CN101374532A - Use of gallium to treat biofilm-associated infectons - Google Patents

Abstract

The invention provides methods, compositions, and kits for treatment or prevention of biofilm-associated infections in an individual. Methods of the invention include administration of a gallium-containing composition for treatment of an established biofilm or prevention of formation of a biofilm. Some methods include administration of a gallium-containing composition in conjunction with an antibiotic substance. Some methods include treatment or prevention of an orally-associated biofilm with a gallium-containing composition in the form of a dentrifice, mouthwash, or chewing gum composition.

Description

Gallium is used for the treatment of the purposes of the infection relevant with biomembrane

The cross reference of relevant application

The application has required the U.S. Provisional Application No.60/763 on January 30th, 2006 application, and 676 and in the U.S. Provisional Application No.60/801 of application on May 16th, 2006,082 priority, the disclosure of the two all is incorporated herein by reference.

Technical field

The present invention relates to contain gallium compositions is used for treating existing biofilms or preventing biological film formed purposes at individuality.

Background technology

The bacterial clump that bacterial biof iotalm is being sealed by extracellular matrix.

The antibacterial that is encapsulated in the biomembrane usually sees through than difficulty detergent and antibiotic.Extensively proved the antibiotic resistance of the antibacterial in the biomembrane, bacterial biof iotalm works in the numerous disease environment, and described disease environment comprises that cystic fibrosis increases the weight of, chronic urinary tract infection, chronic sinus infection, the infection and the dental plaque that are caused by medical apparatus such as conduit and ventilation installation.(see, for example, people such as Costerton (1999), Science 284 (5418) 1318-22)

Biomembranous formation and keep and need chemical element ferrum, pathogenic bacterium to evolve out to extract the special mechanism of ferrum from the host.For example, in order from host environment, to catch extracellular ferrum, opportunistic pathogen-Pseudomonas aeruginosa in cystic fibrosis and the urinary tract infection (Pseudomonas aeruginosa)-two kinds of siderophores of expression, i.e. pyocyanin (pyocydin) and blue or green pyin (pyoverdin).Shown under the situation that has 20 μ g/ml lactoferrin (a kind of key protein in conjunction with ferrum of in host's mucosa secretions, expressing), can suppress the Pseudomonas aeruginosa biomembrane by the ferrum chelating and form (people (2002) Nature 417 (6888) such as Singh: 552-55).Therefore, these antibacterials are to macrolide antibiotics and other aminoglycoside such as tobramycin sensitivity.Replenishing ferrum in culture medium causes significant antibacterial to regrow and the formation of antibacterial drug tolerant bacteria biomembrane.Microscopy when contracting (Time-lapse microscopy) proves with the lactoferrin chelated iron and induces Pseudomonas aeruginosa to cover the surface rather than form petite and gather in the biomembrane.Rich iron bar spare stimulates antibacterial to form population of cells and form biomembranous phenotype subsequently by it.

The main pathogens of chronic urinary tract infection (UTI) is gram negative bacilli such as escherichia coli (Escherichia coli), proteus bacterial strain (Proteus spp.) and pneumobacillus (Klebsiellapneumoniae), has shown that these three kinds of antibacterials all form biomembrane.Though the available antibiotic number of treatment UTI is increasing, and has chemical sproof pathogen also more and more general always.It is many to cause the chemical sproof factor of UTI pathogen to have, and one of them is the formation of bacterial biof iotalm.

Bacterial biof iotalm is relevant with conduit dependency UTI, struvite calculus formation (struvitecalculogenesis) and chronic prostatitis and some other common UTI situation.The bacterial infection relevant with biomembrane usually is hospital's source property in nature, and the skin infection of the pulmonary infection in UTI, intensive care unit, burn victim and reduce in the septicemia of property related to cancer acute rapid with neutrophilic leukocyte.Coagulase negative staphylococcus belongs to (Staphylococci), Enterococcus bacterial strain (Enterococcus spp), pneumobacillus is usually relevant with the biomembrane on the catheter with Pseudomonas aeruginosa.

Fully proved the antibiotic resistance (people such as Costerton, the same) that is embedded in the antibacterial in the biomembrane that adheres to catheter.Such biomembrane may be that reduction causes because biofilm matrix itself is to the metabolic activity in antibiotic poor permeability or the biomembrane to the drug resistance increase of antibiotic therapy.In case lost the protection of biomembrane environment, each antibacterial that is disperseed out by the antibiotic resistance biomembrane has then recovered low-level antibiotic sensitivity.

Need in the art to be used for the treatment of or prevent biological film formed modification method.

The invention summary

The invention provides and be used for that individuality treatment biomembranous method, compositions and the medicine box of needs are being arranged.

On the one hand, the invention provides the biomembranous method of treatment in the individuality that needs is arranged, it comprises the gallium compositions that contains to this individuality administering therapeutic effective dose.Described treatment comprises prevention, treatment or cures.In some embodiments, this method comprises that the prevention biomembrane forms, and it comprises the gallium compositions that contains of using the prevention effective dose to individuality.In one embodiment, this method comprises inhibition or prevents that the infection relevant with biomembrane is diffused into other individual position.In another embodiment, this method comprises destroys the extracellular biofilm matrix, thereby makes host's immune system can remove this infection.

In many embodiments, biomembrane is present in bladder, kidney, the heart, middle ear, hole, skin, lung, joint, subcutaneous tissue, soft tissue, vascular tissue and/or the eye.In one embodiment, this method comprises the biomembrane that treatment is relevant with urinary tract infection.In another embodiment, biomembrane is relevant with the chronic bacterial vaginosis.In another embodiment, biomembrane is relevant with bacterial keratitis.In one embodiment, biomembrane is relevant with prostatitis.In one embodiment, biomembrane is arranged in the lung of the individuality of not suffering from cystic fibrosis.In one embodiment, biomembrane is arranged in individual lung, and wherein this biomembrane does not comprise Pseudomonas aeruginosa.In one embodiment, biomembrane is positioned on the individual skin, and wherein its skin does not comprise burn.

In some embodiments, biomembrane comprises at least a antibacterial.This antibacterial can be gram positive bacteria or gram negative bacteria.Gram positive bacteria includes but not limited to that bacillus (Bacillus), Corynebacterium (Corynebacteria), fusobacterium (Clostridium), Enterococcus (Enterococcus), Listera belong to (Listeria), staphylococcus or Streptococcus (Streptococcus).Gram negative bacteria includes but not limited to Pseudomonas aeruginosa, Branhamella (Branhamella), campylobacter (Campylobacteria), escherichia coli, Enterobacter (Enterobacteria), pasteurella (Pasteurella), proteus (Proteus), Klebsiella (Klebsiella), eisseria (Neisseria), Salmonella (Salmonella), Shigella (Shigella) or Serratia (Serratia).

In some embodiments, this method comprise use at least a antibiotic and with it combination contain gallium compositions.Described at least a antibiotic use can with contain using simultaneously or carrying out in succession of gallium compositions.In some embodiments, antibiotic with contain the collaborative onset treatment of gallium compositions biomembrane.In some embodiments, antibiotic with contain gallium compositions addition onset treatment biomembrane.The antibiotic that can be used for method of the present invention includes but not limited to ciprofloxacin, the ampicillin, azithromycin, cephalosporin, doxycycline, fusidic acid, gentamycin, Linezolid, levofloxacin, norfloxacin, ofloxacin, rifampicin, tetracycline, tobramycin, vancomycin, amikacin, defitazidime, cefepime, trimethoprim/Sulfamethoxazole, piperacillin/tazobactam, aztreonam (aztreanam), meropenem, polymyxin E and chloromycetin.The antibiotic classification that can be used for method of the present invention include but not limited to aminoglycoside, carbacephems (carbacephem), carbapenems, first generation cephalosporin class, second generation cephalosporin class, third generation cephalosporin class, the 4th generation cephalosporins, glycopeptide class, Macrolide, monobactam class (monobactam), penicillins, polypeptide class, quinolones, sulfonamides, Tetracyclines, lincosamide class and oxazolidine ketone.

In some embodiments, containing gallium compositions comprises neutral (neutral) 3:1 (hydroxy pyrone: the co-ordination complex of complex form gallium), wherein each hydroxy pyrone molecule is unsubstituted or by one, two or three C ₁-C ₆Alkyl substituent replaces.In some embodiments, each hydroxy pyrone molecule is selected from 3-hydroxyl-pyrokomane, 3-hydroxy-2-methyl-pyrokomane, 3-hydroxyl-2-ethyl-pyrokomane and 3-hydroxy-6-methyl-4-pyrone.In one embodiment, each hydroxy pyrone molecule is 3-hydroxy-2-methyl-pyrokomane.

In some embodiments, containing gallium compositions is used by parenteral.In some embodiments, contain gallium compositions by Orally administered.In some embodiments, containing gallium compositions is used by limitation (locally) or local (topically).

On the other hand, the invention provides the biomembranous method of treatment in the individuality that needs is arranged, it comprise to this individuality administering therapeutic effective dose contain gallium compositions and antibiotic, wherein contain the collaborative onset treatment of gallium compositions and antibiotic biomembrane.

On the other hand, the invention provides the individual biomembranous method relevant with the oral cavity of treatment, it comprises makes biomembrane contact with the gallium compositions that contains of treatment effective dose.In one embodiment, this method comprises that the gallium compositions that contains by using the prevention effective dose prevents biomembrane formation and/or prevention biomembrane to expand to another position in individuality.

In one embodiment, the biomembrane relevant with the oral cavity is positioned on the tooth, for example, and the dental plaque on the tooth.In other embodiments, relevant with oral cavity biomembrane is positioned on tongue, oral mucosa or the gingiva.Contain gallium compositions and can be configured to dentifrice (dentrifice) for example toothpaste, mouthwash agent composition or chewing gum or be formulated as smears (paint), foam, gel or varnish (varnish), for example, be used for the fluoro-containing composition of fluoride treatment.

In one embodiment, the invention provides the method for the individual bacterial keratitis of treatment, it comprises makes the biomembrane relevant with the bacterial keratitis of individual eyes contact with the gallium compositions that contains of treatment effective dose.This contains gallium compositions can be configured to eye drop or the contact lens solutions that contains gallium.

