CN101795675A - Use has the colonic delivery that the Zn/ pectin beads of Eudragit coating carries out - Google Patents

Abstract

The drug delivery system that therapeutic agent and/or diagnostic agent can be delivered to colon is disclosed.Described system comprises and zinc or the crosslinked pectin beads of any purpose bivalent cation that described beadlet is used then

Description

Use has the colonic delivery that the Zn/ pectin beads of Eudragit coating carries out

Invention field

The present invention with activating agent for example metal enzyme-specific (metallo-specificenzyme) be applied in the field of oral drugs delivery system of colon.

Background of invention

The drug delivery system of specifically bioactive agent delivery being delivered to colon has been known as has important treatment advantage.If active component discharges in the part, will more effectively treat many colon patient's condition so.The example of this type of colonic disorders comprises Crohn disease, ulcerative colitis, colorectal carcinoma and constipation.

When considering that according to treatment when essential delay absorbed, colon discharged the patient is benefited.Example comprise disease for example night asthma or angor treatment (people (1998) such as Kinget R., Colonic Drug Targeting, Journal of Drug Targeting, 6,129).

Colon discharges and also can be used for the administering therapeutic active polypeptide.Polypeptide is used by injection usually, because they can be degraded under one's belt.Because injection tool pain, therefore research is made great efforts to have concentrated on and is used colon as the active polypeptide absorption site of (comprising analgesic, contraceptive, vaccine, insulin etc.).As if the absorption of polypeptide in colon more effective than other positions in digestive tract.This does not exist owing to the relatively more weak proteolytic activity in the small intestinal with the membrane-bound peptidase activity of colon epithelial cell especially.

Behind Orally administered antibiotic, antibiotic is absorbed in small intestinal then by stomach, thereby diffusion and treatment are used their infection happening part to it in whole organism.Equally, move on before the antibiotic (importance of this part changes with the difference of each antibiotic feature) of part absorption is not absorbed and is eliminated in feces and enter colon.These residual antibiotic are absorbed with a part but enter gastral antibiotic again by the mode that bile is got rid of and mix in large intestine.The antibiotic importance of this part changes with the variation of each the antibiotic metabolism and the approach of removing.At last, for some antibiotic, a part of absorbed dosage is directly removed from blood by intestinal mucosa and is got back to the digestive tract inner chamber, and known good example is a ciprofloxacin.Therefore, no matter be to use by Orally administered or parenteral, in colon, find the living antibiotics of residual fraction usually.For for the most antibiotic that are used for the treatment of (unique tangible exception is to discharge negligible antibiotic from amino-glucosides family for intestinal it) of different families, situation comes to this, just the degree difference.For other antibiotic, the intestinal of residual antibiotic activity is discharged will have multiple consequence, and all consequences all are deleterious.In fact, colon has complicated and antibacterial ecosystem (hundreds of different bacterial species very dense; Surpass 10 ¹¹Individual antibacterial/gram colonic contents), it will be subjected to the influence of the arrival of living antibiotics residue.Can be observed following aspect:

1. as dysbacteriosis (Bartlett J.G. (2002) the Clinical practice.Antibioticassociated diarrhea of common (banal) diarrheal main cause of behind antibiotic therapy, taking place, New England Journal of Medicine, 346,334).Even this diarrhoea is usually not serious and stop (spontaneously or after finishing antibiotic therapy) very soon, but the patient has bad sensation to it and has aggravated to leave at it discomfort of the original disease of antibiotic prescription;

2. disturb the resistance (or " screen effect ") that the outer endophytic bacteria that may have infection risk is grown surely, food Salmonella (salmonella) (people (1984) the Drug resistant Salmonella from animals fedantimicrobials such as Holmberg S.D. that poisons for example, New England Journal of Medicine, 311,617);

3. the selection of antibiotic resistance microorganism.This quasi-microorganism can be all kinds:

A) at first they can be for example clostridium difficiles (Clostridiumdifficile) of pathogen, can secrete species (Bartlett J.G. (1997) the Clostridium difficile infection:pathophysiology and diagnosis of the toxin that causes the colitis form that is called pseudomembranous colitis, Seminar in GastrointestinalDisease, 8,12);

B) they can also be have relatively weak pathogenic but its breeding can cause the microorganism of infections relating (vaginal candidiasis or escherichia coli resistance cystitis (Escherichia coli resistantcystitis)).

