptable carrier of pharmacology also can add in the topical formulations of some embodiment of the present invention, and can be the conventional any carrier that uses in this area.Example comprises water, lower alcohol, higher alcohol, Mel, polyhydroxy-alcohol, monosaccharide, disaccharide, polysaccharide, sugar alcohol, for example glycol (2-carbon), triol (3-carbon), erythritol and threitol (4-carbon), arabitol, xylitol and ribitol (5-carbon), mannitol, Sorbitol, galactitol and iditol (6-carbon), 3-hydroxy-2-furyl methyl ketone., maltose alcohol, lactose and polysaccharide polyol, hydrocarbon ils, fatty and oily, wax, fatty acid, silicone oil, nonionic surfactant, ionic surfactant, silicone surfactant and examples of such carriers based on the mixture of water and the mixture of emulsion-based.
Topical formulations embodiment of the present invention can routine be applied to any acute or chronic wounds position (for example wound itself and surrounding tissue; comprise as if uninfection impact or in the normal or healthy surrounding tissue of other side) or skin area or other epithelial tissue surface (for example gastrointestinal tract, respiratory tract, glandular tissue), need to be to realize the necessary frequency of expected results and amount treatment.Therapeutic frequency depends on the character of skin (or other epithelial tissue), situation (for example, acute or chronic wounds or for example may have other skin wound in the cracking that is caused by operative incision, or the skin wound of other type), skin (or other tissue) damage or the degree that worsens, the responsiveness of user skin (or other tissue), active component (for example in the specific embodiments, wound healing as herein described/antibiotic/antibiont film/promotion skin tissue recovering chemical compound, for example BT chemical compound and one or more optional other pharmacy activity components, for example antibiotic, for example amikacin or other antibiotic) intensity, be used for delivering active ingredients and enter the suitable skin layer effect of (or other contains the tissue of epithelial surface), by removing the easiness of preparation or or removal that external fluid cause inherent by sweat or other with the physical contact of binder or other dressing or cover, and to the convenience of experimenter or patient's activity level or life cycle.
For example the typical concentration scope of the active substance of BT chemical compound as herein described, antibiotic/antibiont film/wound healing/promotion skin tissue recovering chemical compound can be that about 0.001-30% weight of for example composition total weight is to about 0.01-5.0% and more preferably about 0.1-2.0% extremely.As a representative example, the compositions of these embodiments of the present invention can equal about 1.0mg/cm 2Skin is to about 20.0mg/cm 2The speed of skin is applied to acute or chronic wounds and/or skin.The representative example of topical formulations includes but not limited to aerosol, alcohol, anhydrous substrate (for example lip pomade and powder), aqueous solution, ointment, Emulsion (comprising Water-In-Oil or oil in water emulsion), fat, foam, gel, water-alcohol solution, liposome, lotion, microemulsion, ointment, oil, organic solvent, polyhydric alcohol, polymer, powder, salt, silicone derivative and wax.Topical formulations can comprise for example chelating agen, conditioner, softening agent, excipient, humidizer, protective agent, thickening agent 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 agen can be chosen wantonly and be included in the topical formulations, and can be selected from any material that is applicable to cosmetic composition, and the ability that can include is 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 agen includes but not limited to EDTA, EDETATE SODIUM, EGTA, citric acid and dicarboxylic acids.
Conditioner also can randomly be included in the topical formulations.The example of skin conditioning agent includes but not limited to acetylcysteine, N-acetyl dihydrosphingosine, acrylate/acrylic acid Shan Yu ester/polydimethylsiloxane acrylate copolymer, adenosine, ring gland glycosides phosphoric acid, adenylic acid, adenosine triphosphate, alanine, albumin, Sargassum extract, allantoin and derivant, aloe vera extract, PCA aluminum (aluminum PCA), amyloglucosidase, arbutin, arginine, azulenes, bromelain, buttermilk powder, butanediol, caffeine, calcium gluconate, capsaicin, Loviscol, carnosine, beta-carotene, casein, catalase, cephalin, ceramide, Flos Matricariae chamomillae (chamomilla recutita) flower extract, cholecalciferol, cholesterol ester, cocoyl-betanin, coenzyme A, modified corn starch, crystalline protein, the ring ethyoxyl polymethyl siloxane, cysteine DNA, cytochrome C darutoside (darutoside), dextran sulfate, dimethicone copolyol, dimethyl-silicon alkanol hyaluronic acid ester, DNA, elastin laminin, elastin laminin aminoacid, epidermal growth factor, ergocalciferol, ergosterol, the PCA Octyl Nitrite, fibronectin, folic acid, gelatin, gliadin, beta glucan, glucose, glycine, glycogen, glycolipid, glycoprotein, glycosaminoglycans, glycosphingolipid, horseradish peroxidase, hydrogenation albumen, hydrolyzed protein, Jojoba oil, keratin, keratin aminoacid and kinetins, lactoferrin, lanosterol, the PCA lauryl, lecithin, linoleic acid, linolenic acid, lipase, lysine, lysozyme, malt extract, maltodextrin, melanocyte, methionine, rock salt, nicotinic acid, nicotiamide, Herba bromi japonici aminoacid, oryzanol, the palmityl hydrolyzed protein, pancreatin, papain, PEG, pepsin, phospholipid, plant sterol, the Placenta Hominis enzyme, Placental Lipids, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate ester, Tricetin, resorcinol acetas (resorcinol acetate), riboflavin, RNA, yeast lysate extract, Silk Amino Acids, sphingolipid, the amino CAB of stearoyl, the stearoyl cetylate, tocopherol, tocopherol acetas, Vitamin E linoleate, ubiquinone, Fructus Vitis viniferae (vitis vinifera) seed oil, Semen Tritici aestivi aminoacid, Xanthan gum and zinc gluconate.Can easily understand such as those skilled in the art, be different from preparation combination that above-listed those skin conditioning agent can provide with disclosed compositions or by it.
Topical formulations can also be chosen wantonly and 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, Sargassum extract, aloe vera extract or gel, the Althaea officinalis L. extract, starch octenyl succinate anhydride, aluminium stearate, Fructus Pruni (prunus armeniaca) core oil, arginine, arginine aspartate, the arnica montana extract, ascorbic acid, ascorbyl palmitate, aspartic acid, cheese pears (persea gratissima) oil, barium sulfate, barrier sphingolipid (barrier sphingolipid), butanols, Cera Flava behenyl alcohol, cupreol, BHT, birch (Betula platyphylla Suk.) bark extract, borage (borago officinalis) extract, 2-bromo-2-nitropropane-1, the 3-glycol, butchers broom (ruscus aculeatus) extract, butanediol, Calendula officinalis extract, calendula oil, the wax Radix Euphorbiae Pekinensis (euphorbia cerifera) wax, Canola oil, the caprylic/capric triglyceride, Elettaria cardamomum (L.) Maton (elettaria cardamomum) oil, babassu (copernicia cerifera) wax, carrageenin (chondrus crispus), Radix Dauci Sativae (daucus carota sativa) oil, Semen Ricini (ricinus communis) oil, ceramide, ceresine, ceteareth-5, ceteareth-12, ceteareth-20, the cetearyl alcohol caprylate, spermol polyethers-20, spermol polyethers-24, cetyl acetate, the spermol caprylate, the spermol cetylate, Anthemis nobilis (anthemis nobilis) oil, cholesterol, cholesterol ester, Cholesteryl hydroxystearate, citric acid, Salvia sclarea (salvia sclarea) oil, cocoa (theobroma cacao) fat, cocoyl-caprylate/decanoin, Cortex cocois radicis (cocos nucifera) oil, collagen, collagen amino acid, Semen Maydis (zea mays) oil, fatty acid, decyl oleate, dextrin, diazolidinylurea (diazolidinyl urea), dimethicone copolyol, dimethiconol, dioctyl adipate, dioctyl succinate, dipentaerythritol six caprylates/six decanoins, DMDM Hydantoin, DNA, erythritol, the ethyoxyl diethylene glycol, Ethyl linoleate, Eucalyptus Globulus oil, Radix Oenotherae erythrosepalae (Oenothera biennis) oil, fatty acid, tructose, gelatin, shametace oil, glycosamine, the glucose glutamate, glutamic acid, glycerin polyether-26, glycerol, glycerol, distearin, hydroxy stearic acid glyceride, glyceryl laurate ester, glyceryl linoleate, myristin, olein, tristerin, tristerin SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycans, Fructus Vitis viniferae (vitis vinifera) seed oil, Semen coryli heterophyllae (corylus americana) oil, Semen coryli heterophyllae (corylus avellana) macadamia nut oil, hexanediol, Mel, hyaluronic acid, Flos Carthami (carthamus tinctohus) oil, castor oil hydrogenated, the hydrogenation glyceryl cocoate, 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 glycosaminoglycans, hydrolysis of keratin, hydrolyzed soybean protein, hydroxylated lanolin, hydroxyproline, imidazolidinyl urea, iodine propilolic alcohol butyl mephenesin Carbamate, iso-spermaceti ester alcohol stearic acid, different spermol stearoyl stearate, Ceraphyl 140A, 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, zostera marina, candlenut tree (aleurites moluccana) oil, lactamide MEA, lanolin alcohol polyethers-16, lanolin alcohol polyethers-10 acetas, lanoline, lanoceric acid, lanolin alcohol, lanolin oil, lanolin wax, lavandula angustifolia (lavandula angustifolia) oil, lecithin, Fructus Citri Limoniae (citrus medica limonum) oil, linoleic acid, linolenic acid, macadimia nut oil, magnesium stearate, magnesium sulfate, maltose alcohol, Flos Matricariae chamomillae (chamomilla recutita) oil, Glucate SS, methyl-monosilane alcohol PCA ester, microwax, mineral oil, ermine oil, Mortierella oil, Tetradecyl lactate, myristyl myristate, the propanoic 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, ethylhexyl salicylate, octyl stearate, oleic acid, Fructus Canarii albi (olea europaea) oil, Citrus (citrus aurantium dulcis) oil, Petiolus Trachycarpi (olea europaea) oil, Palmic acid, pantethine, pantothenylol, DL-Pantyl Ethyl Ether, paraffin, PCA, peach (prunus persica) core oil, Semen arachidis hypogaeae (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 castor oil hydrogenated, Cremophor RH40, the PEG-60 castor oil hydrogenated, the PEG-20 Glucate SS, the full oleate of PEG-40 anhydrosorbitol, the PEG-5 soyasterol, the PEG-10 soyasterol, 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, Herba Menthae (mentha piperita) oil, vaseline, phospholipid, polyamino sugar condensation substance, polyglycereol-3 diisopstearate, polyquaternary ammonium salt-24, polysorbate 20, polysorbate 40, polysorbate 60, polyoxyethylene sorbitan monoleate, polysorbate 85, myristic acid potassium, potassium palmitate, potassium sorbate, potassium stearate, propylene glycol, propylene glycol dicaprylate/dicaprate, the propylene glycol dicaprylate, propylene glycol dipelargonate, the propylene glycol laurate, propylene glycol stearate, propylene glycol stearate SE, PVP, the pyridoxin dipalmitate, quaternary ammonium salt-15, quaternary ammonium salt-18 Strese Hofmann's hectorite., quaternary ammonium salt-22, retinol, retinyl palmitate, rice (oryza sativa) Testa oryzae oil, RNA, Herba Rosmarini Officinalis (rosmarinus officinalis) oil, Oleum Rosae Rugosae, Flos Carthami (carthamus tinctorius) oil, Salvia japonica Thunb. (salvia officinalis) oil, salicylic acid, Lignum Santali Albi (santalum album) oil, serine, serum albumin, Semen Sesami (sesamum indicum) oil, shea butter (Butyrospermum), the silk powder, sodium chondroitin sulfate, DNA sodium, hyaluronate sodium, sodium lactate, sodium palmitate, Anjidew NL50, polyglutamic acid sodium, sodium stearate, soluble collagen, sorbic acid, sorbitan laurate, sorbitan oleate, sorbitan palmitate, the anhydrosorbitol sesquistearate, sorbitan stearate, Sorbitol, Semen sojae atricolor (glycine soja) oil, sphingolipid, squalane, 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, Prunus dulcis (prunus amygdalus dulcis) oil, synthetic bees wax, tocopherol, tocopherol acetas, Vitamin E linoleate San Shan Yu is smart, neopentanoic acid tridecyl ester, stearic acid tridecyl ester, triethanolamine, tristearin, urea, vegetable oil, water, wax, Semen Tritici aestivi (triticum vulgare) germ oil and fragrant cananga (cananga odorata) oil.
In some embodiments, topical formulations can contain suitable excipient, and it should have high-affinity to skin usually, and is well tolerable, and is stable, and produces the denseness that allows easy utilization.The topical vehicle that is fit to and vehicle can be come conventional selection according to special-purpose by those skilled in the art, and with particular reference to one of many received texts in this area, Remington ' s Pharmaceutical Sciences for example, the 18th volume, Mack Publishing Co., Easton, Pa. (1990), particularly the 87th chapter.Randomly, one or more humidizers are also included within the topical formulations.The example of humidizer includes but not limited to aminoacid, chondroitin sulfate, diglycerol, erythritol, fructose, glucose, glycerol, glycerol, ethylene glycol, 1,2,6-hexanetriol, Mel, hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysates, inositol, lactose, maltose alcohol, maltose, mannitol, nature moisturizing factor, the PEG-15 butanediol, polyglycereol Sorbitol (polyglyceryl sorbitol), pyrrolidone carboxylic acid salt, PCA potassium, propylene glycol, D-Glucuronic acid sodium salt, Anjidew NL50, Sorbitol, sucrose, trehalose, urea and xylitol.
Some embodiment expection comprises the topical formulations of one or more other Derma-Guards.The example of Derma-Guard can include but not limited to Sargassum extract, allantoin, aluminium hydroxide, aluminum sulfate, betanin, Folium Camelliae sinensis extract, cerebroside, simethicone, glucuronolactone, glycerol, Kaolin, lanoline, malt extract, mineral oil, vaseline, potassium gluconate and Talcum.Those skilled in the art should be easily understood that, being different from above-listed those Derma-Guard can also be with compositions disclosed by the invention or by its preparation combination that provides.
Surfactant is also expected to be included in some topical formulations 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 ﹠amp; 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, diamidogen 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, sulfate, phosphate ester and polyphosphate; Alkyl phosphate; Monoalkyl phosphoric acid esters (MAP); With perfluorocarboxylic acid salt.The example of zwitterionic surfactant include but not limited to cocoamido propyl hydroxy sulfobetaine (CAPHS) and be the pH sensitivity and other material that in the suitable pH of design preparation, need SC (namely, alkyl aminopropionic acid, imidazoline carboxylate and betanin) 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 BDA00002178874500641