On the other hand, the invention provides and be used for the treatment of the biomembranous gallium compositions that contains.In one embodiment, this contains gallium compositions and is configured to dentifrice, for example toothpaste.In another embodiment, this contains gallium compositions and is configured to collutory.In another embodiment, this contains gallium compositions and is configured to chewing gum.In another embodiment, this contains gallium compositions and is configured to eye drop.In another embodiment, this contains gallium compositions and is configured to contact lens solutions.In another embodiment, this contains gallium compositions and comprises at least a antibiotic, for example ciprofloxacin, ampicillin, azithromycin, cephalosporin, doxycycline, fusidic acid, gentamycin, Linezolid, levofloxacin, norfloxacin, ofloxacin, rifampicin, tetracycline, tobramycin, vancomycin, amikacin, deftazidime, cefepime, trimethoprim/Sulfamethoxazole, piperacillin/tazobactam, aztreonam, meropenem, polymyxin E or chloromycetin, and randomly comprise pharmaceutically useful carrier.In another embodiment, this contains gallium compositions and comprises at least a antibiotic, and this antibiotic is selected from and includes but not limited to following antibiotic classification: aminoglycoside, carbacephems, carbapenems, first generation cephalosporin class, second generation cephalosporin class, third generation cephalosporin class, the 4th generation cephalosporins, glycopeptide class, Macrolide, monobactam class, penicillins, polypeptide class, quinolones, sulfonamides, Tetracyclines, lincosamide class and oxazolidine ketone.

On the other hand, the invention provides the medicine box that is used for the treatment of (the comprising prevention) infection relevant with biomembrane.Medicine box of the present invention comprises and contains gallium compositions and packing.Medicine box can comprise the operation instructions that are used for the treatment of the infection relevant with biomembrane.In some embodiments, medicine box comprises at least a antibiotic.In some embodiments, medicine box comprise be configured to dentifrice such as toothpaste, mouthwash agent composition or chewing gum compositions or be formulated as smears, foam, gel or varnish for example be used for fluoride treatment fluoro-containing composition contain gallium compositions.In some embodiments, medicine box comprises the gallium compositions that contains that is configured to eye drop or contact lens solutions.In some embodiments, medicine box comprises and comprises the pharmaceutical composition that contains gallium compositions and pharmaceutically suitable carrier.

Brief Description Of Drawings

Fig. 1 has described Gallium maltolate (gallium maltolate) and (300mg/kg) has monitored with the bio-photon (biophotonic) that ciprofloxacin acts in Pseudomonas aeruginosa Xen 5UTI mouse model.After conduit is taken out, measure the count plate in the conduit immediately and it is illustrated in the right-hand side (open symbols, it is corresponding to the described treatment of figure top filled symbols) of figure from the mice bladder.

Fig. 2 has represented the real-time monitoring that Gallium maltolate (300mg/kg) and ciprofloxacin act in Pseudomonas aeruginosa Xen5UTI mouse model.Provided the representative animal of each group.

Fig. 3 has represented to deliver medicine to the pharmacokinetic data available of the Gallium maltolate of female CF-1 mice.

Fig. 4 has represented to carry that Pseudomonas aeruginosa is biomembranous shifts out the scanning electron microscope analysis result of (explanted) conduit vertical section.

Detailed Description Of The Invention

The invention provides the method, composition and the medicine box that are used for the treatment of the infection relevant with biomembrane. Particularly, use in the method for the invention and contain gallium compositions with treatment in the individuality of needs is arranged (comprising prevention, treatment and healing) infection relevant with biomembrane, randomly co-administered one or more antibiotic or one or more non-antibiotic antimicrobial.

General technology

Except as otherwise noted, otherwise enforcement of the present invention will utilize molecular biology (comprising recombinant technique), microbiology, cell biology, biochemistry and immunologic routine techniques, and it is in those skilled in the art's skill. Such technology proves absolutely in the literature, for example: molecular cloning: laboratory manual (Molecular Cloning:A Laboratory Manual), second edition (people such as Sambrook, 1989) Cold Spring Harbor Press; Oligonucleotide synthesizes (Oligonucleotide Synthesis) (MJ.Gait edits, 1984); Molecular biology method (Methods in Molecular Biology), Humana Press; Cell biology: laboratory manual (CellBiology:A Laboratory Notebook) (J.E.Cellis edits, 1998) Academic Press; Animal cell culture (Animal Cell Culture) (R.I.Freshney edits, 1987); Cell and tissue culture is introduced (Introduction to Cell and Tissue Culture) (J.P.Mather and P.E.Roberts, 1998) Plenum Press; Cell and tissue culture: laboratory operation (Cell and Tissue Culture:Laboratory Procedures) (A.Doyle, J.B.Griffiths and D.G.Newell edit, 1993-8) J.Wiley and Sons; Enzymology method (Methods in Enzymology) (Academic Press, Inc.); Experiment immunization learns to do volume (Handbook of Experimental Immunology) (D.M.Weir and CC.Blackwell edit); The gene transfer vector of mammalian cell (Gene Transfer Vectors for Mammalian Cells) (J.M.Miller and M.P. Calos edit 1987); Molecular biological popular scheme (Current Protocols in Molecular Biology) (people such as F.M.Ausubel edits 1987); PCR: polymerase chain reaction (PCR:The Polymerase Chain Reaction) (people such as Mullis edits 1994); Immunologic popular scheme (Current Protocols in Immunology) (people such as J.E.Coligan edits 1991); Molecular biological brief scheme (Short Protocols in Molecular Biology) (Wiley and Sons, 1999); Immuno-biology (Immunobiology) (CA.Janeway and P.Travers, 1997); Antibody (Antibodies) (P.Finch, 1997); Antibody: a kind of method of practicality (Antibodies:a practical approach) (D.Catty. edits, IRL Press, 1988-1989); Monoclonal antibody: a kind of method of practicality (Monoclonal antibodies:a practical approach) (P. Shepherd and C.Dean edit, Oxford University Press, 2000); Antibody is used: laboratory manual (Using antibodies:a laboratory manual) (E.Harlow and D.Lane (Cold Spring Harbor Laboratory Press, 1999); And antibody (The Antibodies) (M. Zanetti and J.D.Capra edit, Harwood Academic Publishers, 1995).

Definition

Except as otherwise noted, otherwise the present invention is not limited to concrete synthetic method, analog, substituting group, pharmaceutical preparation, formulation components, method of application etc., and it can change. Should be understood that also term used herein only is in order to describe particular, is not to limit with it.

Unless in context, clearly demonstrate, otherwise used singulative comprises that plural number refers to thing in this specification and the appended claims. Therefore, for example, when relating to " substituting group ", comprise the substituting group that single substituting group and two or more can be identical or different, when relating to " a kind of compound ", comprise combination or mixture and the individualized compound of different compounds, when relating to " a kind of pharmaceutically useful carrier ", comprise two or more such carriers and single carrier etc.

Term used herein " alkyl " refers to side chain or straight chain saturation alkane base, its usually (but be not must) contain 1 to about 24 carbon atoms, such as methyl, ethyl, just-propyl group, isopropyl, just-butyl, isobutyl group, tert-butyl, octyl group, decyl etc., and cycloalkyl such as cyclopenta, cyclohexyl etc. Although neither be essential, alkyl herein generally contains 1 to about 18, preferred 1 to about 12 carbon atoms. Term " low alkyl group " refers to the alkyl of 1 to 6 carbon atom. Preferred low-grade alkyl substituent contains 1 to 3 carbon atom, and particularly preferred this class substituting group contains 1 or 2 carbon atom (that is, methyl and ethyl). " substituted alkyl " refers to have one or more substituent alkyl, and term " contains heteroatomic alkyl " and " assorted alkyl " refers to that wherein at least one carbon atom is described in further detail it hereinafter by the alkyl that hetero atom replaces. If not in addition explanation, then term " alkyl " and " low alkyl group " comprise respectively the unsubstituted, substituted of straight chain, side chain, ring-type and/or contain heteroatomic alkyl or low alkyl group.

Unless otherwise specifically indicated, otherwise term used herein " aryl " refer to contain single aromatic ring or condense the aromatic substituent of a plurality of aromatic rings of directly linking to each other or indirectly linking to each other together (thereby so that different aromatic ring be bonded on a common group such as methylene or the ethylidene part). Preferred aryl contains 5 to 24 carbon atoms, and particularly preferred aryl contains 5 to 14 carbon atoms. The aryl of illustrative contains an aromatic ring or two aromatic rings that condense or link to each other, such as phenyl, naphthyl, xenyl, diphenyl ether, diphenylamine, benzophenone etc. " substituted aryl " refers to the aryl moiety that replaced by one or more substituting groups, term " contains heteroatomic aryl " and " heteroaryl " refers to the aryl substituent that at least one carbon atom is wherein replaced by hetero atom, will further be described in detail it hereinafter. If not in addition explanation, then term " aryl " comprises unsubstituted, substituted and/or contains heteroatomic aromatic substituent.

This term during term for example " contains " " containing heteroatomic alkyl " (be also referred to as " assorted alkyl ") or " containing heteroatomic aryl " (being also referred to as " heteroaryl ") heteroatomic refer to wherein one or more carbon atoms by non-carbon atom for example nitrogen, oxygen, sulphur, phosphorus, germanium or silicon, be generally molecule, bonding or substituting group that nitrogen, oxygen or sulphur, preferred nitrogen or oxo are replaced. Similarly, term " assorted alkyl " refers to contain heteroatomic alkyl substituent, term " heterocyclic radical " refers to contain heteroatomic cyclic substituents, and term " heteroaryl " and " heteroaromatic " refer to respectively contain heteroatomic " aryl " and " aromatics " substituting group etc. The example of assorted alkyl comprises the alkyl, the alkylating aminoalkyl of N-of alkoxy aryl, alkylthio group-replacement etc. The substituent example of heteroaryl comprises pyrrole radicals, pyrrolidinyl, pyridine radicals, quinolyl, indyl, pyrimidine radicals, imidazole radicals, 1,2,4-triazolyl, tetrazole radical etc., the example that contains heteroatomic alicyclic group has pyrrolidino, morpholine subbase, Piperazino, piperidino etc.

" alkyl " refer to contain 1 to about 30 carbon atoms, preferred 1 to about 24 carbon atoms, more preferably 1 to about 18 carbon atoms, the univalence hydrocarbyl of 1 to 12 carbon atom most preferably from about, comprise straight chain, side chain, ring-type, saturated and undersaturated alkyl, such as alkyl, alkenyl, aryl etc. " substituted alkyl " refers to that the alkyl that replaced by one or more substituting groups, term " contain heteroatomic alkyl " and refer to the alkyl that at least one carbon atom is wherein replaced by hetero atom. Except as otherwise noted, otherwise term " alkyl " should be interpreted as comprising substituted and/or containing heteroatomic hydrocarbyl portion.