C) they can be that its propagation and Excreta are removed the avirulence symbiosis fastbacteria of the propagation that will increase antibiotic resistance in the environment at last.Prove that fully antibiotics resistance gene is carried by mobile genetic element or swivel base genetic elements, it can comprise nearly 5 or 6 antibiotics resistance genes, and is easy to be transmitted to other antibacterials, even strides species and propagate.Therefore, these resistance symbiotic bacterias can constitute the important source of the drug resistance that causes the pathogenicity species.Many be the discomforting characteristic aspect that pathogenic species are evolved towards multi-drug resistant for the people, this risk is considered to have significant impact at present.

Therefore expectation has the medicine and the drug delivery system of the amount that can be used for reducing the residual antibiotic that arrives colon behind oral or parenteral antibiotic therapy.

Many strategies of gastral different physiological parameters that utilize have been designed with release of active ingredients in colon.These strategies have concentrated on drug delivery system, described drug delivery system uses based on (1) pH is changed sensitive polymers, (2) depend on the drug release form of time, (3) can be by the prodrug or the polymer of intestinal flora (intestinal flora) bacterial degradation.

It will be favourable having the other drug delivery system that makes it possible to activating agent is applied to colon, and it includes but not limited to reduce the reagent of the amount of residual antibiotic in the colon.The invention provides such delivery system.

Summary of the invention

The drug delivery system that preventive, therapeutic agent and/or diagnostic agent can be delivered to colon is disclosed.This system comprises and metal cation for example zinc or the crosslinked pectin beads of any purpose bivalent cation that described beadlet is used then

-type polymer coating.

Other embodiments are shown in it to be incorporated in the claim of this paper in full by reference.

Described drug delivery system can be Orally administered, but bioactive agent delivery can be delivered to colon.In some embodiments, they can comprise colon with agent administration to the gastrointestinal diverse location.

In some embodiments, therapeutic agent is the reagent that can reduce the residual quantity of the residual antibiotic that arrives colon behind oral or parenteral antibiotic therapy, for example metal dependent enzyme.Illustrate application from the beta-lactamase L1 that has a liking for maltose oligotrophy Zymomonas mobilis (stenotrophomonas maltophilia).Yet, also can use beta-lactamase into nonmetal enzyme (kind A, C or D).In addition, can use for example antibiotic of macrolide, quinolinones and fluoroquinolone, glycopeptide, lipopeptid, cyclin, oxazolidone and other kinds of antibiotic that enzyme (metal dependent enzyme or other enzymes) comes his kind of deactivation.Enzyme can have the sufficient sequence of native enzyme or can be needed only their and keep acceptable activity by truncate or modification in addition.By sending the reagent of the amount that can reduce behind oral or parenteral antibiotic therapy the residual antibiotic that arrives colon, but the development of the resistance of restricting bacterial.

In other embodiments, therapeutic agent includes but not limited to:

● no matter peptide and protein (including, but not limited to enzyme, hormone, cytokine, lymphokine, somatomedin, antibody etc.) they are natural, synthetic or reorganization;

● nucleic acid (includes but not limited to plasmid, few nucleic acid (oligoribonucleotide of different length, deoxyribonucleotide, SiRNA or ShRNA and mixed molecules with comprising from nucleic acid, it comprises natural and/or modified base and randomly comprises displacement and modify) and the chemical compound of the element of peptide nucleic acid(PNA);

● the labyrinth in natural, reorganization or synthetic source, include but not limited to virus (comprise DNA and RNA viruses, targeting zooblast virus, targeted plants cell (vegetalcell) virus or more commonly be called the virus of the targeted bacteria of phage), antibacterial (exists in any form, comprise spore), mycoplasma, yeast and other unicellular eukaryotes (exist in any form, comprise spore)

● natural, synthetic or blended chemical molecular or its mixture of any size, kind or structure;

● because of any reason or the patient's condition comprise that infectious disease (including but not limited to the infectious disease of antibacterial and viral source), inflammatory diseases, cancer are used for the chemical compound of diagnosis, treatment or the research of humans and animals;

● be used to assist, replenish and improve the chemical compound that uses the treatment that anti-infective, antiinflammatory, anticarcinogen, immunomodulator (immuno-modifying agent) wait, particularly auxiliary when this type of, replenish or improve relate to block or the adjusting colon in the activity of receptor or deactivation may regulate the ability of the active other treatment agent of receptor in the colon time.