One or more members' of series (BASF, Mt.Olive, NJ) material is to reduce the gathering of BT microgranule in the microparticle suspending liquid.Any surface activity combination is acceptable.Some embodiment can comprise at least a anionic surfactant and a kind of cationic surface active agent, perhaps at least a cationic surface active agent and a kind of amphoteric surfactant, they are compatible, namely do not form the complex of obvious sediment when mixing.
The example that can also be present in the thickening agent in some topical formulations includes but not limited to acrylamide copolymer, agarose, amylopectin, bentonite, calcium alginate, carboxymethylcellulose calcium, carbomer, carboxymethyl chitin, carboxymethyl cellulose (cellulose gum), dextrin, gelatin, hydrogenated tallow, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl starch, alginic acid magnesium, methylcellulose, microcrystalline Cellulose, pectin, various PEG ' s, polyacrylic acid, polymethylacrylic acid, polyvinyl alcohol, various PPG ' s, sodium acrylate copolymer, chondrus ocellatus Holmes polysaccharide sodium, Xanthan gum and yeast beta-dextran.Being different from above-listed those thickening agent also can be used in embodiment of the present invention.
According to some embodiment of this paper expection, topical formulations can comprise one or more sunscreen or UV absorbent.When needs ultraviolet-(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, Parsol 1789 and isopropyl benzyl salicylate, and composition thereof.It will be understood by those skilled in the art that being different from above-listed those sunscreen and UV absorbent or protective agent can be used in certain embodiments of the present invention.
Topical formulations disclosed herein usually about 2.5 between about 10.0 the pH value effectively.Preferably, the pH of compositions following pH scope or near: about pH 5.5 to about pH 8.5, about pH 5 to about pH 10, about pH 5 to about pH 9, about pH 5 to about pH 8, about pH 3 to about pH 10, about pH 3 to about pH 9, about pH 3 to about pH 8 and about pH 3 to about pH 8.5.Most preferably, pH is that about pH 7 is to about pH 8.Those of ordinary skills can add suitable pH regulator composition to the present composition to regulate pH to acceptable scope.The pH of " pact " appointment is interpreted as that by those skilled in the art the pH that comprises wherein at any given time actual measurement 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, thinks that wherein preparation forms and holding conditions can cause departing from of pH and original value.
Ointment, lotion, gel, ointment, paste etc. can spread upon affected surface and rub in lightly.Solution can be used 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 determine easily, and wound severity and to the responsiveness of initial treatment for example continues to carry out once a day or repeatedly uses but generally include.Those of ordinary skill can be determined optimised quantity, application process and the repetition rate of preparation to be administered easily.Generally speaking, consider these and related embodiment of the present invention preparation will 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, topical formulations used herein also comprises pharmaceutically acceptable carrier, comprises any suitable diluent or excipient, and it comprises any medicament harmless to the experimenter who accepts compositions and that can use without excessive toxicity itself.Pharmaceutically acceptable carrier includes but not limited to liquid, such as water, saline, glycerol and ethanol etc., and can comprise viscosifier (for example balsam fir resin) or film former for example colloid or cellulose nitrate cellulose solution.Comprehensive discussion of pharmaceutically acceptable carrier, diluent and other excipient is referring to REMINGTON ' S PHARMACEUTICAL SCIENCES (Mack Pub.Co., N.J. current edition).
When local preparation is gel or liquid filling capsule for example during the gelatine capsule form, it can also contain liquid-carrier for example Polyethylene Glycol or oil except the material of the above-mentioned type.No matter be solution, suspension or other similar type, the composition of liquid medicine of certain embodiments of the present invention can comprise following one or more: sterile diluent, for example water for injection, saline solution (preferred normal saline), Ringer's mixture, isotonic sodium chloride, can be used as fixed oil (for example synthetic monoglyceride or two glyceride), Polyethylene Glycol, glycerol, propylene glycol or other solvent of solvent or suspension media; Antibacterial, for example benzylalcohol or methyl butex; Other antioxidant, for example ascorbic acid or sodium sulfite; Chelating agen, for example ethylenediaminetetraacetic acid (EDTA); Buffer agent, for example for example sodium chloride or dextrose of acetate, citrate or phosphate and tension regulator.
For local application, carrier can suitably comprise solution, emulsion, ointment or gel-type vehicle.For example, substrate can comprise following one or more: vaseline, lecithin, Polyethylene Glycol, Cera Flava, mineral oil, diluent be water and ethanol for example, and emulsifying agent and stabilizing agent.Thickening agent may reside in the medicine or cosmeceutical composition of local application.If the expection transdermal administration, said composition can comprise transdermal patch or iontophoresis device.Topical formulations can contain the chemical compound of certain embodiments of the present invention of concentration about 0.1% to about 10%w/v (weight/unit volume).The forms such as topical formulations can ointment, lotion, solution, spray, gel, ointment, paste provide, and/or can contain liposome, micelle, microsphere and/or other microgranule or nanoparticle is sent component.Can also the delay time form of release or sustained-release granular formulation or pellet of topical formulations provides, and the ethylene vinyl acetate polymer that for example slowly discharges (for example, 40, Aldrich, Milwaukee, WI) pellet, it can directly be applied to wound location.
Topical formulations can comprise that thereby being bonded to promotion skin tissue recovering chemical compound also assists it to be delivered to skin epithelial cell (for example, keratinocyte) and/or fibroblastic material.The material that is fit to that can play this effect comprises inclusion agents, for example cyclodextrin; Other material can comprise albumen or liposome.
The topical formulations of certain embodiments of the present invention can also can be used as the measurement unit form that aerosol uses and provide.The term aerosol is used for meaning many systems, and scope is from the system of colloidal nature to the system that is comprised of pressurized package.Sending can be by liquefaction or Compressed Gas, perhaps by distributing the pumping system that is fit to of active component.The aerosol of the chemical compound of certain embodiments of the present invention can be single-phase, two-phase or three-phase system are sent, with delivering active ingredients.Sending of aerosol comprises necessary container, activator, valve, sub-container etc., and they can form test kit together.Those skilled in the art need not the preferred aerosol that undo experimentation can be identified for topical formulations is delivered to skin or wound location.
Topical formulations can prepare by the method that pharmaceutical field is known.For example, expection as spray, lotion or irrigation be applied to wound location or skin pharmaceutical composition can by with BT as herein described antibiotic/wound healing/antibiont film/promotion skin tissue recovering chemical compound and sterile distilled water make up to form solution and prepare.Can add surfactant to promote the formation of homogeneous solution or suspension.Surfactant is and the chemical compound of antioxidant activity chemical compound noncovalent interaction to promote that chemical compound dissolves or evenly suspends in the aqueous delivery system.
The BT that is used for topical formulations is antibiotic/and wound healing/antibiont film/promotions skin tissue recovering chemical compound or its pharmaceutically acceptable salt use to treat effective dose, this will change according to many factors, comprise that the character (if relevant) of wound location, the activity of the concrete BT chemical compound that adopts (comprise and comprise or do not contain antibiotic in the preparation, for example aminoglycoside antibiotics, for example amikacin); The metabolic stability of chemical compound and action time length; Experimenter's age, body weight, health status, sex, skin type, immune state and diet; Mode of administration and time; Discharge rate; Drug regimen; The severity that needs the concrete skin wound of skin tissue recovering; With through subject experimenter.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).
Effective dosage ranges provided herein is not the restrictive and preferred dosage range of representative of intention.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 multiple dose or single dose through the time for every kind.Some preferred embodiment expection single application topical formulations every day.Generally speaking, in different embodiments, treatment can be begun by the smaller dose that is lower than the chemical compound optimal dose.After this, dosage is increased by a small margin, until be issued to optimum efficiency at described environment.
Topical formulations can use separately or with use for skin wound or for other treatment and/or the drug regimen of other related symptoms or paathogenic factor.For example, also as mentioned above, topical formulations can also comprise tretinoin.As another example, topical formulations can comprise that as herein described one or more promote the skin tissue recovering chemical compound, perhaps can comprise two or more these compounds with different cell wound repair activity.
The receiver of topical formulations as herein described can be any vertebrates, for example mammal.In the mammal, preferred receiver is the mammal of Primates (comprising people, ape and monkey), Artiodactyla (comprising horse, goat, cow, sheep, pig), Rodentia (comprising mice, rat, rabbit and hamster) and Carnivora (comprising cat and dog).In bird, preferred receiver is turkey, chicken and with other member of purpose.Most preferred receiver is the people, and particularly preferably is the people who has one or more acute or chronic wounds or contain biomembranous wound.
For topical application, preferably use the pharmaceutical composition of effective dose to the acute or chronic wounds of target region such as skin wound such as skin and/or risk zones (such as the wound cracking) etc., described pharmaceutical composition comprise according to the BT chemical compound of embodiment as herein described antibiotic/wound healing/antibiont film/promotion skin tissue recovering chemical compound.This amount will be used about 0.0001mg to the scope of the chemical compound of about 1g certain embodiments of the present invention each usually, and this depends on zone to be treated, wound severity (or severity of operative incision in the past or expection) and the local vectorial character that adopts.Preferred topical formulations is ointment or slow releasing pellet, and wherein every cc ointment base or pellet suspension use about active component of 0.001 to about 50mg.Pharmaceutical composition can be formulated as transdermal composition or transdermal delivery device (" paster ").Such composition comprises for example backing, reactive compound bank, controlling diaphragm, liner and contact adhesive.This type of transdermal patch can be used for providing continuous impulse, and sending of required chemical compound of the present invention perhaps is provided when requiring.
By adopting program known in the art, can prepare the compositions of some embodiment in order to provide the active component that is applied to after the patient fast, continues or postpones to discharge.Controlled release-drug delivery system comprises osmotic pump system and dissolution system, and it contains polymer-coated bank or drug-polymer matrix formulations.The example of controlled release system is referring to U.S. Patent No. 3,845, and 770 and 4,326,525 and P.J.Kuzma etc., Regional Anesthesia 22 (6): 543-551 (1997), it all incorporates this paper by reference into.
Optimal approach will depend on character and the severity of the condition of illness for the treatment of.Those skilled in the art also be familiar with to determine methods of use for topical application (spraying, emulsifiable paste, open applications, closed dressing, immersion, washing etc.), dosage form, suitable drug excipient with chemical compound is delivered in requisition for relevant other material of experimenter.
In this description, 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 " expression comprise and be limited to phrase " by ... form " afterwards any content.Therefore, phrase " by ... form " the listed component of indication is essential or compulsory, and cannot has other component." substantially by ... form " expression comprises listed any component after this phrase, and is 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 " the listed component of indication is 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, indicate in addition unless context is clear, 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.
Following embodiment is as way of example and non-limiting way is provided.
Embodiment
Embodiment 1
The preparation of BT chemical compound
Following BT chemical compound is according to the people's such as Domenico (U.S.RE37,793, U.S.6,248,371, U.S.6,086,921, U.S.6,380,248) method preparation or as the microgranule according to the synthetic schemes of hereinafter describing for BisEDT.For relatively, based on the stoichiometric ratio of the reactant that uses and the bismuth known tendency with sulfur-containing compound formation trivalent complex, shown the atom ratio with respect to single bismuth atom.Numeral in the 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)CPD 1B-1Bis-EDT(1:1)BiC2H4S2
2)CPD 1B-2Bis-EDT(1:1.5)BiC 3H 6S 3
3)CPD 1B-3Bis-EDT(1:1.5)BiC 3H 6S 3
4) (1:1.5) BiC of CPD 1C Bis-EDT (solubility Bi preparation) 3H 6S 3
5)CPD 2A Bis-Bal(1:1)BiC 3H 6S 2O
6)CPD 2B Bis-Bal(1:1.5)BiC 4.5H 9O 1.5S 3
7)CPD 3A Bis-Pyr(1:1.5)BiC 7.5H 6N 1.5O 1.5S 1.5
8)CPD 3B Bis-Pyr(1:3)BiC 15H 12N 3O 3S 3