This term in (mentioning in some above-mentioned definition) such as term " substituted " such as " substituted alkyl ", " substituted aryl " refers in alkyl, aryl or other parts, and the hydrogen atom of at least one and carbon atom (or other atom) bonding is replaced by one or more non-hydrogen substituting groups. Such substituent example includes but not limited to: functional group such as halogen, hydroxyl, sulfydryl, C₁-C ₂₄Alkoxyl, C₂-C ₂₄Alkenyloxy, C₂-C ₂₄Alkynyloxy group, C₅-C ₂₄Aryloxy group, acyl group (comprise C₂-C ₂₄Alkyl-carbonyl (CO-alkyl) and C₆-C ₂₄Aryl carbonyl (CO-aryl)), acyloxy (O-acyl group), C₂-C ₂₄Alkoxy carbonyl ((CO)-O-alkyl), C₆-C ₂₄Aryloxycarbonyl ((CO)-O-aryl), halo carbonyl (CO)-X, wherein X is halogen), C₂-C ₂₄Alkyl carbonic acid closes (carbonato) (O-(CO)-O-alkyl), C₆-C ₂₄Aryl carbonic acid close (O-(CO)-O-aryl), carboxyl (COOH), carboxylic acid close (carboxylato) (COO-), carbamoyl ((CO)-NH₂), list-(C₁-C ₂₄Alkyl)-and the carbamoyl that replaces ((CO)-NH (C₁-C ₂₄Alkyl)), two-(C₁-C ₂₄Alkyl)-and the carbamoyl that replaces ((CO)-N (C₁-C ₂₄Alkyl)₂), list-(C₆-C ₂₄Aryl)-carbamoyl that replaces ((CO)-NH-aryl), two-(C₆-C ₂₄Aryl)-and the carbamoyl that replaces ((CO)-N (aryl)₂), two-N-(C₁-C ₂₄Alkyl), N-(C₆-C ₂₄Aryl)-and the carbamoyl that replaces, thiocarbamoyl ((CS)-NH₂), urea groups (NH-(CO)-NH₂), cyano group (C ≡ N), isocyano group (N⁺≡C ^-), cyanato-(O-C ≡ N), different cyanato-(O-N⁺＝C ^-), different sulfo-cyanato-(S-C ≡ N), azido (N=N⁺＝N ^-), formoxyl ((CO)-H), thioformyl ((CS)-H), amino (NH₂), list-(C₁-C ₂₄Alkyl)-amino, two that replaces-(C₁-C ₂₄Alkyl)-amino, the list-(C that replace₅-C ₂₄Aryl)-amino, two that replaces-(C₅-C ₂₄Aryl)-amino, the C that replace₂-C ₂₄Alkyl amido (NH-(CO)-alkyl), C₆-C ₂₄Aryl acylamino-(NH-(CO)-aryl), imino group (CR=NH, wherein R=hydrogen, C₁-C ₂₄Alkyl, C₅-C ₂₄Aryl, C₆-C ₂₄Alkaryl, C₆-C ₂₄Aralkyl etc.), alkyl imino (CR=N (alkyl), wherein R=hydrogen, C₁-C ₂₄Alkyl, C₅-C ₂₄Aryl, C₆-C ₂₄Alkaryl, C₆-C ₂₄Aralkyl etc.), aryl imino group (CR=N (aryl), wherein R=hydrogen, C₁-C ₂₄Alkyl, C₅-C ₂₄Aryl, C₆-C ₂₄Alkaryl, C₆-C ₂₄Aralkyl etc.), nitro (NO₂), nitroso (NO), sulfo group (SO₂-OH), sulfonic acid closes (sulfonato) (SO₂-O ^-)、C ₁-C ₂₄Alkylthio group (S-alkyl; Be also referred to as " alkyl sulfenyl "), arylthio (S-aryl; Be also referred to as " artyl sulfo "), C₁-C ₂₄Alkyl sulphinyl ((SO)-alkyl), C₅-C ₂₄Aryl sulfonyl kia ((SO)-aryl), C₁-C ₂₄Alkyl sulphonyl (SO₂-alkyl), C₅-C ₂₄Aryl sulfonyl (SO₂-aryl), (P (O) (OH) for phosphono₂), phosphoric acid closes (phosphonato) (P (O) (O^-) ₂), phosphonic acids closes (phosphinato) (P (O) (O^-)), phosphate (PO₂) and phosphino-(PH₂); With hydrocarbyl portion C₁-C ₂₄Alkyl (preferred C₁-C ₁₈Alkyl, more preferably C₁-C ₁₂Alkyl, most preferably C₁-C ₆Alkyl), C₂-C ₂₄Alkenyl (preferred C₂-C ₁₈Alkenyl, more preferably C₂-C ₁₂Alkenyl, most preferably C_2-6Alkenyl), C₂-C ₂₄Alkynyl (preferred C₂-C ₁₈Alkynyl, more preferably C₂-C ₁₂Alkynyl, most preferably C₂-C ₆Alkynyl), C₅-C ₂₄Aryl (preferred C₅-C ₁₄Aryl), C₆-C ₂₄Alkaryl (preferred C₆-C ₁₈Alkaryl) and C₆-C ₂₄Aralkyl (preferred C₆-C ₁₈Aralkyl).

In addition, if special groups allows, above-mentioned functional group can also be further by one or more other functional groups or by one or more hydroxylic moieties as above mask body enumerate those replace. Similarly, above-mentioned hydrocarbyl portion can further be replaced such as those that specifically enumerate by one or more functional groups or other hydrocarbyl portion.

In the time of before term " substituted " appears at the substituted group of a series of possibilities, refer to that this term is applicable to each member of this group. For example, phrase " substituted alkyl, alkenyl and aryl " should be interpreted as " substituted alkyl, substituted alkenyl and substituted aryl ". Similarly, when term " contain heteroatomic " to appear at a series of may contain heteroatomic group before before the time, refer to that this term is applicable to each member of this group. For example, phrase " contains heteroatomic alkyl, alkenyl and aryl " and should be interpreted as " contain heteroatomic alkyl, contain heteroatomic alkenyl and contain heteroatomic aryl ".

" optional " or " randomly " is meant that the incident of describing subsequently can take place or not take place, so this description comprises situation that this incident wherein takes place and this incident situation about not taking place wherein.For example, phrase " randomly substituted " is meant and can has or not exist non-hydrogen substituent group on given atom, so this description comprises and wherein has non-hydrogen substituent structure and wherein do not have non-hydrogen substituent structure.Similarly, with dashed lines _ _ _ _ _ _ phrase of expression " randomly exists " valence link to be meant that this key can exist or not exist.

When the chemical compound of the present invention that relates to as activating agent, the applicant not only comprises specified molecular entity with term " chemical compound " or " activating agent ", but also comprise its pharmaceutically useful salt, pharmacological activity analog, include but not limited to salt, ester, amide, hydrate, solvate, prodrug, conjugates, active metabolite and other this analog derivative, analog and related compound.

Term used herein " treatment " is to instigate the order of severity of symptom and/or frequency reduction, symptom and/or basic reason to disappear, stop symptom and/or its basic reason appearance and/or improvement or correction infringement.Therefore, with chemical compound of the present invention the patient being carried out " treatment " comprises the particular disorder or the bad physiological event of preventing susceptible individuality and controls clinical Symptomatic individuality to suppress disease or disease or to make disease or disease disappears.Treatment can comprise prevention, treatment or cure.For example, biomembranous treatment comprises that prevention easily (for example has high risk) and form that biomembranous patient forms biomembrane and by suppressing disease or making disease disappear to treat having biomembranous patient because of genetic predisposition, environmental factors, procatarxis disease or disease etc.

Term " effective dose " is meant the amount that contains gallium compositions that gallium is provided with the amount that is enough to produce required therapeutic outcome.Effective dose can be contained in one or more dosage, that is, obtaining required treatment terminal point may need single or multiple dosage." treatment effective dose " is meant the amount that contains gallium compositions that is enough to produce required therapeutic outcome (for example, reducing the biomembranous order of severity or elimination biomembrane)." prevention effective dose " is meant when being applied to easy formation biomembrane and/or may forming the biomembranous amount that contains gallium compositions that is enough to stop following biomembrane or reduces its order of severity when individual.

Term " controlled release " is meant the preparation that contains medicine or its fragment that its Chinese medicine does not discharge immediately, that is, when using " controlled release " preparation, use and can not cause medicine to be discharged in the absorption cell immediately.This term can with Remington: pharmaceutical science and put into practice (Remington:The Science andPractice of Pharmacy), the 19th edition (Easton, PA:Mack Publishing Company, 1995) defined in " non-promptly release " exchanges and uses.Generally speaking, term used herein " controlled release " comprises lasting release and delayed release preparation.

" pharmaceutically useful " be meant biologically or others do not have the material of undesirable character, promptly, this material can be blended in the pharmaceutical composition that is applied to the patient, can not cause any significant undesirable biological action or can not interact with deleterious mode is contained in compositions wherein with it other component.When being used for describing pharmaceutical carrier or excipient with " pharmaceutically useful ", it is meant that this carrier or excipient meet toxicology and required standard or its inert fraction that is included in FDA (Food and Drug Adminstration) (U.S.Food and Drug administration) formulation of manufacturing inspection instructs in (Inactive Ingredient Guide).

" individuality " is meant and is generally mammal by vertebrates, usually be the people.

Using method

Provide and to have contained the method that gallium compositions is applied to the individuality of the needs treatment infection relevant with biomembrane.Method of the present invention comprises prevention, treatment or the healing of the infection relevant with biomembrane.Described method comprises with treatment or prevention effective dose uses the one or more unit dose that contain gallium compositions.In the method for the invention, containing gallium compositions generally is applied in pharmaceutically useful carrier.In some embodiments, described method comprises the infection relevant with biomembrane of treatment hospital source property.

In the method for the invention, contain gallium compositions treatment to take place for the infection relevant with biomembrane or effective the measuring of prevention is applied to individuality for the individual existing infection relevant with biomembrane of treatment or prevention are individual.In some embodiments, suppress the infection relevant and be diffused into another individual position with biomembrane.In many embodiments, containing gallium compositions can be by parenteral, oral, limitation or local application.

Contain that gallium compositions can for example every day 2,3,4 or more a plurality of dosage be applied with single daily dose or a plurality of dosage.Generally speaking, when being applied to man-hour, containing gallium compositions and be applied so that about 2mg to be provided the total daily dose to about 800mg.Total daily dose of the gallium that is applied in some embodiments, for about 2mg to about 15mg, about 8mg to about 40mg, about 15mg to about 80mg, about 40mg about 160mg, about 150mg about 325mg or about 300mg about 500mg, about 500mg about 700mg or about 600mg about 800mg extremely extremely extremely extremely extremely.

Actual dose can change according to the gallium compound of being used, and can select so that the Ga that is sent (III) of scheduled volume is provided for the per kilogram weight in patients dosage.For example, certain methods of the present invention can comprise use provide about 0.1 to about 20mg Ga (III)/kg, the gallium compound of about 1 to about 12mgGa (III)/kg usually.