Colon-specific is sent by being used in for example pectin preparation preventive, therapeutic agent and/or diagnostic agent of the particular polymer of degrading in the colon, and for example metal dependent enzyme or other reagent of amount that can reduce the residual antibiotic of arrival colon behind oral or parenteral antibiotic therapy obtains.With pectin and for example zinc cation gelation of cation/crosslinked.Then for example with particular polymer

The preparation that polymer coating exists with the pectin beads form of ionomer usually.

Can be by with divalent metal Ca for example ²⁺Or Zn ²⁺Gelation/crosslinked preventive, therapeutic agent and/or diagnostic agent are regulated with the mixture of pectin and are sent to make it to appear at the delivery location of selecting in advance different in the intestinal.

Effort before concentrates on that for example polymine (PEI), chitosan or other cationic polymer coating pectin beads are degraded in upper gastrointestinal to prevent pectin beads with cationic polymer.Such effort for example is described in the U.S. Patent application 10/524,318 and U.S. Patent application 60/651,352, and its content is integrated with this paper by reference.

The present invention relates to use

Polymer is FS30D, L30D (being also referred to as L30D-55), NE30D, its mixture or other desired types for example

The polymer coating pectin beads discharges with predetermined gastrointestinal tract (GIT) level with preventive, therapeutic agent and/or the diagnostic agent that obtains expectation.

When

For example during pH or time dissolving, beadlet preferentially is found in pectin decomposing enzyme (pectinolytic enzyme) degraded of lower intestine to coating according to some parameter.The degraded of pectin discharges preventive, therapeutic agent and/or the diagnostic agent that is encapsulated in the beadlet then.

One aspect of the present invention provides stable metalloenzyme preparation to be used for this zymoid lower intestinal tract or colonic delivery.When depending on Zn ²⁺Special metal dependent enzyme can interact with other cation classifications the time, if they are used for the gelation pectin beads, it is particularly preferred using the zinc cation cross-linked pectin.This type of interaction can influence the activity of this metalloid dependent enzyme significantly.Therefore, drug delivery system embodiment comprises use Zn ²⁺Be used for pectin beads and other competed the cationic highstrung Zn that exists as cross-linking agent ²⁺The combination of dependent enzyme.Certainly, if enzyme depends on other metal cations, these type of other metal cations (surpass if they have ^{+ 1}Quantivalence) can be used for cross-linked pectin.

The method that obtains such beadlet can comprise can carry out optimization so that the special handling condition of first water beadlet (having the optimized external and interior effect of body), for example gelling, cleaning and exsiccant time to be provided.Therefore, another embodiment of the invention relate to be used to prepare zinc crosslinked and

The method of the pectin beads of-Bao quilt.

The accompanying drawing summary

Fig. 1 shows according to the various every sample electrical conductivity in back (mS/cm) of cleaning to measure, with the crosslinked pectin beads of zinc acetate in remove the figure of the efficient of the cationic water rinse of excess metal from the preparation of beta-lactamase L1.

Fig. 2 shows gelling time, rinse method and the drying time figure to the influence of the active recovery of beta-lactamase L1.

Fig. 3 shows according to response (OD/ minute) L1 concentration (μ g/ml) is measured, and uses the figure of CENTA as the enzymatic activity of the beta-lactamase L1 of substrate.

Fig. 4 be show to use the method preparation of describing herein Eudragit bag quilt beadlet a series of scanning electron micrographs and show the beadlet cross-sectional view of the roughly thickness of Eudragit layer.

Fig. 5 be show according to active (μ g/mg beadlet) to the time (minute) measure, beta-lactamase L1 never wraps the beadlet and the use of quilt or does not use hydroxypropyl emthylcellulose (HPMC) to wrap the diagram of release dynamics of beadlet of the Eudragit bag quilt of quilt in advance.Blue triangle represents not wrap the beadlet of quilt; Red circle represents not have the beadlet with 40%EudragitL30D-55 bag quilt of pre-bag quilt; Green box represent to use 5%HPMC wrap in advance by and with the beadlet of 40%Eudragit L30D-55 bag quilt.