9)CPD 4Bis-Ery(1:1.5)BiC 6H 12O 3S 3
10)CPD 5Bis-Tol(1:1.5)BiC 10.5H 9S 3
11)CPD 6Bis-BDT(1:1.5)BiC 6H 12S 3
12)CPD 7Bis-PDT(1:1.5)BiC 4.5H 9S 3
13)CPD 8-1Bis-Pyr/BDT(1:1/1)
14)CPD 8-2Bis-Pyr/BDT(1:1/0.5)
15) CPD 9Bis-2 hydroxyl, propanethiol (1:3)
16)CPD 10Bis-Pyr/Bal(1:1/0.5)
17)CPD 11Bis-Pyr/EDT(1:1/0.5)
18)CPD 12Bis-Pyr/Tol(1:1/0.5)
19)CPD 13Bis-Pyr/PDT(1:1/0.5)
20)CPD 14Bis-Pyr/Ery(1:1/0.5)
21) CPD 15Bis-EDT/2 hydroxyl, propanethiol (1:1/1)
Microgranule bismuth-1，2-ethandithiol (Bis-EDT, soluble bismuth preparation) is prepared as follows:
The 5%HNO of excessive (11.4L) under stirring at room in the 15L polypropylene carboy 3Aqueous solution slowly drips the Bi (NO of 0.331L (~ 0.575 mole) 3) 3Aqueous 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 dehydrated 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 dehydrated alcohol, the 2-dithioglycol, then stir and prepared individually 1 in five minutes, the alcoholic solution of 2-dithioglycol (CAS 540-63-6) (~ 1.56L, ~ 0.55M).Then in 5 hours, 1，2-ethandithiol/EtOH is slowly dropped to Bi (NO 3) 3/ HNO 3Aqueous solution continues to stir and spends the night.Make the product sedimentation of generation be precipitation, continue about 15 minutes, use afterwards peristaltic pump to remove filtrate with 300mL/min.Then by in the buchner funnel of 15-cm diameter, collecting product in meticulous filter paper filtration, and use successively subsequently the ethanol, USP water of 500-mL volume and washing with acetone three times, to obtain the BisEDT (694.51gm/ mole) as yellow amorphous powder solid, shaped.Product put into 500mL amber glass bottle and under vacuum through CaCl 2Dry 48 hours.(output ~ 200g) gives out the mercaptan characteristic odor to recycled materials.Crude product is dissolved in the 750mL dehydrated alcohol again, stirred 30 minutes, then filter also and use successively 3 * 50mL ethanol, 2 * 50mL washing with acetone, and again use the 500mL washing with acetone.The powder of again washing is ground in 1M NaOH (500mL), filter, and with 3 * 220mL water, 2 * 50mL ethanol and 1 * 400mL washing with acetone, to obtain the pure BisEDT of 156.74gm.The productive rate that batch obtains subsequently about 78-91% for preparing in substantially the same mode.
By 1H and 13The data analysis of C nuclear magnetic resonance, NMR (NMR), infrared spectrum (IR), ultraviolet spectra (UV), mass spectrum (MS) and elementary analysis, product are accredited as has the structure shown in the following formula I.Develop a kind of HPLC method and measured the chemical purity of BisEDT, in DMSO, prepared thus sample (0.5mg/mL).By measuring λ at the DMSO solution of 190 to 600nm scanning BisEDT MaxAt room temperature carry out equal strength HPLC eluting with 1mL/min, mobile phase is acetonitrile: 0.1% formic acid in the water (9:1) has (λ at 265nm Max) the UV detector that detects, 2 μ L volume injected, is furnished with YMC PackPVC SilNP, 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, with the microgranule Eddy diffusion in 2%
Figure BDA00002178874500711
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) recommend to analyze according to the manufacturer.According to the cohersive and integrated data of twice measurement, microgranule shows Unimodal Distribution, and all detectable events are at about 0.6 micron to 4 microns volume mean diameter (VMD), and has peak VMD at about 1.3 microns.By contrast, when BisEDT by existing method (Domenico etc., 1997 Antimicrob.Agents Chemother.41 (8): in 1697-1703) when preparation, the heterogeneous dispersion of majority of particles and have significantly larger size has been got rid of them based on the evaluation of VMD.
Embodiment 2
The bacterium colony biological film model that chronic wounds infects:
Suppress by the BT chemical compound
Because the antibacterial that exists in the chronic wounds is adopted the biomembrane life style, use basically according to described method (Anderl etc., 2003 Antimicrob Agents Chemother 47:1251-56; Walters etc., 2003 Antimicrob Agents Chemother 47:317; Wentland etc., 1996 Biotchnol.Prog.12:316; Zheng etc., 2002 Antimicrob Agents Chemother 46:900) the biomembrane test b Ts of preparation is for the effect of biomembranous antibacterium cell survival.
In brief, the bacterium colony biomembrane 10% tryptic soy agar growth 24 hours, is then transferred to the Mueller Hinton plate that contains therapeutic agent.After the treatment, biomembrane is dispensed in the peptone water that contains 2%w/v glutathion (in and BT), and before the coated plate counting serial dilution to peptone water.Two kinds of antibacterials 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., 2003 Antimicrob Agents Chemother 47:1251-56 as described below; Walters etc., 2003 Antimicrob Agents Chemother 47:317; Wentland etc., 1996 Biotchnol.Prog.12:316; Zheng etc., 2002 Antimicrob Agents Chemother 46:900), the bacterial biof iotalm bacterium colony is grown on the microporous membrane top that agar plate leaves standstill.This bacterium colony biomembrane shows the many common feature of other biological membrane modle, and for example, they are comprised of the cell of assembling in the substrate of high degree of hydration.Also report (Brown etc., J Surg Res 56:562 such as other people; The people such as Millward, 1989 Microbios 58:155; Sutch etc., 1995 J Pharm Pharmacol 47:1094; Thrower etc., 1997 J Med Microbiol 46:425), find that the antibacterial in the bacterium colony biomembrane shows same significantly reduced antimicrobial sensitivity, 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: antibacterial has the Air Interface place growth of the nutrient supplied under the biomembrane and minimum flow velocity.Many nutrient sources are used for cultivating the bacterium colony biomembrane, comprise blood agar, but it is considered to nutritional condition in the analogue body.
The planktonic bacteria liquid culture that drips by the polycarbonate leaching film inoculation 5 μ l at the 25mm diameter prepares the bacterium colony biomembrane.This film was exposed to ultraviolet 10 minutes by every side and is sterilized before inoculation.With inoculum 37 ℃ of grow overnight in bacteria culture media, and before film precipitation, in fresh culture, be diluted under the 600nm 0.1 optical density.Then film is placed on the agar plate that contains growth medium.Then this plate is capped and is inverted in 37 ℃ of incubators.Per 24 hours, use aseptic nipper that film and bacterium colony biomembrane are transferred to new plate.The bacterium colony biomembrane is used for experiment in growth after 48 hours usually, and each film has about 10 at this moment 9Individual antibacterial.The bacterium colony Biofilm Environment successfully is used for cultivating many single strains and mixed bacteria biomembrane.
(for example, the BT chemical compound comprises the compositions of BT chemical compound in order to measure the combating microorganisms agent; Antibiotic and BT chemical compound-antibiotic composition) sensitivity, the bacterium colony biomembrane is transferred to the agar plate that has replenished the agent of candidate's antimicrobial therapy.The persistent period that wherein is exposed to antimicrobial therapy surpasses 24 hours, and be transferred to new treatment plate with the bacterium colony biomembrane every day.In the treatment end of term, the bacterium colony biomembrane is put into the pipe that contains the 10ml buffer and 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 with the cell suspending liquid serial dilution that obtains and coated plate with the antibacterial of counting survival, it is reported as 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 chemical compounds.Comprise BT and antibiotic tobramycin, amikacin, imipenum, cefazolin and the ciprofloxacin that is referred to herein as BisEDT and chemical 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 chemical 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 chemical compounds show the remarkable effect to the PA bacteria living, and two kinds of BT chemical compounds proofs under test concentrations to the remarkable effects of MRSA survival; 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 chemical compound 2B (for the PA test) and Fig. 2 for BT chemical compound 2B and 8-2 (testing for SA).Also as illustrated in fig. 1 and 2, with shown in antibiotic combinations shown in the adding of BT chemical compound cause synergism, the effect that reduces thus bacteria living with respect to independent antibiotic or separately the antibacterial action of BT chemical compound be enhanced.In the PA survival is measured, concentration is that the chemical compound 15 (Bis-EDT/2 hydroxyl, propanethiol (1:1/1)) of 80 μ g/mL 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:
Suppress by the BT chemical compound
The authoritative model that is used to form and tests the biomembranous effect of candidate's antimicrobial compound antibacterium that the representative of drip biomembrane is art-recognized.The drip biomembrane produces at the print (substrate) that goes that places the drip-flow reactor passage.Many dissimilar materials can be used as the film formed substrate of bacterium living beings, comprise the ground glass microscope slide.Then Nutrient broth flows along downward 10 gradients of coupongs major axis by splashing near the indoor drip bioreactor Cytology Lab that enters the top.
Biomembrane is grown in the drip bioreactor, and be exposed to separately or with the BT chemical compound of other antibacterial (comprising the BT chemical compound) combination and/or be exposed to separately or with the Antibiotique composition of other antibacterial combinations, perhaps be exposed to other routines or candidate therapeutic for chronic wounds.Therefore, identified the effect of BT chemical compound to bacterial biof iotalm in the drip-flow reactor.Biomembrane prepares (for example, Stewart etc., 2001 J Appl Microbiol.91:525 according to fixed method in the drip-flow reactor; Xu etc., 1998 Appl.Environ.Microbiol.64:4035).This design is included on the polystyrene coupongs that have a down dip in the covering chamber and cultivates biomembrane.Exemplary culture medium contains 1g/l glucose, 0.5g/l NH 4NO 3, 0.25g/l KCl, 0.25g/lKH 2PO 4, 0.25g/l MgSO 4-7H 2O has replenished adult's donor Ox blood serum (ph 6.8) of the serum of 5%v/v simulation rich in proteins, and the ferrum restrictive condition is similar in the body biofilm development condition in the chronic wounds for example.This culture 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 37 ℃ of incubators, and the bacterial cell culture medium is heated by making it to pass the aluminium radiator that keeps in the incubator.The method has produced the antibiotic resistance phenotype of observing in some biomembrane, the low fluid shearing environment of simulation and near the interface feature of chronic wounds, continuous nutritional supplementation is provided simultaneously, and compatible with the analytical method of many antibiotic scheme effects of candidate for the identification of introducing with monitoring.Drip-flow reactor successfully has been used for cultivating many pure and hybrid biomembranes.Biomembrane was grown 2 to 5 days before application of antimicrobial reagents usually.
In order to measure the biomembranous effect of antibiont membrane to growing in the drip-flow reactor, pass biomembranous flow and (for example be corrected or be supplemented with the treatment preparation that needs, one or more BT chemical 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.This sample uses Potter-Elvehjem Tissue Grinders rapid processing (common 30 seconds to 1 minute) with the disperse bacterial aggregation.Suspension microorganism to survive according to standard microorganism method counting by serial dilution and coated plate.
Embodiment 4
The wound biomembrane that the keratinocyte scratch is repaired suppresses:
Suppress biomembrane by the BT chemical compound
Present embodiment has been described the modification that the external keratinocyte of the wound healing of having determined is scraped wound model, has with biomembrane relevant wounds pathological changes and wound healing and particularly with acute or chronic wounds or contain the model of biomembranous wound dependency described herein to reach.Keratinocyte according to the effect of chronic wounds biomembrane is scraped wound model, independent indoor the carrying out that the cultivation of mammal (for example people) keratinocyte and bacterial biof iotalm colony is communicated with at mutual fluid affects the effect of condition of effect of the soluble component Human Keratinocytes wound healing event of biomembrane generation to allow assessment.
Newborn people's foreskin cell in the vinyl disc of processing as monolayer culture, wherein " wound " of monolayer control or scratch are by mechanical system (for example, by the physical damage of monolayer, for example by using for example acellular district of substantial linear between aseptic operation cutter, razor, cell scraper, tweezers or other instruments scraping monolayer district of suitable instrument) form.Known external keratinocyte single-layer model system responds injured event and stands cellularity and function course in the mode that stimulates the body internal injury healing.According to embodiment disclosed herein, observe the existence of bacterial biof iotalm to the impact of 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's antimicrobial (for example antibiotic and antibiont film) treatment.
The injured keratinocyte monolayer of in the presence of biomembrane, cultivating according to morphology, biochemistry, molecular genetics, cytophysiology and other parametric tests, whether change (for example, increase or reduce in the mode with respect to suitable contrast statistically significant) biomembranous detrimental effect with the introducing of determining the BT chemical compound.Wound at first is exposed to each independent BT chemical compound, and is exposed to the combination of the BT chemical compound of consideration, with the toxicity of every kind of BT compounds for treating of test before the effect that biomembrane is affected the model wound healing process in this type for the treatment of of assessment.
In representative embodiment, three days biomembranes (for example are incubated on the film that remains in the above-mentioned tissue culture hole, TransWell film inserts etc.) and with keratinocyte monolayer fluid be communicated with, the keratinocyte monolayer is scratched to begin wound healing process.The biomembrane of cultivating outside real acute or chronic wounds is considered for these and related embodiment.