In some methods of the present invention that relate to systemic administration (for example parenteral use, Orally administered), will contain that gallium compositions is applied to individuality with the amount that is enough to the treatment to be provided or to prevent effective serum gallium level so that prevention or treatment biomembrane.In one embodiment, containing gallium compositions is applied with the unit dose of generation in about 24 hours after using at least about the gallium serum levels of 10ng/mL.In many embodiments, use the back about 24 hours the treatment or prevent effective serum gallium level be at least about 10,25,50,100,200,500,1000,2000,3000,4000,5000,6000 or 7000ng/mL in any.Usually after will containing gallium compositions to be applied to individuality, reach treatment or prevent effective serum levels in about 1,2,6,12,24,48 or 72 hour.

In some embodiments, method of the present invention comprises the infection relevant with biomembrane that gallium compositions is treated its bladder, kidney, the heart, middle ear, hole, skin, lung, joint, subcutaneous tissue, soft tissue, vascular tissue and/or eye that contain to the individual administering therapeutic effective dose that needs are arranged.In some embodiments, relevant with biomembrane infection is at least one position except that lung and/or skin.In one embodiment, the gallium compositions that contains of treatment effective dose is applied to the individuality that needs are arranged and treats the urinary tract infection relevant with biomembrane.In another embodiment, the gallium compositions that contains with the treatment effective dose is applied to the individuality that needs are arranged and treats the chronic bacterial vaginosis relevant with biomembrane.In another embodiment, the gallium of treatment effective dose is applied to there is the individuality that needs to treat the prostatitis relevant with biomembrane.In another embodiment, the gallium of treatment effective dose is applied to has the individuality that needs to treat the bacterial infection that be derived from diabetes relevant with biomembrane, as the diabetic skin ulcer.In another embodiment, the gallium of treatment effective dose is applied to there is the individuality that needs to treat pressure ulcer.In another embodiment, the gallium of treatment effective dose is applied to there is the individuality that needs to treat relevant with the biomembrane ulcer relevant with venous duct.In another embodiment, the gallium of treatment effective dose is applied to there is the individuality that needs to treat the surgical wound relevant (for example, surgical site infection) with biomembrane.

In one embodiment, biomembrane is arranged in individual lung, wherein should not have cystic fibrosis by individuality.In one embodiment, biomembrane is arranged in individual lung, and wherein this biomembrane does not comprise Pseudomonas aeruginosa.The example of the pulmonary infection of available the inventive method treatment includes but not limited to that pulmonary actinomycosis, Nocardia (Nocardia) infection, pulmonary abscess, infectious bacteria bronchitis and bacterial pneumonia (for example, comprise streptococcus pneumoniae (Streptococcus pneumoniae), hemophilus influenza (H.influenzae), Klebsiella, staphylococcus aureus (Staphylococcus aureus), legionella pneumophilia (Legionella pneumophila), escherichia coli, Rhodopseudomonas (Pseudomonas), Enterobacter or Serratia.

In one embodiment, biomembrane is positioned on the individual skin, and wherein this skin does not comprise burn.The example of the skin infection of available method treatment of the present invention includes but not limited to bacterial skin infection, kawasaki disease (Kawasaki disease), pseudofolliculitis barbae (Pseudofolliculitis barbae), sarcoidosis, scalp folliculitis (Scalp folliculitis), diabetic ulcer and pressure ulcer (pressure ulcer).In one embodiment, biomembrane is arranged under the skin surface, is positioned at subcutaneous tissue, as dark tissue injury or surgical site infection.

In some embodiments, method of the present invention further comprises the antibiotic of using one or more unit dose, and described antibiotic includes but not limited to ciprofloxacin, the ampicillin, azithromycin, cephalosporin, doxycycline, fusidic acid, gentamycin, Linezolid, levofloxacin, norfloxacin, ofloxacin, rifampicin, tetracycline, tobramycin, vancomycin, amikacin, deftazidime, cefepime, trimethoprim/Sulfamethoxazole, piperacillin/tazobactam, aztreonam, meropenem, polymyxin E or chloromycetin.In some embodiments, method of the present invention further comprises the antibiotic that uses one or more unit dose, and described antibiotic is selected from and includes but not limited to following antibiotic classification: aminoglycoside, carbacephems, carbapenems, first generation cephalosporin class, second generation cephalosporin class, third generation cephalosporin class, the 4th generation cephalosporins, glycopeptide class, Macrolide, monobactam class, penicillins, polypeptide class, quinolones, sulfonamides, Tetracyclines, lincosamide class and oxazolidine ketone.

Contain that gallium compositions can be worked in coordination with antibiotic or the infection relevant with biomembrane treated in the addition onset.Containing gallium compositions and antibiotic can be identical or independently use simultaneously or sequential application in the compositions.

In some embodiments; method of the present invention further comprises the non-antibiotic antimicrobial of using one or more unit dose, and described non-antibiotic antimicrobial includes but not limited to thioridazine, benzoyl peroxide, taurolidine and the hexitidine of Sertraline, raceme and stereoisomeric forms in any ratio.Contain that gallium compositions can be worked in coordination with non-antibiotic antimicrobial or the infection relevant with biomembrane treated in the addition onset.Containing gallium compositions and non-antibiotic antimicrobial can be identical or independently use simultaneously or sequential application in the compositions.

In some embodiments, method of the present invention comprises the biomembrane relevant with the oral cavity that treatment is individual, and it comprises makes oral surfaces contact with the gallium compositions that contains of treatment effective dose.Some methods of the present invention comprise that the gallium compositions that contains by use the prevention effective dose to individuality prevents the biomembrane relevant with the oral cavity.The biomembrane relevant with the oral cavity can be dental plaque for example, contains that gallium compositions can be configured to dentifrice such as toothpaste is treated or pre-preventing dental plaque.In other embodiments, biomembrane can be positioned on tongue, oral mucosa or the gingiva.In some embodiments, contain gallium compositions and be configured to collutory.In some embodiments, contain gallium compositions and be configured to smears, foam, gel or varnish, for example, the compositions of fluoride.In one embodiment, containing gallium compositions is to be arranged in patient wear number minute gel or the foamy form with the mouth guard that carries out the fluoride treatment.

In certain methods as herein described, two or more can be contained gallium compositions and use jointly.In some embodiments, one or more can be contained for example one or more antibiotic, iron chelating agent deferoxamine (desferoxamine) (people (1997) Blood 89 (3) such as Olivieri: 739-61) or quorum sensing (quorum-sensing) medicine, for example suppress the peptide (RIP) people (2004) J Infect Dis 190:318-20 such as () Dell ' Acqua of RNAIII and use jointly for example of the useful material of gallium compositions and one or more treatment.

Contain gallium compositions

According to method of the present invention as herein described, can use and contain gallium compositions, its comprise co-ordination complex, the gallium (III) of gallium (III) for example salt, the gallium (III) beyond the salt inorganic compound or with protein bound gallium (III).For the using of individuality, can use and comprise the pharmaceutical composition that contains gallium compositions and pharmaceutically suitable carrier as herein described.

Gallium (III) co-ordination complex is the complex that comprises with the coordinate Ga of one or more parts (III) center.The co-ordination complex of gallium (III) include but not limited to the heterocyclic gallium of N-(III) complex (as three (oxine closes (quinolinolato)) galliums (III)), with gallium (III) complex that hydroxy pyrone forms, the gallium salt complex of gallium complex, gallium porphyrin (as gallium (III) protoporphyrin IX), 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. ftivazide gallium (III) and the pfpe acid that comprise the gallium complex (as Gallium maltolate) of 3-hydroxyl-pyrokomane of neutral 3:1, forms with pyridone ketone or substituted pyridone ketone.Such co-ordination complex includes but not limited to comprise those of three bidentate ligands or a tridentate ligand.Bidentate ligand is separately by two oxygen, nitrogen or sulphur atoms and gallium (III) center coordination; Two coordination atoms can be identical or different.Similarly, tridentate ligand is by three oxygen, nitrogen or sulphur atoms and gallium (III) center coordination; Three coordination atoms can be identical or different.These ligands can be all identical or can be the mixture of different ligands.

Bidentate ligand can be for example unsubstituted hydroxy pyrone or on 2-, 5-and/or 6-position by C ₁-C ₆The hydroxy pyrone that alkyl replaces.Bidentate ligand can be the hydroxy pyrone that 2-replaces or 5-replaces especially, as 3-hydroxy-2-methyl-pyrokomane (maltol) and 3-hydroxyl-2-ethyl-pyrokomane (ethyl maltol).Other example of bidentate ligand unsubstituted pyridone ketone is arranged or on 2-, 5-and/or 6-position by C ₁-C ₆The pyridone ketone that alkyl replaces.An example of tridentate ligand is the 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. ftivazide.

In addition, described part can also be the part of formula Ar-O-, and wherein Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl.For example, the Ar group can be the anion of randomly substituted heteroaryl such as oxine.

Described part also can be selected from the carboxylate part of the structure with R-(CO)-O-, and wherein R is alkyl, substituted alkyl, contains heteroatomic alkyl or substitutedly contain heteroatomic alkyl.

In one embodiment, be applicable to that the gallium compositions of method of the present invention comprises the gallium complex of 3-hydroxyl-pyrokomane, for example Gallium maltolate.To the synthetic and preparation example of complex in pharmaceutical preparation of such complex as in U.S. Patent No. 5,258,376,5,574,027,5,883,088,5,968,922,5,981,518,5,998,397,6, the existing description in 004,951,6,048,851 and 6,087,354.

Gallium salt comprises inorganic salt and organic salt.The example of inorganic salt and relevant inorganic compound includes but not limited to gallium chloride, Ganite (Fujisawa)., gallium sulfate, carbonic acid gallium and phosphoric acid gallium.The hydrated form and the solvation form that comprise these salt.The example of organic salt includes but not limited to acetic acid gallium, gallium citrate, gallium formate, hydroxamic acid gallium, oxalic acid gallium, glutamic acid gallium, Palmic acid gallium and tartaric acid gallium and their hydrated form and solvation form.The example of the inorganic gallium compound except that gallium salt has gallium oxide and gallium oxide hydroxide and their hydrated form and solvate forms.

Other compositions that is applicable to method of the present invention comprises peptide and the protein that contains bonded to some extent gallium.The example of this based composition comprises gallium-lactoferrin and gallium-transferrins.In some embodiments, described protein derived is from the kind of being treated.In some embodiments, compositions and one or more other active substance yokes that contains with the gallium of protein bound closes.The example of such conjugates has gallium-transferrins-amycin conjugates.