Fig. 6 be show according to residual amoxicillin (%) to the time (minute) measure, that quilt is not wrapped in the amoxicillin and use or do not use hydroxypropyl methyl fiber (HPMC) to wrap the diagram of hydrolysis of beadlet of the Eudragit bag quilt of quilt in advance.Blue triangle represents not wrap the beadlet of quilt; Red circle represents not have the beadlet with 40%Eudragit L30D-55 bag quilt of pre-bag quilt; Green box represent to use HPMC wrap in advance by and with the beadlet of Eudragit L30D-55 bag quilt.

Fig. 7 be show according to the antibacterial (%) of resisting amoxicillin to handle the persistent period (day) measure, the pectin beads of Eudragit bag quilt that comprises beta-lactamase L1 is to the diagram with the influence of the appearance of antiviral antibiotic antibacterial in the piglets of amoxicillin processing.Blue triangle is represented untreated animal (n=12); Red rhombus is represented the animal (n=12) with amoxicillin and the processing of placebo pectin beads; Green box is represented with the amoxicillin and is comprised the animal (n=4) that the pectin beads of the Eudragit bag quilt of beta-lactamase L1 is handled together.

Detailed Description Of The Invention

To understand better the drug delivery system of describing herein with reference to following detailed description.

I. pectin beads

Pectin beads is by pectin, zinc ion and in addition use

The dressing of polymer forms, and encapsulates one or more activating agents.

Pectin beads in stomach medium and intestines medium stability and protective effect by

Polymer coating is guaranteed. On the contrary, the not coated bead of pectin tends to unstable in such environment and may be not enough to protect their content to avoid degraded and/or deactivation.

Dressing guarantees that they resist the sufficiently long time so that their content can complete arrival colon.

Pectin

Pectin is that it is widely used for agro-food industry (as coagulant or the thickener of jam, ice cream etc.) and medicine from the polysaccharide of the cell membrane separation of higher plant (superior plant). It is polymolecular and polydisperse. Its composition changes with the different of source, extraction conditions and environmental factor.

Pectin mainly is comprised of the linear chain (described chain is scattered with the unit of rhamnose sometimes) of β-Isosorbide-5-Nitrae-(D)-galacturonic acid. Can be with the carboxy moiety esterification of galacturonic acid to produce methylated pectin. Two types pectin can according to they methylation (DM: the methoxyl group number of per 100 galacturonic acid units) distinguish:

(HM: high methoxyl), wherein methylated degree changes between 50 to 80%-hyper-methylation pectin. It is slightly soluble in water and forms gel at acid medium (pH＜3.6) or in the situation that sugar exists.

-a little less than methylate that (LM: low-methoxy), its methylation changes pectin between 25 to 50%. More soluble in water than HM pectin, it is at bivalent cation Ca for example²⁺Produce gel in the situation that ion exists. In fact, Ca²⁺Ion forms " bridge " between the free carboxy (carboxylated group) of galacturonic acid moieties. The network structure that forms is described (people (1973) the Biological interactions between polysaccharidesand divalent cations:the egg-box model such as Grant G.T. by people such as Grant with the title of " egg-BOX Model " (egg-box model), FEBS Letters, 32,195).

Also there is amidated pectin. With WITH AMMONIA TREATMENT pectin with some methyl carboxylic acids ester group (COOCH₃) convert formamido (CONH to₂). This amidatioon gives pectin new characteristic, particularly to the resistance of the variation of pH. Amidated pectin tends to more tolerate the variation of pH, and studied matrix tablet for the preparation of colonic delivery (matricial tablet) (people (1997) the Studies on amidated pectins aspotential carriers in colonic drug delivery such as Wakerly Z., Journal ofPharmacy and Pharmacology.49,622).

The pectin origin comes from the enzyme degraded of higher plant and various microorganism (fungi, bacterium etc.) (wherein bacterium is from people's colonic microflora). The mixture that is comprised polysaccharase, glycosidase and esterase by the enzyme of microbiota (microflora) generation.