Therefore, developed for assessment of the vitro system of solubility biomembrane component to the effect of the migration of people's keratinocyte and propagation.This system uses dialyzer separating bio film and keratinocyte.Keratinocyte is cultivated (Fleckman etc., 1997 J Invest.Dermatol.109:36 from newborn foreskin as previously mentioned; Piepkorn etc., 1987 J Invest.Dermatol.88:215-219) and at the glass cover slide be grown to confluent monolayer.Then, keratinocyte can be scratched to produce " wound " with homogeneous width, monitors subsequently cytothesis process (for example, Tao etc., 2007 PLoS ONE 2:e697; The 2007 Eur.J Cell Biol.86:747 such as Buth; The 2000 Ann.Acad.Med.Singapore 29:27 such as Phan).Then artificial wound is placed the bottom of aseptic bilateral chamber, and use aseptic 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 was cultivated 2 hours with the microbionation of wound separation and under static conditions, so that antibacterial can be attached to the surface in the chamber.After the setting stage, the fluid medium chamber of being flowing in begins to remove the cell that does not adhere to.Then media flow continues to minimize the upper indoor cell growth rate that swims, by washing the cell that does not adhere to off.After 6 to 48 hours culture period, system's (suprabasil bacterial biof iotalm of the keratinocyte on the coverslip and film) is decomposed, and takes out coverslip and analysis.In related embodiment, biofilm is being grown in upper chamber before the assembly chamber.In other related embodiment, biomembrane and scratch keratinocyte monolayer cultivate separately altogether one or more BT chemical compounds do not exist and in the presence of carry out, choose wantonly and comprise or get rid of one or more antibiotic, for example BT chemical compound or potential collaborative BT chemical compound+antibiotic combinations be (for example to measure candidate agent, BT chemical compound provided herein, the BT that for example provides with particulate form and following one or more: amikacin, the ampicillin, cefazolin, cefepime, chloromycetin, ciprofloxacin, clindamycin (or another kind of Lincoln's amide antibiotic), daptomycin
Figure BDA00002178874500761
Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid
Figure BDA00002178874500762
Minocycline, nafcillin, paromomycin, rifampicin, Sulfamethoxazole, tobramycin and vancomycin) effect that the keratinocyte of scratch is repaired, for example, (for example change to identify, increase or reduce in the statistically significant mode with respect to suitable contrast) at least one index of scratch healing for example the agent of wound repair time of carrying out or other wound repair indexs or agent combination (for example, Tao etc., 2007 PLoS ONE 2:e697; The 2007 Eur.J Cell Biol.86:747 such as Buth; The 2000 Ann.Acad.Med.Singapore 29:27 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, cultivate on coverslip the people's keratinocyte that separates and scratch.Injured culture is being remained on the film support that is communicated with the keratinocyte culture fluid separately or under the common biomembranous condition of culture of cultivating of existence.Then the scratch closing time interval that redefines the keratinocyte monolayer is distinguished in keratinocyte growth and/or migration between test period in scraping.Fig. 3 has described the biomembrane fluid and has been communicated with the existence of (but not being direct contact) to the effect of the healing time of scraping keratinocyte monolayer.
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 candidate's antibiont membrane exist lower, in the presence of bacterial biof iotalm cultivation scratch cell (for example keratinocyte or fibroblast) monolayer; And be evaluated at the healing index that there is not and exists lower scratch cell monolayer in candidate's antibiont membrane, (for example wherein promote the material of at least one healing index, the BT chemical compound, basically monodispersed BT microparticle suspending liquid 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, chloromycetin, ciprofloxacin, clindamycin, daptomycin
Figure BDA00002178874500771
Doxycycline, Gatifloxacin, gentamycin, imipenum, levofloxacin, Linezolid
Figure BDA00002178874500772
Minocycline, nafcillin, paromomycin, rifampicin, 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
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-resistant bacteria).
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) 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-A2 and Informational Supplement M100-S10.NCCLS in, Wayne, PA, USA).
In brief, prepare 0.5McFarland standard suspension with the bacterial cultures that spends the night, it further dilutes 1:50 (~ 2 * 10 in the Mueller-Hinton broth bouillon (BBL, Cockeysville, MD, USA) that cation is regulated 6Cfu/mL).Add BT (as above preparation) and antibiotic with progressive concentration, keep final volume constant in 0.2mL.Culture was hatched 24 hours at 37 ℃, assess turbidity by using ELISA to read plate device (Biotek Instruments, Winooski, VT, USA) according to the absorption that the manufacturer recommends to be used in 630nm.Minimal inhibitory concentration (MIC) is represented as and suppresses 24 hours lowest concentration of drug of growth.Measure live bacteria count (cfu/mL) by the standard coated plate on Nutrient agar.Smallest bacteria concentration (MBC) is expressed as the drug level that reduced initial viability 99.9% when hatching in 24 hours.
Assess the activity of antimicrobial combination with the chessboard method.According to (Eliopoulos and Moellering such as Eliopoulos, (1996) Antimicrobial combinations.Antibiotics in Laboratory Medicine (Lorian, V. edit), the 330-96 page or leaf, 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 Chemotherapy 52:1).Concertedness also is the minimizing of antibiotic concentration 〉=4 times by usual definition.
The results are shown in table 2-17.
Table 2
Staphylococcus aureus-nafcillin resistance
BE=0.2 μ g/ml BisEDT; Bacterial isolates is available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Nafcillin is available from Sigma (St.Louis, MO).
Table 3
Staphylococcus aureus-nafcillin resistance
BE=0.2 μ g/ml BisEDT; Bacterial isolates is available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Nafcillin is available from Sigma.
Table 4
Staphylococcus aureus
Rifampicin/neomycin/paromomycin
Figure BDA00002178874500791
BE=0.2 μ g/ml BisEDT; Bacterial strain S2446-3 is available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Antibiotic is available from Sigma.
Table 5
Staphylococcus epidermidis-GM resistance
Figure BDA00002178874500792
The GM=gentamycin; Bacterial strain S2400-1 is available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Gentamycin is available from the Pharmacy department of Winthrop; Concertedness is overstriking
Table 6
Staphylococcus epidermidis-S2400-1
The biomembrane prevention
Data represent 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 department of Winthrop.
Table 7
Staphylococcus epidermidis-S2400-1
MIC
Figure BDA00002178874500802
Data represent 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 department of Winthrop.
Table 8
Staphylococcus epidermidis-S2400-1
MBC
Figure BDA00002178874500811
Data represent 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 department of Winthrop.
Table 9
Staphylococcus epidermidis
ATCC 35984
MIC
Figure BDA00002178874500812
Data represent with μ g/ml; Antibiotic is available from the Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 10
Escherichia coli-ampicillin/chlorampenicol resistant
The AB=antibiotic; CM=chloromycetin; 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 the Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 11
Escherichia coli-tetracycline-resistance:
Doxycycline+BisEDT
Figure BDA00002178874500821
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 the Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 12
Pseudomonas aeruginosa-tobramycin-resistance:
The BisEDT concertedness
Figure BDA00002178874500822
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 the Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 13
Burkholderia cepacia
Tobramycin+BE concertedness
MIC
Figure BDA00002178874500831
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 the Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 14
Burkholderia cepacia
Tobramycin+BE concertedness
MBC
Figure BDA00002178874500832
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 department of Winthrop university hospital, Mineola, NY.
Table 15
The tobramycin resistant strain
MIC
Figure BDA00002178874500841
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 and Biochemistry, Laurentian University, Ontario, CN; (the M bacterial strain is the mucoid Burkholderia cepacia; The PA=Pseudomonas aeruginosa; The SA=staphylococcus aureus).Tobramycin is available from Pharmacy department of Winthrop university hospital, Mineola, NY.
Table 16
The tobramycin resistant strain
MBC
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 and Biochemistry, Laurentian University, Ontario, CN; (the M bacterial strain is the mucoid Burkholderia cepacia; The PA=Pseudomonas aeruginosa; The SA=staphylococcus aureus).Tobramycin is available from Pharmacy department of Winthrop university, Mineola, NY.
Table 17
BisEDT-PTO concertedness
Figure BDA00002178874500851
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-resistant bacteria bacterial strain
In the present embodiment, assessed BisEDT and compared agent for the external activity of 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; Ceftazidime (Sigma #C3809), 64-0.06 μ g/mL and 32-0.03 μ g/mL; Imipenum (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; Gentamycin (Sigma #G3632) 32-0.03 μ g/mL and 16-0.015 μ g/mL.Except gentamycin, all specimen are dissolved in DMSO; Gentamycin is dissolved in water.Stock solution prepares in test board to maximum concentration with 40 times.The final concentration of DMSO in test macro is 2.5%.
Microorganism.Test microbes is available from following clinical laboratory: 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 is separated in the agar culture medium line that is fit to separately microorganism.By swab picking colony and put into the suitable meat soup that contains cryoprotective agent 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-ethandithiol; LZD, Linezolid; DAP, daptomycin; VA, vancomycin; CAZ, ceftazidime; IPM, imipenum; CIP, ciprofloxacin; GM, gentamycin; 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 sensitivity enterococcus.
Separated strain is rule from cryovial to appropriate culture medium: trypticase soy agar (Becton-Dickinson, Sparks, MD) be used for most of microorganism, perhaps the trypticase soy agar adds 5% Blood In Sheep (Cleveland Scientific, Bath, OH) for streptococcus.With plate 35 ℃ of overnight incubation.Comprise the quality control microorganism.The culture medium that is used for MIC mensuration is Mueller Hinton II meat soup (MHB II-Becton Dickinson, #212322), is used for most of microorganism.MHB II has replenished the horse blood (Cleveland Scientific lot number H13913) of 2% dissolving to adapt to the growth of micrococcus scarlatinae and streptococcus agalactiae.Culture medium prepares to offset to each little dilution plate hole with 102.5% normal weight adds the dilution that 5 μ L drug solutions are produced.In addition, in order to test daptomycin, culture media supplemented extra 25mg/LCa 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-the 7th edition.Clinical and Laboratory Standards Institute file M7-A7[ISBN 1-56238-587-9] .Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898USA, 2006) and adopt the automatic fluid operator to carry out serial dilution and liquid transfer.The automatic fluid operator comprises Multidrop 384 (Labsystems, Helsinki, Finland), Biomek 2000 and Multimek 96 (Beckman Coulter, Fullerton CA).The hole of the 2-12 row of the little dilution plates in standard 96 holes (Falcon 3918) is filled 150 μ l DMSO or water, is used for the gentamycin on the Multidrop 384.Medicine (300 μ l) is dispensed into the 1st row of suitably going in these plates.These will become motherboard, therefrom prepare test board (daughter board).Biomek 2000 has finished in mother matrix through the 11st transfer that is listed as.The hole of the 12nd row does not contain medicine and is the growth of microorganism control wells in the daughter board.Use Multidrop 384 to load the suitable test media (above-mentioned) of 185 μ l as daughter board.Daughter board prepares at Multimek 96 instruments, the separately respective aperture of Multimek 96 instruments from each hole transferase 45 μ l drug solution of motherboard to each daughter board in single step.
The standardization inoculum of each microorganism is according to CLSI method preparation (ISBN 1-56238-587-9, the same quoting).Suspension is prepared in MHB, to equal the turbidity of 0.5McFarland standard.Suspension is diluted 1:9 in the meat soup that is fit to microorganism.The inoculum of each microorganism is dispersed to the aseptic reservoir (Beckman Coulter) of longitudinal subdivision, and uses Biomek 2000 inoculation plates.Daughter board is inverted and is placed on the Biomek2000 working surface, so that inoculation drug level from low to high carries out.Biomek 2000 sends 10 μ l standardization inoculums into each hole.This causes about 5 * 105 colony-forming units in final cell concentration position/mL in the daughter board.Therefore, the Kongzui of daughter board contains 185 μ l meat soups, 5 μ l drug solutions and 10 μ l bacterial inoculums eventually.With plate three floor heights that superpose, uppermost plate covers with blanketing, puts into plastic bag, and hatches about 18 hours at 35 ℃ for most of separated strains.With streptococcus plate reading after hatching 20 hours.Use the plate visualizer to watch microplate from the bottom.For every kind of test media, observe nonvaccinated dissolubility control board Chinese medicine precipitation sign.Read MIC and be recorded as the lowest concentration of drug that suppresses visible growth of microorganism.
The result.All marketed drug are soluble in broth bouillon under all test concentrations.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 the MIC mensuration.According to circumstances, the MIC value that obtains 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[ISBN 1-56238-653-0] .Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2008) compare.