Biomembrane

" biomembrane " used herein be meant have promote the germs collect thing on the surface as adhesion on inside or outside organization or the organ and the germs collect thing of building the extracellular matrix of trooping and growing.Biomembrane can be made up of antibacterial, fungus, yeast, protozoacide or other microorganism.Bacterial biof iotalm is usually to be feature to antibiotic high drug-resistance, usually than the identical drug-resistance of bacteria of in biomembrane, not growing greatly up to 1,000 times.

In some embodiments, method of the present invention comprises that treatment (comprising prevention) internal or tissue are as the biomembrane on bladder, kidney, the heart, middle ear, hole, lung, joint, eye, outside organization such as the skin.In some embodiments, method of the present invention comprises the biomembrane on treatment (comprising prevention) oral surfaces such as tooth, tongue, oral mucosa or the gingiva.Method of the present invention can be used for treating the disease relevant with biomembrane such as soft tissue infection, chronic sinusitis, endocarditis, osteomyelitis, urinary tract infection, chronic bacterial vaginosis, dental plaque or halitosis, bacterial keratitis or prostatitis.

The biomembrane of antibacterial both can be formed by gram positive bacteria, can be formed by gram negative bacteria again.The example that can form biomembranous gram-positive bacterium includes but not limited to staphylococcus aureus, coagulase negative staphylococcus such as staphylococcus epidermidis (Staphylococcus epidermis), streptococcus pyogenes (Streptococcus pyogenes) (A group), Streptococcus species (Streptococcus viridans (viridans) group), streptococcus agalactiae (Streptococcus agalactiae) (B group), bargen's streptococcus (S.bovis), Streptococcus (anaerobism species), streptococcus pneumoniae (Streptococcus pneumoniae) and Enterococcus species.Other Gram-positive bacillus comprises anthrax bacillus (Bacillus anthracis), diphtheria corynebacterium (Corynebacterium diptheriae) and is the corynebacterium species of corynebacterium diphtheroides (Corynebacteriumdiptheroids) (aerobic with anaerobic), Listeria monocytogenes (Listeria monocytogenes), clostridium tetani and clostridium difficile.The example that can form biomembranous gram negative bacteria includes but not limited to escherichia coli, Enterobacter species, proteus mirabilis (Proteus mirablis) and other species, Pseudomonas aeruginosa, pneumobacillus (Klebsiellapneumoniae), Salmonella, Shigella, Serratia and campylobacter jejuni (Campylobacterjejuni), eisseria, mucositis Branhamella catarrhalis (Branhamellacatarrhalis) and pasteurella.

Can form biomembranous other organism and include but not limited to that dermatophytes (for example, Microsporon (Microsporum) species such as the little spore of Canis familiaris L. mould (Microsporum canis), Trichophyton (Trichophyton) species such as trichophyton purpureatum (Trichophyton rubrum) and Trichophyton mentagrophytes (Trichophyton mentagrophytes), yeast (for example, candida albicans (Candidaalbicans), Candida parapsilosis (Candida parapsilosis), Candida glabrata (Candidaglabrata), candida tropicalis (Candida tropicalis) and other candida mycoderma species (comprising drug-fast candida mycoderma species), acrothesium floccosum (Epidermophytonfloccosum) Blighted bran shape fish-scale mould (Malassezia fuurfur) (Pityrosporum orbiculare (Pityropsporon orbiculare), pityrosporum ovale (Pityropsporon ovale)), novel Cryptococcus (Cryptococcus neoformans), Aspergillus fumigatus (Aspergillus fumigatus) and other aspergillus (Aspergillus) species, zygomycete (Rizopus, mucor (Mucor)), thread mould genus (hyalohyphomycosis) (Fusarium (Fusarium) species), Paracoccidioides brasiliensis (Paracoccidiodes brasiliensis), dermatitis budding yeast (Blastmyces dermatitides), capsule tissue spore slurry bacterium (Histoplasma capsulatum), Blastomyces coccidioides (Coccidiodes immitis), Sporothrix schenckii (Sporothrix schenckii) and budding yeast belong to (Blastomyces).

Method of application

The method according to this invention contain using of gallium compositions can be by providing required treatment or preventive effect for example to reduce, eliminate or preventing biomembranous any approach to carry out.

In some embodiments, one or more contain gallium compositions and are used for limitation or local application is treated or prevention is relevant with the oral cavity biomembrane by preparation.For example can be applied to position, oral cavity such as tooth, tongue, oral mucosa or gingiva.In some embodiments, contain gallium compositions and be configured to dentifrice, for example dentifrice composition.In some embodiments, contain gallium compositions and be configured to collutory.In some embodiments, contain gallium compositions and be configured to smears, foam, gel or varnish, for example, comprise the compositions of fluoride.

Except one or more contain gallium compositions, dentifrice composition also (for example can randomly contain one or more abrasivuss (abrasive), Alumina, hydrated SiO 2, dicalcium phosphate, salt, Pumex, Kaolin, bentonite, calcium carbonate, sodium bicarbonate, calcium pyrophosphate (calcium pyrophosphagae)), the component of one or more preventing corruption (for example, sodium monofluorophosphate, stannous fluoride, sodium fluoride, xylitol), one or more antibacterial (for example, triclosan, Sanguinaria canadensis (sanguinaria) extract, sodium bicarbonate, Zinc citrate trihydrate., polyhydric phenols, stannous fluoride), one or more tartar controlling agents (for example, tetrasodium pyrophosphate, Gantrez S-70, sodium tripolyphosphate), the enzyme of one or more enhancing saliva antibacterial properties (for example, glucoseoxidase, lactoperoxidase, lysozyme), one or more desensitizeies (for example, potassium nitrate, strontium chloride, sodium citrate), one or more coloring agent, one or more detergents (for example, sodium lauryl sulphate, sodium lauroyl sarcosine, the N-sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium stearyl fumarate (sodium stearyl funarate), sodium stearoyl lactate, dodecyl sulfoacetic acid sodium), one or more correctivess (for example, Herba Menthae, menthol, lavender, Herba Menthae Rotundifoliae, Cortex cinnamomi japonici (Ramulus Cinnamomi), Ilicis Purpureae (wintergreen), Fructus Foeniculi), one or more wetting agent (for example, sorbitol, pentatol, glycerol, gelatin, propylene glycol, Polyethylene Glycol, water, xylitol, PEG8 (polyoxyethylene glycol ester), PPG (polyoxyethylene ether), one or more thickening agents (for example, carrageenin, cellulose gum, xanthan gum, arabic gum, sodium carboxymethyl cellulose, cellulose ether, sodium alginate, card pool general class (carbopols), silicon dioxide thickening agents, sodium aluminium silicate, clay), one or more antiseptic (for example, sodium benzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate), one or more sweeting agents (for example, Calcium o-benzolsulfimide or saccharin sodium, aspartame), water, one or more brightening agents (whiteners) (for example, peroxide, citroxain, titanium dioxide) and/or one or more benefit materials (for example, stabilized chlorine dioxide, mellaleuca, neem, CPP-ACP).

Except one or more contain gallium compositions, mouthwash agent composition also can (for example randomly contain one or more antimicrobial compounds, quaternary ammonium compound, boric acid, benzoic acid), one or more phenoloids, one or more correctivess (for example, glucide or glycerol), one or more astringents (for example, zinc chloride), ethanol (being generally the 18-26% aqueous solution), one or more buffer agents, one or more (for example prevent putrid component, sodium fluoride, stannous fluoride) and/or one or more anti-speckle component (for example, chlorhexidines, heavy metallic salt, Sanguinaria canadensis).

In some embodiments, one or more contain gallium compositions and are used for the treatment of by preparation or prevent bacterial keratitis.This contains, and gallium compositions can be configured to eye drop or contact lens cleans or Wetting Solution.In one embodiment, said composition can be locally applied to eye with the form of eye drop.

In some embodiments, one or more contain gallium compositions and are applied in one or more that comprise unit dose contain the pharmaceutical composition of gallium compositions and pharmaceutically suitable carrier.For example, can be oral or parenteral (for example intravenous, subcutaneous, intramuscular, transdermal, skin, through mucous membrane (comprising cheek, nose, rectum, Sublingual and vagina) use, by suction use or implantation storage Cush by being arranged in dosage form with).

In some embodiments, contain gallium compositions for example gallium (III) co-ordination complex for example Gallium maltolate by Orally administered.In some embodiments, this co-ordination complex is the complex of gallium (III) and 3-hydroxy-2-methyl-pyrokomane.In some embodiments, for reach and keep treatment or prevent effective serum gallium level, for example at least about 10,25,50,100,200,500,1000,2000,3000,4000,5000,6000 or the serum levels of 7000ng/ml, this complex is once Orally administered every day.

Method of application according to expection; pharmaceutical preparation can be solid, semisolid or liquid; for example tablet, capsule, Caplet (caplet), liquid, suspensoid, Emulsion, gel, ointment, suppository, granule base, piller, globule, powder etc. preferably are suitable for the unit dosage forms of single administration of precise dosages.The appropriate drug compositions can be prepared with the conventional method of describing in known to the skilled and relevant textbook of field of pharmaceutical preparations and the document with dosage form, for example, referring to Remington: pharmaceutical science and put into practice (Easton, PA:Mack Publishing Co., 1995).For oral activated those chemical compounds, general preferred oral dosage form, comprise tablet, capsule, Caplet, solution, suspensoid and syrup, and can comprise many granules, globule, powder or piller that it can be entrapped or not entrapped.Preferred peroral dosage form is tablet and capsule.

Tablet can prepare with the film-making agent operation and the device of standard.Preferred direct compression and granulation technique.Except activating agent, tablet generally also comprises pharmaceutically suitable carrier material of non-activity such as binding agent, lubricant, disintegrating agent, filler, stabilizing agent, surfactant, coloring agent etc.Come for tablet provides cohesion with binding agent, thereby and guarantee that tablet is kept perfectly.Suitable adhesive material includes but not limited to starch (comprising corn starch and pregelatinized Starch), gelatin, saccharide (comprising sucrose, glucose, dextrose and lactose), Polyethylene Glycol, wax class and natural and rubber polymer class, for example, arabic gum, sodium alginate, polyvinylpyrrolidone, cellulosic polymer (comprising hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, microcrystalline Cellulose, ethyl cellulose, hydroxyethyl-cellulose etc.) and Veegum.With lubricator make the preparation tablets transfiguration easily, promote flow of powder and prevent that when pressure is removed granule from taking off lid (, grain breakage).Useful lubricant has magnesium stearate, calcium stearate and stearic acid.Promote the disintegrate of tablet with disintegrating agent, it generally is starch based, clay class, cellulose family, alginate (algins), gummy class or cross linked polymer.Filler comprises for example material such as silicon dioxide, titanium dioxide, Alumina, Pulvis Talci, Kaolin, Powderd cellulose and microcrystalline Cellulose and solable matter such as mannitol, carbamide, sucrose, lactose, dextrose, sodium chloride and sorbitol.Also be that well-known stabilizing agent is used for suppressing or delaying the medicine decomposition reaction in the art, described decomposition reaction comprises for example oxidation reaction.