Measure day at each, suitable quality control bacterial strain is included in the MIC mensuration.According to circumstances, the MIC value that obtains 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 Informational Supplement.CLSI file M100-S18[ISBN 1-56238-653-0]) compare.Wherein disclose in 141 values of quality control bacterial strain of quality control clearance, 140 (99.3%) in specified scope.An exception is imipenum and staphylococcus aureus 29213, takes turns producing a value (＜0.008 μ g/mL) one, and this is a dilution that is lower than disclosed QC scope.This takes turns every other quality control result 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 microorganism groups is 0.5 μ g/mL.BisEDT shows the activity greater than Linezolid and vancomycin, and is equal to the activity of daptomycin.Imipenum aspect anti-MSSA than BisEDT more effective (MIC90=0.03 μ g/mL).Yet MRSA and CAMRSA be to the imipenum resistance, and BisEDT has proved and activity to being equal to shown in the 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 imipenum more has activity.BisEDT is the most activated anti-MRSE agent of test.
BisEDT is presented at the activity that anti-vancocin sensitivity enterococcus faecalis (VSEfc) aspect and daptomycin, vancomycin and imipenum 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 sensitivity enterococcus faecalis (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 active high dilution factor of vancomycin.BisEDT and Linezolid are the most activated anti-enterococcus faecalis (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, greater than Linezolid and be slightly less than daptomycin and ceftazidime.This chemical 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 streptococcus agalactiae, the MIC90 value of wherein observing is 16 μ g/mL.The specific activity of BisEDT all test substances except gentamycin are all low.
The activity of the gram negative bacteria that BisEDT is included with comparing the agent antagonism shows the BisEDT effect (the MIC90 value is 2 μ g/mL) of resisting Acinetobacter baumannii, makes BisEDT become the most activated test compounds.Relatively agent causes these agent not conform to the MIC90 value of scale for the MICs of the raising of a large amount of test separated 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 imipenum of this chemical compound is low, but higher than ceftazidime, ciprofloxacin and gentamycin.BisEDT has also proved the activity of antagonism pneumobacillus, and the MIC90 value is 8 μ g/mL, this equates imipenum.This is the microorganism group of height antibiotic resistance for the relative high MIC90 value indication that imipenum, ceftazidime, ciprofloxacin and gentamycin show.BisEDT is the most effective resisting pseudomonas aeruginosa agent in the 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 is to representing the wide spectrum effect of a plurality of clinical separation strains of a plurality of kinds, comprise usually with the people in the acute kind relevant with the skin texture infection with chronic skin.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 chemical compound has proved broad spectrum activity, and for the many test microbes in this research, BisEDT is the most effective in the 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 streptococcus agalactiae (MIC90=16 μ g/mL).
Embodiment 8
Particles B T-antibiotic strengthens and synergistic activity
Present embodiment shows that microgranule bismuth-mercaptan (BTs) promotes antibacterial activity by enhancing and/or cooperative interaction.
The main deterioration factor was that resistance appears in bacterial antibiotic when treatment was infected.Methicillin resistance in staphylococcus epidermidis (MRSE) and the staphylococcus aureus (MRSA) has in fact reflected Multidrug resistance, so that these pathogen are difficult to eradicate.Yet, from the bacterial strain of hundreds of tests, do not have the staphylococcus demonstration to the resistance of BTs.In addition, inferior (subMIC) concentration that suppresses has reduced some important antibiotic resistances.
Staphylococcus aureusThe graphic extension (Fig. 4) of the antibiotic of subMIC bismuth dithioglycol (BisEDT) to MRSA-again sensibilization is provided, show some type antibiotic, comprise the antibiotic effect of the enhancing of gentamycin, cefazolin, cefepime, imipenum, Sulfamethoxazole and levofloxacin.Therefore, the most of antibiotic activity of the non-specific enhancing of BisEDT.
The antibiotic that uses BisEDT some and the subMIC level to make up carries out the meat soup dilution antimicrobial Study of Sensitivity (table 18) for 12 kinds of MRSA bacterial strains.In particular organisms film culture medium (BHIG/X), measure biomembrane prevention concentration (BPC) and minimal inhibitory concentration (MIC) both.By MIC and the BPC of subMIC BisEDT (BisEDT MIC, 0.2-0.4 μ g/ml) reduction gentamycin and cefazolin, but not below the sensitivity flex point.SubMIC BisEDT Enhanced MR SA is to the MRSA sensitivity close to Gatifloxacin and the cefepime of sensitivity flex point.These bacterial strains are responsive to vancomycin, but all the more so when having subMIC BisEDT.Usually, use 2 to 5 times of subMIC BisEDT reduction MIC and BPC.
Table 18.
The BT-antibiotic composition is to the antimicrobial acivity of MRSA
Figure BDA00002178874500901
12 kinds of MRSA clinical isolates are grown in BHIG/X and be exposed in the antibiotic of the serial dilution that has 0-0.1 μ g/ml BisEDT.MIC and the meansigma methods ± standard deviation of BPC as testing from least three times take μ g/ml calculating.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 11 the cefepime 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 sensitivity flex point place.
Table 19
Cefepime resistance MRSA is by the BisEDT sensitization
Figure BDA00002178874500911
The sensitivity 48h of the cefepime that MRSA pair of 12 cefepime resistance of test and subMIC BisEDT make up in the BHIG/X of polystyrene board culture medium under 37 ℃.
The table 20 that the results are shown in celbenin or gentamycin combination research.Reduce celbenin with the BisEDT (0.2 μ g/ml) of celbenin combination the MIC90 of MRSA is reached (FIC, 0.74) more than 4 times.Reduce gentamycin with the BisEDT of gentamycin combination the MIC90 of MRSA is surpassed 10 times (FIC, 0.6).BT has reversed the gentamycin resistance separated strain of whole four kinds of tests to the resistance [Domenico etc., 2002] of clinical respective concentration.Basically reduce the MIC of these antimicrobials, particularly gentamycin.The meat soup that is used for these researchs is the trypticase soybean broth (TSB) that contains 2% glucose, sees in the result of its demonstration and the Mueller-HintonII meat soup that has added 1% Sanguis caprae seu ovis that the result's is similar.
Table 20
MRSA: celbenin or gentamycin+BisEDT concertedness
Figure BDA00002178874500921
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, clindamycin and Gatifloxacin show stronger to staphylococcus epidermidis significantly antibiont film activity (Fig. 5) when making up with BisEDT.With the statement of different term, when having subMIC BisEDT, reduce respectively 50 times, 10 times and 4 times for the BPC of clindamycin, Gatifloxacin and gentamycin.
Notice for minocycline, vancomycin and cefazolin and prevent only moderate reduction in the concentration (BPC) at biomembrane, and remain unaffected at 0.05 μ g/ml BisEDT rifampicin and celbenin.Do not detect biomembrane at 0.1 μ g/mlBisEDT, no matter whether adopt antibiotic, showing does not have antagonism to occur.This BisEDT concentration for staphylococcus epidermidis close to MIC[Domenico etc., 2003] (referring to Fig. 5).
About growth inhibited, there are 7 to strengthen significantly antagonism staphylococcus epidermidis (Fig. 6) when having 0.1 μ g/ml (0.5 μ Μ) BisEDT in the antibiotic of 8 tests.The most obvious for clindamycin and gentamycin MIC variation, secondly be vancomycin, cefazolin, minocycline, Gatifloxacin and celbenin, rifampicin is unaffected.This bacterial strain is in the antibiotic (NC, CZ, GM, CM) of resistance to it, and only the resistance of cefazolin is reversed to clinical respective horizontal by BisEDT.
Antibiotic and subMIC BisEDT for the great majority test reduce slightly to the staphylococcic minimum bactericidal concentration of epidermis (MBC).Gentamycin 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 rifampicin maintenance is substantially constant.Clindamycin is antibacterial, and this illustrates that it lacks bactericidal activity.The cefazolin resistance is reversed [Domenico etc., 2003] for MBC.These effects are accumulated.
The potentiation (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.
Such as table 21 summary, with 0.1 μ g/ml BisEDT, 10 μ g/ml RIP and 10 μ g/ml rifampicin dipping implant, the rat of implanted s.c alone or in combination.The use tuberculin syringe will be with 2 * 10 7The physiological solution (1ml) that cfu/ml contains MS and MR bacterial strain is inoculated into graft surface.All grafts transplanting be moved out of in the time of rear 7 days and in sterile saline solution ultrasonic 5 minutes to remove the antibacterial of adhesion.Obtain the quantitative of antibacterial that live by cultivate dilution at the blood agar plate.Detectable limit is approximately 10cfu/cm 2
Table 21
Staphylococcus epidermidis in the anti-graft infection model of RIP, BTs and rifampicin
Figure BDA00002178874500931
aEach group has 15 animals; MS, methicillin-sensitivity staphylococcus epidermidis; MR, methicillin resistance staphylococcus epidermidis
bWith 0.1mg/l BT, 10mg/l RIP, the impregnated terylene graft of 10mg/l rifampicin segment
cStatistically significant when comparing with MR with matched group MS
dStatistically significant when comparing with the MS3 group
eStatistically significant when comparing with the MR3 group with MR1, MR2
Gram negative bacteriaThe activity of tobramycin antagonism Pseudomonas aeruginosa strengthens several times (table 22) with subMIC BisEDT.In these trials, more properly MIC is defined as IC 24
Table 22
Tobramycin resistance Pseudomonas aeruginosa: BisEDT effect
Figure BDA00002178874500941
Resistant strain with Pseudomonas aeruginosa when having tobramycin (NN) and BisEDT (BE:0.33 μ g/ml) is incubated at Mueller-Hinton II meat soup at 37 ℃.MIC is determined as 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 BDA00002178874500951
aTo from further research, be got rid of by three bacterial strains that the BisEDT of 0.4 μ g/ml suppresses.FIC index≤0.5 expression concertedness: FICI〉0.5 and＜1.0 expression enhancings.
Make chloromycetin and ampicillin resistance escherichia coli to these medicaments insensitives (table 24) by adding subMIC BisEDT.
Table 24
Chloromycetin/ampicillin resistance escherichia coli: BisEDT effect
Figure BDA00002178874500952
Colibacillary resistant strain is incubated in the Mueller-HintonII meat soup at 37 ℃ existing alone or in combination under chloromycetin (CM) or ampicillin (AMP) and the BisEDT (BE:0.33 μ g/ml).MIC is determined as the antibiotic concentration that suppresses long-living 24 ± 1h.
Make the tetracyclin resistance escherichia coli responsive to doxycycline by adding subMICBisEDT (table 25).Described combination show needle has the summation action for TET A and TET B bacterial strain to the concertedness of TET M and TET D bacterial strain (FIC≤0.5).
Table 25
Tetracyclin resistance escherichia coli: BisEDT effect
Figure BDA00002178874500961
Under having alone or in combination doxycycline (DOX) and BisEDT (BE:0.33 μ g/ml), 37 ℃ of escherichia coli resistant strains are incubated in the Mueller-Hinton II meat soup.MIC is determined as 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 Dis 11:170-175;Domenico P，D Parikh,BA Cunha.1994.Bismuth modulation of antibiotic activity against gastrointestinal bacterial pathogens.Med Microbiol Lett 3:114-119;Domenico P，Kazzaz JA,Davis JM,Niederman MS.2002.Subinhibitory bismuth ethanedithiol(BisEDT)sensitizes resistant Staphtlococcus 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 Chemother 3:79-85;Domenico P，E Gurzenda,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.Peptides 25:2047-2053;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 Pharmaceut 358:278-84;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 Pharmaceut 373:141-6;Veloira WG，Gurzenda EM,Domenico P，Davis JM,Kazzaz JA.2003.Synergy of tobramycin and bismuth thiols against Burkholderia cepacia.JAntimicrob Chemother 52:915-919.
Embodiment 9
Particles B T-antibiotic strengthens and synergistic activity
Present embodiment show microgranule bismuth mercaptan BisEDT by with promote antibacterial activity for the organic concrete antibiotic enhancing of concrete microorganism target and/or cooperative interaction.Show according to the basically combination in the generation table 26 of the method for using among the embodiment 8 for separately one point data.
Table 26
FICI value for single-point BisEDT-antibiotic composition
Figure BDA00002178874500981
SA, staphylococcus aureus; MRSA, methicillin resistance staphylococcus aureus; EFc, enterococcus faecalis; SP, streptococcus pneumoniae; PRSP, the penicillin resistance streptococcus pneumoniae; 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 the particles B is-EDT that test prepares as mentioned above and four kinds of Bis-EDT analog and anti-some Gram-negative pathogen.Measure the concertedness (FICI≤0.5) of utilizing FIC (FIC) and FIC index (FICI) with improved General Purpose Laboratory method, 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, the 3rd edition, V Lorian. edits Williams and Wilkins, Baltimore, MD, the 432-492 page or leaf; Odds, 2003 J.Antimicrob.Chemother.52 (1): 1).Use checkerboard to measure FIC index and employing in this research.
Table 27
Fractions tested
The stock solution of all test article is prepared as 40 * final goal concentration in the appropriate solvent.In all test article solution under these conditions.Final drug level in the FIC analysis plates is set as each reagent of comprising to the MIC value of each test microbes, unless bacterial strain is to the test agent complete resistance.The concentration range of test is shown in the table 27.The test organism is original to be accepted in clinical source, or from the biological product of Unite States Standard collecting center.During reception, separator is scoring on the tryptic soy agar II (TSA).Gather in the crops the clone and during comprising the suitable meat soup growth medium of cryoprotector, prepare cell suspending liquid from these plates.Then at-80 ℃ of lower freezing equal portions things.The freezing seed of microorganism to be tested in given analysis is thawed, separator is scoring on the TSA plate, and under 35 ℃, hatches.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 in the final test plate, compensate the medicine of 5% volume.
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 A erobically; Approved Standard-the 8th edition.CLSI file M07-A8[ISBN 1-56238-689-1] Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009).
The meat soup microdilution of describing before using (Sweeney etc., 2003Antimicrob.Agents Chemother.47 (6): 1902-1906) measure the FIC value.Be the preparation test board, (Multidrop 384, Labsystems, Helsinki, Finland to use the automated fluid processor; Biomek 2000 and Multimek 96, Beckman Coulter, Fullerton CA) carry out serial dilution and liquid shifts.
Use Multidrop 384 in the 2-12 row, the suitable solvent of 150 μ L is inserted in the appropriate well of the little dilution plate in standard 96-hole (Falcon 3918).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 from the 1st hole that is listed as of motherboard, to shift each second drug solution (40 *) of 150 μ L with Biomek 2000, and carry out 11 2 times of serial dilutions.Use the multichannel pipet, manually with the from the top to bottom serial dilution of motherboard of Bis-EDT (and analog).Make up two motherboards (is used for each second medicine and and is used for Bis-EDT (or analog)) with formation " checkerboard " pattern by shifting equal-volume (using the multichannel pipet) to the drug regimen plate.The serial dilution of each self-contained independent a kind of reagent of measuring for MIC of capable and 12 row of H.
Use Multidrop 384 in " daughter board " the 180 μ L test media of packing into, then, in independent step, use Multimek 96 to shift 10 μ L drug solutions from each hole of drug regimen motherboard to daughter board separately the corresponding hole.At last, inoculate daughter board with test microbes.Prepare the standardized inoculum of each microorganism according to disclosed guide (CLSI, 2009).For all separators, the inoculum of each microorganism is distributed to the aseptic depository of being cut apart by length (Beckman Coulter), and inoculates plate with Biomek 2000.Instrument send the standardized inoculum of 10 μ L to each hole in daughter board, to produce about 5 * 10 5The final cell concentration of colony-forming units/mL.
In creating 8 * 12 checkerboards, produce the test lattice, wherein with the drug level that changes recently separately (the 12nd row and H are capable) and each chemical compound of combined test.Three height of all microorganism stack of plates with covering, are put into plastic bag at top board, and hatch about 20 hours at 35 ℃.After hatching, from incubator, remove microplate and use ScienceWare plate reader to observe from the bottom.The hole of the MIC (H is capable) of the medicine 1 of the reading card of labelling preparation, the MIC of medicine 2 (12 row) and growth-non-growth interface.
Use the Excel program according to the MIC of the independent chemical compound 1 of the MIC/ of the chemical compound 1 of following formula mensuration FIC:(combination)+(MIC of the chemical compound 2 that the MIC/ of the chemical compound 2 of associating is independent).By independent FIC through 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 underproof MIC result's the situation MIC value during the height concentration of next is calculated as FIC at single reagent.
Particles B isEDT, four kinds of particles B T analog and all other reagent (with the combination of reagent) be soluble in all final test concentration.MIC and the FICI value measured are shown in the following table.
Table 28
For the minimal inhibitory concentration of MB-1B-3 and piperacillin and gathering of FIC result
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 29
For the minimal inhibitory concentration of MB-1B-3 and aztreonam and gathering of FIC result
Figure BDA00002178874501021
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 30
The minimal inhibitory concentration of MB-15 and piperacillin and FIC result gather
Figure BDA00002178874501022
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 31
The minimal inhibitory concentration of MB-15 and aztreonam and FIC result gather
Figure BDA00002178874501031
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 32
The minimal inhibitory concentration of MB-8-2 and piperacillin and FIC result gather
Figure BDA00002178874501032
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 33
The minimal inhibitory concentration of MB-8-2 and aztreonam and FIC result gather
1MIC, minimal inhibitory concentration
2FlCI, FICI
Table 34
The minimal inhibitory concentration of MB-11 and piperacillin and FIC result gather
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 35
The minimal inhibitory concentration of MB-11 and aztreonam and FIC result gather
Figure BDA00002178874501051
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 36
The minimal inhibitory concentration of MB-2B and piperacillin and FIC result gather
Figure BDA00002178874501052
11MIC, minimal inhibitory concentration
2FICI, FICI
Table 37
The minimal inhibitory concentration of MB-2B and aztreonam and FIC result gather
Figure BDA00002178874501061
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 38
The minimal inhibitory concentration of MB-1B-3 and cefotaxime and FIC result gather
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 39
The minimal inhibitory concentration of MB-1B-3 and cefepime and FIC result gather
Figure BDA00002178874501071
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 40
The minimal inhibitory concentration of MB-15 and cefotaxime and FIC result gather
Figure BDA00002178874501072
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 41
The minimal inhibitory concentration of MB-15 and cefepime and FIC result gather
Figure BDA00002178874501081
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 42
The minimal inhibitory concentration of MB-8-2 and cefotaxime and FIC result gather
Figure BDA00002178874501082
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 43
The minimal inhibitory concentration of MB-8-2 and cefepime and FIC result gather
Figure BDA00002178874501091
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 44
The minimal inhibitory concentration of MB-11 and cefotaxime and FIC result gather
Figure BDA00002178874501092
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 45
The minimal inhibitory concentration of MB-11 and cefepime and FIC result gather
Figure BDA00002178874501101
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 46
The minimal inhibitory concentration of MB-2B and cefotaxime and FIC result gather
Figure BDA00002178874501102
1MIC, minimal inhibitory concentration
2FICI, FICI
Table 47
The minimal inhibitory concentration of MB-2B and cefepime and FIC result gather
Figure BDA00002178874501111
1MIC, minimal inhibitory concentration
2FICI, FICI
Embodiment 11
Bismuth mercaptan is to the effect of the critical infection in damaged of rat femur
The working standard of compound fracture nursing is flushing, debridement and antibiotic; Its objective is that the bacterial loads that reduces in the wound is to the degree that does not infect.Although these treatments are arranged, infecting still for open tibial fracture, deterioration reaches 75% severity.What is interesting is, even usually cause early infection by gram negative bacteria, infect due to that Gram-positive infects the late period that also can will be referred to healing problem and excision, usually staphylococcus kind (Johnson 2007).
One of reason of the anti-standard care of staphylococcus aureus is that they can form biomembrane.Antibacterial in the biomembrane can be resisted the Antimicrobe compound (Costerton 1987) that will kill the similar microorganism in the culture medium.
The purpose of this research is to measure BTs or whether will fall infection in the oligosaprobic open fracture model independently or with antibiotic.The rat femur critical defective model that pollutes is good Acceptance Model and is used for the described experiment of 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 to have shown two kinds of BIS-BiS analog resisting the antibacterial potential that biomembrane in vitro conceals table 1), although activity profile is different from Bis-EDT chemical compound (CPD) CPD-8-2 (bismuth pyrithione/succinimide mercaptans:.
When with not with polymethyl methacrylate (PMMA) adhesive pearl vehicle in tobramycin and vancomycin when 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.Be clinically useful hydrogel gel form as herein described with the production of three kinds of particles B Ts preparations.With these BTs with 5mg/ml -1Concentration be suspended in the gel and test, found that this concentration is the debita spissitudo that gel is sent.Gel preparation is laminated with in the wound profile, need to not remove after application.
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.
Cultivated rear six hours with staphylococcus aureus, remove wound, insert in the breach with normal saline washing and with 1ml BT gel.
(b) BT and systemic antibiotics (ABx).
Cultivated rear six hours with staphylococcus aureus, remove wound, insert in the breach with normal saline washing and with the BT gel that 1ml adds.The antibiotic that uses is for being equivalent to 5mgKg -1The cefazolin of dosage, damage is by by twice subcutaneous injection totally 3 days every day.Before removing, use immediately the first dosage.This dosage of data show in the past will cause bacteria levels by ≈ 10 6Be reduced to ≈ 10 4Therefore, still allow the dependent interaction of different B Ts to be measured.
(c) contrast
Cultivated rear six hours with staphylococcus aureus, remove and irrigate with saline.Also treat in the manner described above control animal with cefazolin.
Program:
As described in the people such as Chen, carry out the in vivo program of Damage of Rats model.(2002 J.Orthop.Res.20:142;2005 J.Orthop.Res.23:816;2006 J.Bone Joint Surg.Am.88:1510;2007 J.Orthop.Trauma 21:693)。With 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.(27 * 4 * 4mm) are put on the anterolateral surface of femur will to gather the acetyl substrate.The preboring orifice plate is to accept the wire kirschner wire of 0.9mm diameter.Form the substrate of these plates to be fit to femur backbone's profile.Use plate as template pilot hole to be drilled through two shells of femur, and the wire kirschner wire is inserted through plate and femur.To remove guide as bone from the otch of plate 6mm.Produce defective with little reciprocating sow, tissue is cooled off to make great efforts the prevention hot injury by continuous flushing simultaneously.
With 1 * 10 5The staphylococcus aureus of CFU inoculates each 10 animal of some groups, and treats 6 hours separately or with antibiotic combination with BT after cultivating as mentioned above.Organize as follows: the Bis-EDT gel; The MB-11 gel; The MB-8-2 gel; Bis-EDT Ning Jiao ﹠amp; Abx; MB-11 Ning Jiao ﹠amp; Abx; MB-8-2 Ning Jiao ﹠amp; Abx; Contrast (Abx is independent).
Perform the operation and anaesthetized animal in rear 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 the matched group 25% difference.The expection standard deviation of this support 35% and 0.05 α.
As shown in Figure 7, strengthened antibacterial activity with the infection of staphylococcus aureus of 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 chemical compound.Compare with independent cefazolin, the cefazolin that makes up with MB-11 and MB-8-2 shows that the antibacterial activity that strengthens is to reduce the infection of staphylococcus aureus that detects on the hardware.As if Bis-EDT does not affect the activity of cefazolin in this.
List of references:
Costerton JW, Cheng KJ, Geesey GG etc.Bacterial Biofilms in Nature and Disease.Ann Rev Microbiol.1987;41:435-64
Domenico P，Baldassarri L,Schoch PE,Kaehler K,Sasatsu M,Cunha BA.Activities of Bismuth Thiols against Staphylococci and Staphyloccocal Biofilms.Antimicrob Agents and Chemother.2001;45(5):1417-21
Halwani M, Blomme S, Suntres ZE etc.Liposomal bismuth-ethanedithol formulation enhances antimicrobial activity of tobramycin.Iht J Pham.2008;358:278-84
Johnson EN,Burns TC,Hayda RA,Hospenthal DR,Murray CK.Infection complications of open type III tibial fractures among combat casualties.Clin Infect Dis.2007;45(4):409-415
Other citing document and pertinent literature
Domenico etc., Canadian J.Microbiol.31:472-78 (1985); Domenico etc., Reduction of capsular polysaccharides and potentiation of aminoglycoside inhibition in gram-negative bacteria with bismuth subsalicylate.J Antimicrob Chemo 1991; 28:801-810; Domenico etc., Infection 20:66-72 (1992); Domenico etc., Infect.Immun.62:4495-99 (1994); Domenico etc., J.Antimicrol.Chemothr.38:1031-40 (1996); Domenico etc., Enhancement of bismuth antibacterial activity with lipophilic thiol chelators.Antimicrob Agents Chemother 1997; 41:1697-703; Domenico etc., Surface antigen exposure by bismuth-dimercaprol suppression of Klebsiella pneumoniae capsular polysaccharide.Infect Immun67:664-669 (1999); Domenico etc., 2000.The potential of bismuth-thiols for treatment and prevention of infection.Infect Med 17:123-127; Domenico etc., Activities of bismuth thiols against staphylococci and staphylococcal biofilms.Antimicrob Agents Chemother 2001; 45:1417-21; Domenico etc., Combating antibiotic resistance with bismuth-thiols.Research Advances in Antimicrob Agents Chemother 2003; 3:79-85; Domenico etc., Reduction of capsular polysaccharides and potentiation of aminoglycoside inhibition in gram-negative bacteria with bismuth subsalicylate.J Antimicrob Chemo 1991; 28:801-810; Domenico etc., BisEDT and RIP act in synergy to prevent graft infections by resistant staphylococci.Peptides 2004.; 25:2047-53; Domenico etc., 2005.Pyrithione enhanced antimicrobial activity of bismuth.Antibiotics for Clinicians 9:291-297; U.S. Patent No. 6,582,719; U.S.RE37,793; U.S. Patent No. 6,248,371; U.S. Patent No. 6,086,921; U.S. Patent No. 6,380,248; U.S. Patent No. 6,582,719; U.S. Patent No. 6,380,248; U.S. Patent No. 6,875,453.
Above-mentioned various embodiments capable of being combined are to provide other embodiments.By with reference to its integral body with relate in this description and/or the application data page or leaf in all United States Patent (USP)s, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and the non-patent disclosure listed incorporate this paper into.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 if need.
Can carry out these and other change to embodiment according to above-mentioned detailed description.Usually, in following claims, the term that uses should not be construed as claim is limited to disclosed specific embodiments in description and the claim, and should be interpreted as comprising all possible embodiment with whole equivalency range of this claim defined.Therefore, claim is not limited by disclosure.