Capsule also is preferred peroral dosage form, in this case, the compositions that contains activating agent can be encapsulated in the capsule with liquid or solid (comprising particle such as granule, globule, powder or piller) form.Suitable capsule can be hard or soft capsule, is generally made by gelatin, starch or cellulosic material, preferred gelatine capsule.Dimeric hard gelatin capsule preferably seals, for example with sealings such as gelatin bands.Referring to for example above-cited Remington: pharmaceutical science and practice, it has described the material and the method for preparation entrapped drug.

If necessary, peroral dosage form (no matter being tablet, capsule, Caplet or particle) can be configured to lasting gradually release bioactive agent of a period of time of going through prolongation.Generally speaking, as those of ordinary skills should recognize, sustained release forms was by preparing in the substrate of material that activating agent is scattered in hydrolysis gradually such as hydrophilic polymer or by with such material the solid dosage forms that contains medicine being carried out coating.Can be used for providing the hydrophilic polymer that continues release coating or substrate for example to comprise: cellulosic polymer such as hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, cellulose acetate and sodium carboxymethyl cellulose; Acrylate copolymer and copolymer, preferably form, for example the copolymer of acrylic acid, methacrylic acid, acrylic acid methyl ester., ethyl acrylate, methyl methacrylate and/or ethyl methacrylate by acrylic acid, methacrylic acid, alkyl acrylate, alkyl methacrylate etc.; With polyvinyl and copolymer such as polyvinylpyrrolidone, polyvinyl acetate and vinyl-vinyl acetate copolymer.

Of the present inventionly be used for the preparation that parenteral uses and comprise aseptic aqueous and non-aqueous solution, suspensoid and Emulsion.Injectable aqueous solution contains the activating agent of water-soluble form.The example of non-aqueous solvent or medium comprises fatty oils such as olive oil and Semen Maydis oil, synthetic fatty acid esters such as ethyl oleate or triglyceride, low-molecular-weight alcohols such as propylene glycol, hydrophilic synthetic polymer such as Polyethylene Glycol, liposome etc.Parenteral formulation also can comprise adjuvant such as solubilizing agent, antiseptic, wetting agent, emulsifying agent, dispersant and stabilizing agent, and aqueous suspension can comprise the material that increases this suspensoid viscosity, as sodium carboxymethyl cellulose, sorbitol and glucosan.By sneaking into biocide, making injectable preparation aseptic with the filter filtration of holding back antibacterial, radiation or heating.It also can prepare with injectable aseptic vehicle.Activating agent also can be exsiccant for example cryodesiccated form, and it can be at once with suitable medium aquation again before injection is used.

Chemical compound of the present invention can also be used by skin with conventional transdermal drug delivery systems, and activating agent is comprised in and is fixed on the skin in the layer structure as drug delivery device in this delivery system.In this class formation, pharmaceutical composition is contained in one deck or " the storage storehouse " that is arranged in below the backing layer.This layer structure can comprise single storage storehouse, and perhaps it can comprise a plurality of storages storehouse.In one embodiment, the storage storehouse comprises the polymeric matrix that is used for during the drug delivery this system being fixed to the pharmaceutically useful contact sticky material on the skin.Perhaps, contain the storage storehouse of medicine and contact skin sticker independently to exist with the form of different layers, sticker is positioned at below the storage storehouse, and storing the storehouse in this case can be above-mentioned polymeric matrix, perhaps it can be liquid or hydrogel storage storehouse, perhaps can take some other form.Transdermal drug delivery systems can also comprise dermal osmosis accelerator.

Except foregoing preparation, chemical compound can also be formulated as and be used to go through a period of time sustained release activating agent of prolongation, preferably continue the durative action preparation (depotpreparation) of release bioactive agent.These sustained release formses are generally used by implanting (for example, subcutaneous or intramuscular or by intramuscular injection).

Can rectum or vaginal application, preferably carry out rectum or vaginal application with suppository, except activating agent, described suppository also comprises excipient such as suppository wax.

The preparation that is used for nose or sublingual administration also is to prepare with standard excipients well-known in the art.Pharmaceutical composition of the present invention also can be used for sucking by preparation, for example is mixed with the solution, dry powder or the aerosol that are arranged in saline.

Gallium and at least a antibiotic combined administration

In some embodiments, one or more above-mentioned are contained gallium compositions and one or more antibiotic are co-administered.Described one or more contain gallium compositions can with one or more antibiotic simultaneously or sequential application.For using simultaneously, can will contain gallium compositions and antibiotic identical or independently use in the pharmaceutical composition.In the biomembranous method of treatment as herein described, can use the antibiotic that contains gallium compositions and one or more unit dose of one or more unit dose.

Can be used for antibiotic in the method for the present invention and include but not limited to the ciprofloxacin, ampicillin, azithromycin, doxycycline, fusidic acid, gentamycin, Linezolid, levofloxacin, norfloxacin, ofloxacin, rifampicin, tetracycline or the tobramycin that are used alone or in combination.If two or more antibiotic are used in combination, then they can while or sequential application.

In some embodiments, described one or more contain gallium compositions and can work in coordination with onset with a kind of and multiple antibiotic and treat the infection relevant with biomembrane.In other embodiments, but one or more contain gallium compositions and treat the infection relevant with biomembrane with one or more antibiotic addition onsets.

Antibiotic can be by providing required treatment or preventive effect for example to reduce, eliminate or preventing biomembranous any approach and contain gallium compositions co-administered.In some embodiments, antibiotic is used by parenteral, is for example used in intramuscular, intravenous, subcutaneous, intraperitoneal or the sheath.In some embodiments, antibiotic is by Orally administered.In some embodiments, antibiotic is by limitation or local application.

Bacterial keratitis

Cause the destructive infectious bacteria of corneal epithelium can cause bacterial keratitis, it is a kind of process that threatens vision.The virulence antibacterial of some penetrable complete epitheliums (for example, Diplococcus gonorrhoeae (Neisseria gonorrhoeae)) also can cause bacterial keratitis.

Bacterial keratitis can develop rapidly, and some have more antibacterial 24-48 hour of virulence just may take place completely that cornea destroys.Corneal ulcer, substrate abscess form, corneal edema and leading portion inflammation are the features of this disease on every side.

Cause the common bacteria species of bacterial keratitis that Streptococcus, Rhodopseudomonas, Enterobacter (comprising Klebsiella, Enterobacter, Serratia and proteus) and staphylococcus species are arranged.Infecting simultaneously with antibacterial of fungal keratitis (particularly candidiasis) case up to 20%.

The major risk factors of modal reason of corneal epithelium wound and bacterial keratitis is to use contact lens, particularly the long periods of wear contact lens.

If there is not the identification of organism body, then the existing nursing standard to bacterial keratitis is to begin with broad ectrum antibiotic, as tobramycin (14mg/ml), every 1 hour 1, with the cefazolin sodium of strengthening (50mg/ml) (every 1 hour 1) be used alternatingly.If corneal ulcer is little, be positioned at periphery and do not have the tendency perforation, then a kind of treatment for alternative is the reinforcement monotherapy that carries out with fluoroquinolones.

Gallium maltolate is by direct bacteria growing inhibiting, killing bacteria and/or promote biomembranous destruction to can be used for treating bacterial keratitis.Biomembrane is sealed and is made the standard antibiotic treatment can not eradicate infection fully, and can cause infecting rapid sending out after antibiotic therapy finishes.Gallium maltolate can destroy the biomembranous substrate of cornea, thereby makes infectious bacteria to the antibiotic therapy sensitivity.

Eye drop and contact lens cleaning and repair solution and need be maintained under the strict aseptic condition corneal infection with the vision of avoiding threatening.Contain growth of microorganism in the ophthalmic solution with some different antiseptic.These antiseptic comprise the hydrogen peroxide of 0.001% polihexanide (polyhexanide), 3% microporous filter, the sodium perborate and the sodium benzoate of usefulness phosphoric acid stabilize.Because many patients are to the antiseptic sensitivity, so these solution usually do not contain antiseptic.In ophthalmic solution, can stop bacteria living and growth as antiseptic with Gallium maltolate.

Compositions

The invention provides and be used for the treatment of (for example prevent, treat or cure) biomembrane and/or prevent that the infection relevant with biomembrane is diffused into the compositions at another position of body.

In one embodiment, the invention provides and comprise the pharmaceutical composition that contains gallium compositions and pharmaceutically suitable carrier, wherein to contain gallium compositions be the biomembranous treatment effective dose of treatment or prevent biological film formed prevention effective dose.In some embodiments, this pharmaceutical composition further comprises antibiotic or non-antibiotic antimicrobial, its amount can be effectively with contain the collaborative or addition onset of gallium compositions and treat the prior biological film, prevent that biomembrane from forming or prevent that the infection relevant with biomembrane from expanding to another position of body.

In another embodiment, the invention provides and be used for the treatment of or biomembrane that prevention is relevant with the oral cavity, for example be positioned at biomembranous compositions on tooth, tongue, oral mucosa or the gingiva.In some embodiments, said composition comprise be configured to dentifrice for example toothpaste form contain gallium compositions.In other embodiments, said composition comprises the gallium compositions that contains that is configured to the collutory form.In other embodiments, said composition comprises and contains gallium compositions, and it is configured to smears, foam, gel or the varnish that is used for tooth and uses, and for example, is used for the compositions of fluoride treatment.

In another embodiment, the invention provides the compositions that is used for the treatment of or prevents bacterial keratitis.In some embodiments, said composition comprises the gallium compositions that contains that is configured to the eye drop form.

In another embodiment, the invention provides and be used for preventive solution bacterial growth and/or biological film formed contact lens solutions, it comprises the gallium as antiseptic and/or antibiont membrane.Medicine box

The invention provides and be used in treatment as herein described (for example prevent, treat or cure) biomembrane and/or prevent that the infection relevant with biomembrane from expanding to the medicine box in the method at another position of body.In some embodiments, medicine box comprises the gallium compositions that contains that generally is configured to pharmaceutical compositions.This medicine box also can randomly comprise antibiotic.In some embodiments, medicine box comprises and is used for the treatment of biomembranous the contain gallium compositions relevant with the oral cavity, as dentifrice (for example toothpaste), chewing gum or mouthwash agent composition or gel, foam, smears or varnish, for example, be used for the compositions of the fluoride of fluoride treatment.In some embodiments, medicine box comprises the gallium compositions that contains that is used for the treatment of bacterial keratitis, as eye drop or contact lens solutions.In some embodiments, medicine box comprises the contact lens solutions that contains gallium, and wherein gallium is as preventing in the solution that bacterial growth and/or biological film formed antiseptic are provided.Can comprise description, described description contains gallium compositions according to method as herein described with this and treats biomembranous information for healthcare provider, patient or consumer provide.Described description can be provided with printing form or with the form of electronic media such as floppy disk, CD or DVD or with the form of the interconnected network address that can obtain such description.