Claims (47)

1. bismuth-composition of mercaptans, it comprises:
A plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically, and wherein said BT chemical compound comprises bismuth or bismuth salt and contains the chemical compound of mercaptan.
2. bismuth-composition of mercaptans, it comprises:
A plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically, and produce by the process that may further comprise the steps:
(a) in the condition of the solution that is enough to obtain to be substantially free of solid precipitation with mix under the time: (i) comprise bi concns at least 50mM bismuth salt and do not contain the acidic aqueous solution of hydrophilic, polarity or organic solubilized agent, be enough to obtain to comprise the by volume ethanol of the amount of the mixture of about 25% ethanol with (ii); With
(b) under the condition that is enough to form the precipitation that comprises the microgranule that contains described BT chemical compound and time, add the alcoholic solution that comprises the chemical compound that contains mercaptan in the mixture of (a) obtaining reaction solution, the wherein said chemical compound that contains mercaptan in described reaction solution with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 exist.
3. bismuth-composition of mercaptans according to claim 2, wherein said bismuth salt is Bi (NO 3) 3
4. bismuth-composition of mercaptans according to claim 2, wherein said acidic aqueous solution comprises by weight at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth.
5. bismuth-composition of mercaptans according to claim 2, wherein said acidic aqueous solution comprises by weight at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid.
6. bismuth-composition of mercaptans claimed in claim 2, the wherein said chemical compound that contains mercaptan comprises that one or more are selected from the material by the following group that forms: 1,2-dithioglycol, 2,3-dimercaptopropanol, BAL, PTO, 1,4-Dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propanol, 1,4-Dithioerythritol, alpha-lipoic acid, dithiothreitol, DTT, methanthiol (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]); coenzyme A; thioctamide; glutathion; cysteine; cystine; 2 mercapto ethanol; dithiothreitol, DTT; 1,4-Dithioerythritol; the 2-sulfydryl indole; T-5398; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); the functionalized golden nanometer particle of (11-sulfydryl undecyl) four (ethylene glycol); 1; 1 '; 4 '; 1 " terphenyl-4-mercaptan; 1; 11-hendecane two mercaptan; 1; 16-hexadecane two mercaptan; technical grade 1; the 2-dithioglycol; 1; the 3-dimercaptopropane; 1; the 4-benzene dimethanethiol; 1; the 4-succinimide mercaptans; 1; 4-succinimide mercaptans diacetate esters; 1; the 5-pentane disulfide thioalcohol; 1; the 6-ethanthiol; 1; hot two mercaptan of 8-; 1; 9-mercaptan in the ninth of the ten Heavenly Stems two; diamantane (obsolete) 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 the golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propanol; l-mercaptan in the ninth of the ten Heavenly Stems; the l-octadecanethiol; the l-spicy thioalcohol; the l-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; 11-bromo-1-hendecane 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; the 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; 6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; 3-chloro-1-propanethiol; 3-sulfydryl-1-propanol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionic acid amide.; the 3-mercaptopropionic acid; the silica gel that 3-sulfydryl propyl group is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4; 4 '-two (mercapto methyl) biphenyl; 4; 4 '-dimercapto stilbene; 4-(6-sulfydryl hexyloxy) 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-capryl alcohol; the 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; xenyl-4,4 '-two 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 TMACID 11, NanoThinks TMACID 16, NanoThinks TMALCO 11, NanoThinks TMTHIO8, functionalized golden nanometer particle, the average M of PEG two mercaptan of spicy thioalcohol n8,000, PEG two mercaptan molar average molecular weight 1,500, PEG two mercaptan molar average molecular weight 3,400, S-(11-bromo-n-11 base) thiacetate, S-(4-cyano group butyl) thiacetate, phenylmercaptan., 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 "-two mercaptan, uncle's lauryl mercaptan and uncle's nonyl mercaptan.
7. method for the preparation of bismuth-composition of mercaptans, described bismuth-composition of mercaptans comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, basically all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m, said method comprising the steps of:
(a) in the condition of the solution that is enough to obtain to be substantially free of solid precipitation with mix under the time: (i) comprise bi concns at least 50mM bismuth salt and do not contain the acidic aqueous solution of hydrophilic, polarity or organic solubilized agent, be enough to obtain to comprise the by volume ethanol of the amount of the mixture of about 25% ethanol with (ii); With
(b) under the condition that is enough to form the precipitation that comprises the microgranule that contains described BT chemical compound and time, add the alcoholic solution that comprises the chemical compound that contains mercaptan in the mixture of (a) obtaining reaction solution, the wherein said chemical compound that contains mercaptan in described reaction solution with respect to the about 1:3 of bismuth extremely the mol ratio of about 3:1 exist.
8. method according to claim 7 also comprises and reclaims described precipitation to remove impurity.
9. method according to claim 7, wherein said bismuth salt is Bi (NO 3) 3
10. method according to claim 7, wherein said acidic aqueous solution comprises by weight at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth.
11. method according to claim 7, wherein said acidic aqueous solution comprise by weight at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid.
12. method according to claim 7, the wherein said chemical compound that contains mercaptan comprises that one or more are selected from the material by the following group that forms: 1,2-dithioglycol, 2,3-dimercaptopropanol, BAL, PTO, 1,4-Dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propanol, 1,4-Dithioerythritol, dithiothreitol, DTT, alpha-lipoic acid, methanthiol (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]); coenzyme A; thioctamide; glutathion; cysteine; cystine; 2 mercapto ethanol; dithiothreitol, DTT; 1,4-Dithioerythritol; the 2-sulfydryl indole; T-5398; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); the functionalized golden nanometer particle of (11-sulfydryl undecyl) four (ethylene glycol); 1; 1 '; 4 '; 1 " terphenyl-4-mercaptan; 1; 11-hendecane two mercaptan; 1; 16-hexadecane two mercaptan; technical grade 1; the 2-dithioglycol; 1; the 3-dimercaptopropane; 1; the 4-benzene dimethanethiol; 1; the 4-succinimide mercaptans; 1; 4-succinimide mercaptans diacetate esters; 1; the 5-pentane disulfide thioalcohol; 1; the 6-ethanthiol; 1; hot two mercaptan of 8-; 1; 9-mercaptan in the ninth of the ten Heavenly Stems two; diamantane (obsolete) 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 the golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propanol; l-mercaptan in the ninth of the ten Heavenly Stems; the l-octadecanethiol; the l-spicy thioalcohol; the l-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; 11-bromo-1-hendecane 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; the 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; 6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; 3-chloro-1-propanethiol; 3-sulfydryl-1-propanol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionic acid amide.; the 3-mercaptopropionic acid; the silica gel that 3-sulfydryl propyl group is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4; 4 '-two (mercapto methyl) biphenyl; 4; 4 '-dimercapto stilbene; 4-(6-sulfydryl hexyloxy) 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-capryl alcohol; the 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; xenyl-4,4 '-two 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 TMACID 11, NanoThinks TMACID 16, NanoThinks TMALCO 11, NanoThinks TMTHIO8, functionalized golden nanometer particle, the average M of PEG two mercaptan of spicy thioalcohol n8,000, PEG two mercaptan molar average molecular weight 1,500, PEG two mercaptan molar average molecular weight 3,400, S-(11-bromo-n-11 base) thiacetate, S-(4-cyano group butyl) thiacetate, phenylmercaptan., 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 "-two mercaptan, uncle's lauryl mercaptan and uncle's nonyl mercaptan.
13. protect one or more the method in self-faced opposing bacterial pathogens, fungal pathogens and the viral pathogen for one kind, it comprises:
The BT compositions that makes described surface and effective dose contacts under one or more condition and time below being enough to satisfy:
(i) the described surface of prevention is infected by described antibacterial, fungus or viral pathogen,
(ii) suppress cell viability or the Growth of Cells of basically all cells that swim of described antibacterial, fungus or viral pathogen,
(iii) suppress biofilm formation by described antibacterial, fungus or viral pathogen, and
(iv) suppress basically biomembrane vigor or the biofilm development of all biomembrane form cells of described antibacterial, fungus or viral pathogen,
Wherein said BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically.
14. method according to claim 13, wherein said bacterial pathogens comprise with lower at least a:
(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 bacterial pathogens by the following group that forms: staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), staphylococcus epidermidis, MRSE (methicillin resistance staphylococcus epidermidis), mycobacterium tuberculosis, 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, Yersinia enterocolitica, vibrio cholera, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, anthrax bacillus, yersinia pestis, Pseudomonas aeruginosa, streptococcus pneumoniae, the penicillin resistance streptococcus pneumoniae, escherichia coli, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and Acinetobacter baumannii.
15. method according to claim 13, wherein said bacterial pathogens shows antibiotic resistance.
16. method according to claim 13, wherein said bacterial pathogens show being selected from the antibiotic resistance by the following group that forms: methicillin, vancomycin, nafcillin, gentamycin, ampicillin, chloromycetin, doxycycline and tobramycin.
17. method according to claim 13, wherein said surface comprise the epithelial tissue surface that is selected from the group that is comprised of epidermis, corium, respiratory tract, gastrointestinal tract and gland lining.
18. method according to claim 13, wherein said contact procedure is carried out one or many.
19. method according to claim 18, wherein at least one contact procedure comprises spraying, washes, floods and smears the one in the described surface.
20. method according to claim 18, wherein at least one contact procedure comprises the one in suction, picked-up and the dentilave.
21. method according to claim 18, wherein at least one contact procedure comprises by being selected from following approach and is applied to the experimenter: part, intraperitoneal, oral, parenteral, intravenous, intra-arterial, transdermal, Sublingual, subcutaneous, intramuscular, through cheek, intranasal, in suction, ophthalmic, atrium, in the ventricle, in subcutaneous, the fat, in intraarticular and the sheath.
22. the described method of claim 13, wherein said BT compositions comprise one or more BT chemical compound: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and the Bis-EDT/2-hydroxyl-1-propanethiol that is selected from by the following group that forms.
23. method according to claim 13, wherein said bacterial pathogens shows antibiotic resistance.
24. each described method of claim 13-23, described method also comprises the step that contacts with described BT compositions with described surface simultaneously or successively and with any order, and in the collaborative antibiotic of described surface and (i) and (ii) cooperative antimicrobial efficacy enhancing antibiotic at least one contacted.
25. method according to claim 24, wherein said collaborative antibiotic or cooperative antimicrobial efficacy strengthen antibiotic and comprise the antibiotic that is selected from by the following group that forms: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase resistance Penicillin antibiotics and Aminopenicillin antibiotic.
26. method according to claim 25, it is the aminoglycoside antibiotics that is selected from by the following group that forms that wherein said collaborative antibiotic or cooperative antimicrobial efficacy strengthen antibiotic: amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
27. the method for the antibiotic resistance on the self-faced that overcomes the bacterial pathogens that wherein has antibiotic resistance, it comprises:
Be enough to satisfy under following one or more the condition and time, making the described epithelial tissue surface while or can strengthen or contact with the synergistic antibiotic of described at least a BT compositions successively and so that (1) at least a bismuth-mercaptan (BT) compositions of any order and effective dose and (2) are at least a:
(i) the described epithelial tissue of prevention surface is infected by described bacterial pathogens,
(ii) cell viability or the Growth of Cells of basically all cells that swim of the described bacterial pathogens of inhibition,
(iii) suppress biofilm formation by described bacterial pathogens, and
(iv) basically biomembrane vigor or the biofilm development of all biomembrane form cells of the described bacterial pathogens of inhibition,
Wherein said BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically; Thereby and overcome at the lip-deep antibiotic resistance of described epithelial tissue.
28. method according to claim 27, wherein said bacterial pathogens is selected from the group that is comprised of following: staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), staphylococcus epidermidis, MRSE (methicillin resistance staphylococcus epidermidis), mycobacterium tuberculosis, 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, Yersinia enterocolitica, vibrio cholera, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, anthrax bacillus, yersinia pestis, Pseudomonas aeruginosa, streptococcus pneumoniae, the penicillin resistance streptococcus pneumoniae, escherichia coli, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and Acinetobacter baumannii.
29. method according to claim 27, wherein said bacterial pathogens show being selected from the antibiotic resistance by the following group that forms: methicillin, vancomycin, nafcillin, gentamycin, ampicillin, chloromycetin, doxycycline, tobramycin, clindamycin and Gatifloxacin.
30. method according to claim 27, wherein said surface comprise the epithelial surface of the tissue that is selected from the group that is comprised of epidermis, corium, respiratory tract, gastrointestinal tract and gland lining.
31. method according to claim 27, wherein said contact procedure is carried out one or many.
32. method according to claim 31, wherein at least one contact procedure comprises spraying, washes, floods, is coated with and smears the one in the described surface.
33. method according to claim 31, wherein at least one contact procedure comprises the one in suction, picked-up and the dentilave.
34. method according to claim 31, wherein at least one contact procedure comprises by being selected from following approach and is applied to the experimenter: part, intraperitoneal, oral, parenteral, intravenous, intra-arterial, transdermal, Sublingual, subcutaneous, intramuscular, through cheek, intranasal, in suction, ophthalmic, atrium, in the ventricle, in subcutaneous, the fat, in intraarticular and the sheath.
35. method according to claim 27, wherein said BT compositions comprise one or more BT chemical compound: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and the Bis-EDT/2-hydroxyl-1-propanethiol that is selected from by the following group that forms.
36. method according to claim 35 is wherein said collaborative or strengthen antibiotic and comprise the antibiotic that is selected from by the following group that forms: clindamycin, Gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase resistance Penicillin antibiotics and Aminopenicillin antibiotic.
37. method according to claim 36 is wherein said collaborative or to strengthen antibiotic be the aminoglycoside antibiotics that is selected from by the following group that forms: amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
38. an antimicrobial composition that is used for the treatment of the self-faced that contains bacterial biof iotalm, it comprises:
(a) at least a BT compositions, described BT compositions comprises the microgranule of a plurality of bismuth-containing-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically; (b) at least aly can or strengthen the Antibiotique composition of described BT chemical compound with described BT chemical compound synergism.
39. described compositions according to claim 38, wherein said BT chemical compound is selected from the group that is comprised of following: BisBAL, BisEDT, Bis-dimercaptopropanol, BAL, 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-propanol and Bis-EDT/2-hydroxyl-1-propanethiol.
40. described compositions according to claim 38, wherein said BT chemical compound is selected from the group that is comprised of BisEDT and BisBAL.
41. comprising, described compositions according to claim 38, wherein said Antibiotique composition be selected from following antibiotic: methicillin, vancomycin, nafcillin, gentamycin, ampicillin, chloromycetin, doxycycline, tobramycin, clindamycin, Gatifloxacin, cefazolin and aminoglycoside antibiotics.
42. described compositions according to claim 41, wherein said aminoglycoside antibiotics is selected from the group that is comprised of following: amikacin, arbekacin, gentamycin, kanamycin, neomycin, netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
43. described compositions according to claim 41, wherein said aminoglycoside antibiotics is amikacin.
44. a method that is used for the treatment of the self-faced that contains bacterial biof iotalm, it comprises:
(a) with in the described surface or lip-deep antibacterial infect be accredited as comprise one of following: (i) gram positive bacteria, (ii) gram negative bacteria, and (iii) comprise (i) and (ii) both; With
(b) comprise the preparation of one or more bismuth mercaptan (BT) compositionss to described surface applied, wherein:
(i) comprise gram positive bacteria if described antibacterial infects, then described preparation comprise effective dose at least a BT chemical compound and at least a be the antibiotic of rifamycin,
(ii) comprise gram negative bacteria if described antibacterial infects, then described preparation comprises at least a BT chemical compound and the amikacin of effective dose,
(iii) if described antibacterial infects and to comprise gram positive bacteria and gram negative bacteria, then described preparation comprises one or more BT chemical compounds, rifamycin and the amikacin of effective dose, thereby and treats described surface.
45. described method according to claim 44, wherein said antibacterial infect and comprise one or more antibiotic resistance bacterium.
46. described method according to claim 45, wherein said treatment comprise in following at least one: (i) eradicate described bacterial biof iotalm, (ii) reduce described bacterial biof iotalm, and (iii) weaken the growth of described bacterial biof iotalm.
47. each described method according to claim 44-46, wherein said BT compositions comprises a plurality of microgranules that comprise bismuth-mercaptan (BT) chemical compound, and all described microgranules have about 0.4 μ m to the volume mean diameter of about 5 μ m basically.
CN2011800153054A 2010-02-03 2011-02-03 Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses Pending CN103079557A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710523562.8A CN107308186A (en) 2010-02-03 2011-02-03 It is used for the biomedical applications and the bismuth mercaptan of other purposes for the treatment of for including bacterial biof iotalm as antiseptic