Suitable packing is provided." packing " used herein is meant and is usually used in system and can holds in fixed limit being suitable for being applied to individual solid matrix that contains gallium compositions or material.Such material comprises glass and plastics (for example polyethylene, polypropylene and Merlon) bottle, bottle, paper, plastics and plastics-paper tinsel lamination big envelope etc.If use e-light beam sterilization technology, then Bao Zhuan density should be low to moderate is enough to make inclusions to be sterilized.

In some embodiments, this medicine box comprises the gallium compositions that contains that is configured to dosage form, and what each dosage form comprised unit dose contains gallium compositions and pharmaceutically suitable carrier, and wherein said unit dose provides the gallium that is enough to treat individual biomembranous treatment or prevention effective dose.Described dosage form can be randomly by independent sealed and can take out separately.Medicine box can randomly further comprise at least a antibiotic or non-antibiotic antimicrobial, it randomly is configured to one or more dosage forms, the antibiotic or the non-antibiotic antimicrobial of its each self-contained pharmaceutically useful carrier and unit dose, wherein said unit dose provides to be enough to and the antibiotic of individual biomembranous treatment of co-administered treatment that contains gallium compositions as herein described or prevention effective dose, wherein antibiotic or non-antibiotic antimicrobial randomly with contain the collaborative or addition onset of gallium compositions and treat biomembrane.In some embodiments, the gallium compositions that contains in the medicine box is orally active form, and pharmaceutically suitable carrier is applicable to that oral drugs send, and medicine box comprises describes the mode Orally administered description of this dosage form with effective treatment infection relevant with biomembrane.

Come the present invention is carried out non-limitative illustration with the following examples.

Embodiment

Embodiment 1

The effect of Gallium maltolate in the urinary tract infection (UTI) relevant of mice with the Pseudomonas aeruginosa biomembrane

As people such as Kadurugamuwa (2005) Infection and Immunity 73 (7): 3878-87) described with Pseudomonas aeruginosa Xen5 (10 ⁶The CFU/ conduit) in the CF-1 female mice, sets up the UTI relevant with conduit.With the effect of bioluminescence engineering Pseudomonas aeruginosa Xen5 assessment Gallium maltolate (GaM) independent or that be used in combination with ciprofloxacin (Cipro) to Pseudomonas aeruginosa urinary tract infection (UTI), this model makes can use Xenogen in CF-1 female mice UTI model Imaging System monitors in real time to infection.

In mice, use Pseudomonas aeruginosa (10 ⁶Individual colony forming unit (CFU)/conduit) set up the UTI relevant with conduit, back 2 days of infection only with GaM or only treated 4 days with Cipro or with the combination of GaM and Cipro is continuous.Begin second treatment cycle at 9-11 days, finished this research at the 21st day.Contrast comprises the not infected and infected animal with saline treatment.

(American Pharmacopeia (US Pharmacopeia), Rockville MD) use by oral gavage with Gallium maltolate ciprofloxacin.Ciprofloxacin is given in 0.2mL water, and Gallium maltolate is given in 0.2mL comprises the water of 1% carboxymethyl cellulose.By implanting infected conduit and handling with second treated animal as untreated infection matched group with saline.In another matched group, to animal implant sterile catheter and with it as negative control.

As shown in table 1, excite back 2 days on antibacterial and begin to treat having the infected animals relevant with conduit.

Table 1. animal groups and treatment general introduction

Group	Chemical compound	Number of mice	Dosage	Therapeutic frequency
					1	Gallium maltolate	4	30mg/kg?q.d.	2-5 and 9-11 days
2	Gallium maltolate	4	100mg/kg?q.d.	2-5 and 9-11 days
					3	Gallium maltolate	4	300mg/kg?q.d.	2-5 and 9-11 days
4	Ciprofloxacin	8	30mg/kg?b.i.d.	2-5 and 9-11 days
					5	Gallium maltolate+ciprofloxacin	4	Gallium maltolate 30mg/kgq.d.+ ciprofloxacin 30mg/kg b.i.d	2-5 and 9-11 days
6	Gallium maltolate+ciprofloxacin	4	Gallium maltolate 100mg/kgq.d.+ ciprofloxacin 30mg/kg b.i.d.	2-5 and 9-11 days
					7	Gallium maltolate+ciprofloxacin	4	Gallium maltolate 30mg/kgq.d.+ ciprofloxacin 30mg/kg b.i.d.	2-5 and 9-11 days
8	The contrast of infecting	12	Saline q.d.	2-5 and 9-11 days
					9	The not contrast of Gan Raning	6	Saline q.d.	2-5 and 9-11 days

Zero all substances are all by orally give.

Zero when experiment finishes, and a conduit that derives from the 1st, 2,4,6 and 8 group is sent to carried out the EM analysis.

After treatment in initial 4 days stops 4 days, with therapeutic agent continuous administration 3 days again.In Fig. 1, provided animal with the maximum dose level treatment of the Gallium maltolate of testing.

After placing the conduit of colonyization in advance, the bioluminescence signal that writes down in the mice bladder reached about 10 in back 1 day in implantation ⁷Photons/second (Fig. 1).Compare with the matched group for the treatment of, after treatment 4 days, the animal organism luminous signal for the treatment of with ciprofloxacin is dropped rapidly to almost undetectable level.But, interrupting ciprofloxacin treatment back about 2 days, the intensity of bioluminescence signal begins to increase, and shows after stopping antibiotic therapy, infects and recovers.What is interesting is, as (people (2005) Infection and Immunity 73 (7) such as Kadurugamuwa: 3878-87), stopping initial treatment after 2 days, 3 days antibiotic of continuous administration make the bioluminescence signal reduce once more again shown in before.But, after interrupting the ciprofloxacin treatment, reappear rapidly once more and infect and it almost reaches the level for the treatment of, show that antibacterial obviously regrows in this group.

After with the treatment of 300mg/kg Gallium maltolate, also observed noctilcent reduction.Though its signal intensity never reaches the not level of infected group, its signal continues to maintain about 10 when this experiment in the 21st day finishes ⁵Photon/conduit low-level.Different with ciprofloxacin treatment group, though Gallium maltolate use stop after, this low level signal also never significantly increases, and shows high-caliber infection and recurrence does not take place in this treated animal.Compare with untreated matched group, with 30 and the Gallium maltolate of the dosed administration of 100mg/kg also show the activity (table 2) of bacteria growth.

The monitoring of Pseudomonas aeruginosa Xen5 growth during table 2. is treated with Gallium maltolate and ciprofloxacin

The antibiotic effect of Gallium maltolate dosage more independent and that be used in combination with the antibiotic ciprofloxacin.The result is expressed as the growth percentage ratio of comparing the antibacterial of Drug therapy with the bacterial growth of untreated matched group.The growth percentage ratio of medication therapy groups is low more, and treatment is effective more to infecting.

What is interesting is, when infection animal being treated, observe the bioluminescence signal and reduce (Fig. 1 and 2 and table 2) rapidly with maximum dose level (300mg/kg) Gallium maltolate and ciprofloxacin.After treatment 4 days, this combined therapy makes bioluminescence be reduced to undetectable level.This Gallium maltolate dosage does not produce ill effect in the oral mice of feeding, show that this medicine can be tolerated.Importantly, when with antibiotic and Gallium maltolate combination medicine-feeding, do not observe the infection of seeing in the group that gives ciprofloxacin separately and recover, prove that Gallium maltolate and ciprofloxacin are having synergism aspect the elimination chronic infection.

Table 3. in bladder by the mortality rate of Pseudomonas aeruginosa Xen5 mice infected and the diffusion velocity in kidney

Group	Number of animals/animal the sum that had the kidney signal at the 21st day	Mortality rate %
			Not treatment	4/7	41.7％
Ciprofloxacin 30mg/kg	1/7	12.5％
			Gallium maltolate 30mg/kg	0/3	25.0％
Gallium maltolate 100mg/kg	0/3	25.0％
			Gallium maltolate 300mg/kg	0/4	0.0％
Gallium maltolate 30mg/kg+ ciprofloxacin	0/4	0.0％
			Gallium maltolate 100mg/kg+ ciprofloxacin	0/4	0.0％
Gallium maltolate 300mg/kg+ ciprofloxacin	0/4	0.0％

It should be noted that under all proof loads, give independent and when research finishes, all do not have kidney to infect (table 3) with the animal of the Gallium maltolate of ciprofloxacin combination.This has shown that gallium is suppressing the other effect of pathogen from the diffusion of primary infection position.The bioluminescence signal of untreated infected group is initial to keep stable, but logarithm value descends approximately half after infecting 10 days.The reduction of sort signal intensity is owing to the infection animal death with strong signal causes.But because the infection order of severity of surviving animals increases, so signal intensity recovered (Fig. 1) after several days.

Table 4. is in the count of bacteria of infecting with Pseudomonas aeruginosa Xen5 in the urine of back

Group	Metainfective natural law	Count of bacteria scope (CFU/ml) in the urine	Geometrical mean
				Not treatment	7111416 ＊1721	3.0×10 5-6.0×10 51.4×10 5-2.4×10 76.0×10 4-5.2×10 54.0×10 4-1.6×10 64.0×10 5-1.6×10 61.2×10 5-2.4×10 8	9.0×10 52.9×10 62.1×10 52.5×10 57.9×10 59.1×10 5
Ciprofloxacin	71114161721	2.0×10 2-7.0×10 52.0×10 22.0×10 2-1.2×10 72.0×10 2-6.0×10 52.0×10 2-8.0×10 62.0×10 2-3.6×10 7	3.3×10 32.0×10 21.1×10 53.2×10 41.2×10 52.2×10 5
				Gallium maltolate 30mg/kg	71114161721	N/A1.2×10 5-1.8×10 5N/A1.2×10 5-6.0×10 54.0×10 4-6.0×10 51.2×10 4-2.0×10 6	N/A1.5×10 5N/A2.4×10 51.6×10 51.6×10 5
Gallium maltolate 100mg/kg	71114161721	N/A2.0×10 2-6.0×10 6N/A2.0×10 2-3.0×10 62.0×10 2-2.0×10 62.0×10 2-1.4×10 6	N/A4.6×10 4N/A1.1×10 42.9×10 48.2×10 3
				Gallium maltolate 300mg/kg	71114161721	1.3×10 5-1.5×10 62.2×10 4-6.2×10 51.2×10 5-6.0×10 63.2×10 5-8×10 54.0×10 4-1.6×10 61.6×10 5-5.6×10 6	3.0×10 51.1×10 52.3×10 55.8×10 53.2×10 53.1×10 5
Gallium maltolate 30mg/kg+ ciprofloxacin	71114161721	N/A2.0×10 2N/A2.0×10 2-4.0×10 52.0×10 2-2.0×10 62.0×10 2-2.8×10 6	N/A2.0×10 2N/A2.5×10 34.3×10 34.8×10 3
				Gallium maltolate 100mg/kg+ ciprofloxacin	71114161721	N/A2.0×10 2N/A2.0×10 2-6.0×10 62.0×10 2-1.0×10 62.0×10 2	N/A2.0×10 2N/A6.2×10 33.4×10 32.0×10 2
Gallium maltolate 300mg/kg+ ciprofloxacin	7 ＊111416 ＊1721	2.0×10 22.0×10 22.0×10 22.0×10 2-1.0×10 42.0×10 2-4.0×10 32.0×10 2-3.1×10 4	2.0×10 22.0×10 22.0×10 21.4×10 35.4×10 27.2×10 2

N/A: urine CFU data are failed to obtain in this sky

^*The sampling owing to fail, the urine sample number is less than 3.

Antibacterial lower limit＜10 of in urine, detecting with the CUF method ²CFU/ml

Pharmacokinetics

Every day by oral gavage with 30 and the 300mg/kg Gallium maltolate the female CF-1 mice that grows up (the initial weight scope is the 32-39 gram) is treated, treated continuously 4 days.Two dosage are all used with identical drug solution volume, that is, 480 μ L2.5 and 25mg/mL are arranged in the Gallium maltolate of 1% carboxymethyl cellulose.After using last dosage, get blood: 0,0.5,1,3,6,9,12,24,33 and 48 hour at following time point.The blood of getting ' 0 ' time is to get blood after administration immediately.Blood sample collection in the time of point+/-5% at the fixed time.Get whole blood (500 to 1000 μ L) by cardiac puncture from each mice, put to death 4 mices at each time point for each administration group.After blood sampling, keep at room temperature making it to form clot in sample, thus centrifugal then acquisition serum.With the gallium concentration in inductively coupled plasma (Inductively Coupled Plasma)-mass spectrography (ICP-MS) mensuration 100 μ L serum.

Setting up weighted linear regression analysis calibration curve and after Quality Control Analysis checking, the serum gallium concentration in the measuring samples is also mapped the result.

Under two dosage, serum gallium concentration reaches peak value and decline gradually during 48 hours assessment in half an hour after administration, and initially eliminating the half-life is 8-12 hour.Pharmacokinetic analysis result as shown in Figure 3.

Carry the biomembranous scanning electron microscope analysis that shifts out the vertical section of conduit of Pseudomonas aeruginosa

The 21st day (last administration after 10 days), derive from the conduit of organizing below with one and at room temperature place in 2.5% glutaraldehyde fixative with the PBS washing and with it and spend the night: untreated contrast, 30mg/kg GaM, 100mg/kgGaM, 300mg/kg GaM, 30mg/kg Cipro, 30mg/kgGaM+30mg/kg Cipro and 100mg/kg GaM+30mg/kg Cipro; Then it is sent to scanning electron microscope (SEM) analysis of carrying out.The result as shown in Figure 4.

In contrast conduit transverse section, untreated antibacterial shows as the stub form that is embedded in the polymeric matrix.Unexpectedly, the bacterial morphological that derives from the conduit of Gallium maltolate treatment group shows as a sample, even also is like this under minimum test concentrations.It is relevant with the treatment of the cumulative Gallium maltolate of relevant reduction and the concentration of polymer material outward of biomembrane inner cell that the cellular morphology of this bacterium living beings membrane structure significantly changes.

Treat the stub sample form that can not change this antibacterial with ciprofloxacin.As seeing in the untreated matched group, this bacterial cell tightly is embedded in the polymeric matrix.

The combined therapy that carries out with Gallium maltolate and ciprofloxacin has caused the antibacterial rod and the silk sample antibacterial of elongation.When ciprofloxacin and Gallium maltolate were used in combination, the biofilm matrix tightness degree of the consolidation of seeing in not treatment group or ciprofloxacin treatment group diminished.

Should be noted that in these scanning electron micrographs gallium was observed treating for the last time with Gallium maltolate the influence of ne ar and biofilm structure in back 10 days, show that after the serum gallium is by eluting for a long time these new roles still continue to exist.

Describe in detail though aforementioned the present invention has been carried out some, it will be apparent for a person skilled in the art that and under the situation that does not break away from purport of the present invention and scope, to carry out some change and modification by description and embodiment for clear understanding.Therefore, this description should not be regarded as the described scope of the present invention of appended claims is limited.

All publications, patent and patent application that this paper quoted all are incorporated herein by reference at this, and it is used for all purposes, and the introducing degree just specifically and is separately provided as each publication, patent or patent application.

Claims (38)

1. treatment has the biomembranous method of the individuality that needs, it comprises the gallium compositions that contains to this individuality administering therapeutic effective dose, and wherein said biomembrane is positioned at least and is selected from a following position: bladder, kidney, the heart, middle ear, hole, skin, joint, subcutaneous tissue, soft tissue, vascular tissue and eye.

2. method according to claim 1, wherein said biomembrane is relevant with the urinary tract infection relevant with biomembrane.

3. method according to claim 1, wherein relevant with the biomembrane diffusion of infection to another position of individuality is suppressed.

4. method according to claim 1, wherein said biomembrane comprises at least a gram negative bacteria.

5. method according to claim 4, wherein said biomembrane comprises following antibacterial: Pseudomonas aeruginosa (Pseudomonas aeruginosa), Branhamella (Branhamella), campylobacter (Campylobacteria), escherichia coli (Escherichia coli), Enterobacter (Enterobacteria), pasteurella (Pasteurella), proteus (Proteus), Klebsiella (Klebsiella), eisseria (Neisseria), Salmonella (Salmonella), Shigella (Shigella) or Serratia (Serratia).

6. method according to claim 1, wherein said biomembrane comprises at least a gram-positive bacterium.

7. method according to claim 6, wherein said biomembrane comprises following antibacterial: bacillus (Bacillus), Corynebacterium (Corynebacteria), fusobacterium (Clostridium), Enterococcus (Enterococcus), Listera belong to (Listeria), staphylococcus (Staphylococcus) or Streptococcus (Streptococcus).

8. method according to claim 1, it further comprises to individual administration of antibiotics.

9. method according to claim 8, wherein said antibiotic is selected from ciprofloxacin, ampicillin, azithromycin, cephalosporin, doxycycline, gentamycin, levofloxacin, norfloxacin, ofloxacin, tetracycline, tobramycin, vancomycin, amikacin, deftazidime, cefepime, trimethoprim/Sulfamethoxazole, piperacillin/tazobactam, aztreonam, meropenem, polymyxin E and chloromycetin.

10. method according to claim 8 wherein saidly contains the collaborative onset of gallium compositions and described antibiotic and treats described biomembrane.

11. method according to claim 8 wherein saidly contains gallium compositions and described biomembrane is treated in described antibiotic addition onset.

12. method according to claim 1, the wherein said gallium compositions that contains comprises neutral 3:1 (hydroxy pyrone: the co-ordination complex of complex form gallium), each hydroxy pyrone molecule is unsubstituted or by one, two or three C in this complex ₁-C ₆Alkyl substituent replaces.

13. method according to claim 12, wherein each hydroxy pyrone molecule is selected from 3-hydroxyl-pyrokomane, 3-hydroxy-2-methyl-pyrokomane, 3-hydroxyl-2-ethyl-pyrokomane and 3-hydroxy-6-methyl-4-pyrone.

14. method according to claim 13, wherein each hydroxy pyrone molecule is 3-hydroxy-2-methyl-pyrokomane.

15. method according to claim 1, the wherein said gallium compositions that contains is used by parenteral.

16. method according to claim 1, the wherein said gallium compositions that contains is by Orally administered.

17. method according to claim 1, the wherein said gallium compositions that contains is by limitation or local application.

18. method according to claim 17, the wherein said gallium compositions that contains is locally applied to eye with the form of eye drop.

19. method according to claim 1, wherein said biomembrane is relevant with the chronic bacterial vaginosis.

20. method according to claim 1, wherein said biomembrane is relevant with bacterial keratitis.

21. method according to claim 8 wherein saidly contains gallium compositions and described antibiotic is used simultaneously.

22. method according to claim 8, wherein said gallium compositions and the described antibiotic of containing is by sequential application.

23. the biomembranous method relevant with the oral cavity that treatment is individual, it comprises makes oral surfaces contact with the gallium compositions that contains of treatment effective dose.

24. method according to claim 23, described method comprise that the described gallium compositions that contains by the administering therapeutic effective dose prevents the biomembrane of described individuality to form.

25. method according to claim 24, wherein relevant with oral cavity biomembrane is the dental plaque that is positioned on the tooth.

26. method according to claim 24, the wherein said gallium compositions that contains is configured to dentifrice.

27. the described method of claim 26, wherein said dentifrice is dentifrice composition.

28. method according to claim 23, wherein said biomembrane is positioned on tongue, oral mucosa or the gingiva.

29. method according to claim 23, the wherein said gallium compositions that contains is configured to collutory, chewing gum, smears, foam, gel or varnish.

30. method according to claim 23 wherein saidly contains the 3:1 that gallium compositions comprises not effect (hydroxy pyrone: the co-ordination complex of complex form gallium), each hydroxy pyrone molecule is unsubstituted or by one, two or three C in this complex ₁-C ₆Alkyl substituent replaces.

31. method according to claim 30, wherein each hydroxy pyrone molecule is selected from 3-hydroxyl-pyrokomane, 3-hydroxy-2-methyl-pyrokomane, 3-hydroxyl-2-ethyl-pyrokomane and 3-hydroxy-6-methyl-4-pyrone.

32. method according to claim 31, wherein each hydroxy pyrone molecule is 3-hydroxy-2-methyl-pyrokomane.

33. method according to claim 23, wherein biomembrane is suppressed to the diffusion at another position of individuality.

34. be used for the gallium compositions that contains of local oral administration, wherein said compositions is configured to dentifrice, collutory, chewing gum, smears, foam, gel or varnish.

35. contain gallium compositions, it is configured to the ophthalmic solution for topical application to eye.

36. medicine box, its comprise the described compositions of claim 34 be used for the treatment of or biomembranous method that prevention is relevant with the oral cavity in operation instructions.

37. medicine box, it is used in the described method of claim 1, comprises to contain gallium compositions and the operation instructions in being used for the treatment of biomembranous method.

38. according to the described medicine box of claim 37, it further comprises antibiotic.

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