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
USPCT/US2010/023108 2010-02-03
PCT/US2010/023108 WO2010091124A2 (en) 2009-02-03 2010-02-03 Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications
US37318810P 2010-08-12 2010-08-12
US61/373,188 2010-08-12
PCT/US2011/023549 WO2011097347A2 (en) 2010-02-03 2011-02-03 Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201710523562.8A Division CN107308186A (en) 2010-02-03 2011-02-03 It is used for the biomedical applications and the bismuth mercaptan of other purposes for the treatment of for including bacterial biof iotalm as antiseptic

Publications (1)

Publication Number Publication Date
CN103079557A true CN103079557A (en) 2013-05-01

Family

ID=51355699

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201710523562.8A Pending CN107308186A (en) 2010-02-03 2011-02-03 It is used for the biomedical applications and the bismuth mercaptan of other purposes for the treatment of for including bacterial biof iotalm as antiseptic
CN2011800153054A Pending CN103079557A (en) 2010-02-03 2011-02-03 Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201710523562.8A Pending CN107308186A (en) 2010-02-03 2011-02-03 It is used for the biomedical applications and the bismuth mercaptan of other purposes for the treatment of for including bacterial biof iotalm as antiseptic

Country Status (7)

Country Link
EP (1) EP2536406A4 (en)
JP (1) JP2013518895A (en)
CN (2) CN107308186A (en)
AU (1) AU2011212941B2 (en)
CA (1) CA2788669C (en)
MX (1) MX346409B (en)
WO (1) WO2011097347A2 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109939090A (en) * 2017-11-16 2019-06-28 帝斯曼知识产权资产管理有限公司 Novel purposes
CN110387416A (en) * 2018-04-16 2019-10-29 华东理工大学 The double probe systems of the nanogold of controllable polymerization adjusting function and its application
CN110691603A (en) * 2016-12-05 2020-01-14 抗菌技术生物技术研究与发展股份有限公司 Bacteriophage compositions comprising respiratory antibacterial bacteriophage and methods of use thereof
CN110870874A (en) * 2018-08-13 2020-03-10 中山大学 Medicine with antibacterial effect and application thereof
CN112425608A (en) * 2019-08-23 2021-03-02 香港科技大学 Elastase inhibitors, bacteriostatic agents with anti-biofilm activity effective against both single-and multi-species biofilms
CN112788950A (en) * 2018-07-31 2021-05-11 微生物公司 Bismuth-thiol compositions and methods for treating wounds
CN112804878A (en) * 2018-07-31 2021-05-14 微生物公司 Bismuth-thiol compositions and methods of use
CN113712842A (en) * 2020-05-25 2021-11-30 基元美业生物科技(上海)有限公司 Composition and application thereof in preparation of cosmetics and medical instruments
CN113766832A (en) * 2019-01-31 2021-12-07 帕尔斯希拉公司 Germicidal methods and compositions
CN114025801A (en) * 2019-06-20 2022-02-08 韩国地质资源研究院 Oral pharmaceutical composition for eradicating the antibiotic resistant helicobacter pylori comprising a complex of a non-absorbable antibiotic substance and a clay mineral
CN114984746A (en) * 2022-08-05 2022-09-02 山东建筑大学 System method and device for treating VOCs waste gas in disinfectant and aquaculture wastewater pool
CN117919248A (en) * 2024-03-22 2024-04-26 四川兴泰普乐医疗科技有限公司 Injectable hair growth composition and preparation method and application thereof
CN117919248B (en) * 2024-03-22 2024-06-04 四川兴泰普乐医疗科技有限公司 Injectable hair growth composition and preparation method and application thereof

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8957034B2 (en) 2004-01-28 2015-02-17 Johns Hopkins University Drugs and gene carrier particles that rapidly move through mucous barriers
CA2871745C (en) 2012-05-03 2023-01-24 Kala Pharmaceuticals, Inc. Pharmaceutical nanoparticles showing improved mucosal transport
KR102140989B1 (en) 2012-05-03 2020-08-04 칼라 파마슈티컬스, 인크. Pharmaceutical nanoparticles showing improved mucosal transport
US11596599B2 (en) 2012-05-03 2023-03-07 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
ES2688381T3 (en) * 2012-09-28 2018-11-02 Stelo Technologies Methods for making silver nanoparticles and their applications
CN103667119B (en) * 2013-11-26 2015-07-29 浙江大学 For the bacterial strain of sulfur alcohol of degrading and cultural method thereof and application
US9622483B2 (en) 2014-02-19 2017-04-18 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US11039621B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US11039620B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
WO2015131220A1 (en) * 2014-03-07 2015-09-11 Mark Tuffley Composition and method for enhancing wound healing
CN105572126B (en) * 2015-04-07 2018-10-23 湖南华纳大药厂股份有限公司 A kind of colloidal bismmth pectin pharmaceutical composition
BR112017021271A2 (en) 2015-04-08 2018-06-26 Biomendics Llc formulation and process for modulating wound healing
WO2017145142A1 (en) 2016-02-25 2017-08-31 Nobio Ltd. Micro and nanoparticulate compositions comprising anti-microbially active groups
US20200016231A1 (en) * 2016-12-22 2020-01-16 Whiteley Corporation Pty Ltd Biofilm disrupting composition
EP3675802A4 (en) 2017-08-30 2021-03-03 Nobio Ltd. Compositions and medical devices comprising anti-microbial particles
CA3132400A1 (en) * 2019-03-18 2020-09-24 Cedars-Sinai Medical Center Compositions and methods to treat gastrointestinal diseases and disorders
CN111034711B (en) * 2019-12-19 2022-04-05 海南一龄医疗产业发展有限公司 Composition and method for efficiently removing microbial contamination in cell culture process
CN111175103B (en) * 2020-01-16 2023-07-04 江西业力医疗器械有限公司 Leucorrhea sample pretreatment liquid for fluorescent detection of mycotic vaginitis and preparation method thereof
US20230124862A1 (en) * 2020-03-24 2023-04-20 Jeffrey W. MILLARD Bismuth thiol compounds and compositions and methods of treating microbial co-infections
CN112618716B (en) * 2021-01-11 2022-04-08 福州大学 Photodynamic combined lysozyme antibacterial method
CN113930462A (en) * 2021-10-19 2022-01-14 江南大学 Method for synthesizing hexanoic acid by using homoserine lactone signal molecule to promote carbon chain elongation microorganisms
CN115532295B (en) * 2022-09-27 2023-07-25 苏州大学 Application of nanomaterial containing Zn-N-C active center in removal of bacterial biofilm

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1283996A (en) * 1997-10-28 2001-02-14 温斯洛普大学医院 Method/thiol biochdes

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5999828A (en) * 1997-03-19 1999-12-07 Qualcomm Incorporated Multi-user wireless telephone having dual echo cancellers
AU2656799A (en) * 1998-02-04 1999-08-23 Winthrop-University Hospital Metal-thiols as imminomodulating agents
US6682724B2 (en) * 1999-02-23 2004-01-27 Arch Chemcials, Inc. Sonic method of enhancing chemical reactions to provide uniform, non-agglomerated particles
US7381751B2 (en) * 2003-08-26 2008-06-03 Shantha Sarangapani Antimicrobial composition for medical articles
US8343536B2 (en) * 2007-01-25 2013-01-01 Cook Biotech Incorporated Biofilm-inhibiting medical products
US8389021B2 (en) * 2009-02-03 2013-03-05 Microbion Corporation Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1283996A (en) * 1997-10-28 2001-02-14 温斯洛普大学医院 Method/thiol biochdes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAJED HALWANI,ET AL: "Liposomal bismuth-ethanedithiol formulation enhances antimicrobial activity of tobramycin", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110691603A (en) * 2016-12-05 2020-01-14 抗菌技术生物技术研究与发展股份有限公司 Bacteriophage compositions comprising respiratory antibacterial bacteriophage and methods of use thereof
CN110691603B (en) * 2016-12-05 2024-01-30 抗菌技术生物技术研究与发展股份有限公司 Phage compositions comprising respiratory antibacterial phage and methods of use thereof
CN109939090A (en) * 2017-11-16 2019-06-28 帝斯曼知识产权资产管理有限公司 Novel purposes
CN110387416A (en) * 2018-04-16 2019-10-29 华东理工大学 The double probe systems of the nanogold of controllable polymerization adjusting function and its application
CN112788950A (en) * 2018-07-31 2021-05-11 微生物公司 Bismuth-thiol compositions and methods for treating wounds
CN112804878A (en) * 2018-07-31 2021-05-14 微生物公司 Bismuth-thiol compositions and methods of use
CN110870874A (en) * 2018-08-13 2020-03-10 中山大学 Medicine with antibacterial effect and application thereof
CN113766832A (en) * 2019-01-31 2021-12-07 帕尔斯希拉公司 Germicidal methods and compositions
CN114025801A (en) * 2019-06-20 2022-02-08 韩国地质资源研究院 Oral pharmaceutical composition for eradicating the antibiotic resistant helicobacter pylori comprising a complex of a non-absorbable antibiotic substance and a clay mineral
CN112425608A (en) * 2019-08-23 2021-03-02 香港科技大学 Elastase inhibitors, bacteriostatic agents with anti-biofilm activity effective against both single-and multi-species biofilms
CN112425608B (en) * 2019-08-23 2023-07-21 香港科技大学 Elastase inhibitor and antibacterial agent with anti-biofilm activity
CN113712842B (en) * 2020-05-25 2023-06-13 基元美业生物科技(上海)有限公司 Composition and application thereof in preparation of cosmetics and medical devices
CN113712842A (en) * 2020-05-25 2021-11-30 基元美业生物科技(上海)有限公司 Composition and application thereof in preparation of cosmetics and medical instruments
CN114984746A (en) * 2022-08-05 2022-09-02 山东建筑大学 System method and device for treating VOCs waste gas in disinfectant and aquaculture wastewater pool
CN117919248A (en) * 2024-03-22 2024-04-26 四川兴泰普乐医疗科技有限公司 Injectable hair growth composition and preparation method and application thereof
CN117919248B (en) * 2024-03-22 2024-06-04 四川兴泰普乐医疗科技有限公司 Injectable hair growth composition and preparation method and application thereof

Also Published As

Publication number Publication date
WO2011097347A2 (en) 2011-08-11
MX2012009054A (en) 2012-12-17
CA2788669A1 (en) 2011-08-11
MX346409B (en) 2017-03-17
AU2011212941B2 (en) 2016-03-03
CN107308186A (en) 2017-11-03
EP2536406A2 (en) 2012-12-26
EP2536406A4 (en) 2014-04-09
WO2011097347A3 (en) 2011-12-22
JP2013518895A (en) 2013-05-23
CA2788669C (en) 2021-05-25
AU2011212941A1 (en) 2012-09-27

Similar Documents

Publication Publication Date Title
CN102341105B (en) Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications
US10960012B2 (en) Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses
CN103079557A (en) Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses
AU2018204190B2 (en) Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses
AU2018204188A1 (en) Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications
AU2013202847B2 (en) Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20130501