Zinc cation

Divalent zinc cation from different zinc salts can be used for cross-linked pectin. Example comprises zinc sulfate, zinc chloride and zinc acetate.

In the present invention, the reagent that is used for enteric coating is preferably methacrylic acid-alkyl acrylate copolymer, for example

Polymer.

Polymer

The medicine carrying core for example dressing of tablet, capsule, granula, pill or crystallization provides the many favourable aspect of the homologue that is better than not being coated with, for example the higher physical and chemical stability of active component, the better effect of compliance and increase. In fact, the effect of medicament not only depends on the active component that it comprises but also depends on preparation and processing.

Poly-(methyl) acrylate has proved and has been especially suitable for use as coating material. This base polymer (usually only using with several milligrams amount) is the pharmacology inertia, is namely drained without change.

Be the trade name of the copolymer of deriving from the ester of acrylic acid and methacrylic acid, its character is determined by functional group. Different

Grade is different in the ratio of their neutrality, alkalescence or acidic-group, thereby different aspect physicochemical property. Different

The ingenious use of polymer and combination provide in various medicines and technology application and have been used for the perfect solution that controlled drug discharges.

The functional film that is used for sustained-release tablet and coating of pill is provided. Described polymer is described in International Pharmacopoeia for example Ph.Eur., USP/NF, DMF and JPE.

Polymer can be controlled drug release following probability is provided:

● gastrointestinal tract targeting (stomach resistance (gastroresistance) discharges in colon)

● protectiveness coating (sense of taste and abnormal smells from the patient are sheltered, moisture protection)

● the drug release of delay (slow releasing preparation).

Polymer can obtain with various concentration and physical form, comprises aqueous solution, aqueous dispersion, organic solution and solid matter.

The pharmaceutical properties of polymer is determined by the chemical property of their functional group.Produce difference between aspect following:

● poly-(methyl) acrylate is dissolved in Digestive system (by the formation of salt) and has acidity or basic group L (methacrylic acid copolymer), S (methacrylic acid copolymer), FS and E (alkaline butylation methacrylate (butylatedmethacrylate) copolymer) polymer allows the pH dependent release of active component.

Use: by the exclusive resistance of gastric juice is discharged from simple taste masking to the controlled drug all parts of intestinal.

● poly-(methyl) acrylate is insoluble to Digestive system

Has basic group

RL and RS (ammonium methacrylate copolymer) polymer and have neutral group

When making it possible to control by the swelling that does not rely on pH, the NE polymer discharges (controlled time release) active component.

Information about the Eudragit polymer sees: http://www.pharma-polymers.com/pharmapolymers/en/eudragit/enter iccoatings/ and see http://www.pharma-polymers.com/pharmapolymers/en/eudragit/regul atorytoxicology/

Enteric coating: stomach resistance and the release in colon

Intestinal

Coating protective effect is provided in case medicine discharge under one's belt and make its can be in intestinal controlled release.Recommend to be used for specific application or therapeutic strategy by the drug release of targeting in the gastrointestinal tract, for example when medicine is slightly soluble in upper digestive tract, or when medicine can be degraded by gastric juice.The second, this dosage form to the patient as mild as a dove because it stress stomach, and owing to sending of prolonging, the dosage number of medicine can significantly reduce.The main criterion that discharges is that some part (pH 5 is to surpassing 7) at intestinal but not the coating that depends on pH that takes place in stomach (pH 1-5) dissolve.Use for these, can will comprise the anion of carboxyl

Grade is mixed mutually.This makes may adjust dissolving pH subtly, thereby determines the drug release position in the intestinal.

L and S grade are suitable for enteric coating.

FS30D (based on the aqueous dispersion of the anionic copolymer of acrylic acid methyl ester., methyl methacrylate and methacrylic acid) is used in particular for the controlled release in the colon.

Intestinal

The application benefit of coating comprises:

● depend on the drug release of pH

● to the protective effect of the active component of gastric juice sensitivity

● the protection gastric mucosa is avoided the damage of aggressive active component

● the increase of efficacy of drugs

● stability for storage

● the controlled release in colon/GI targeting

Activating agent

Activating agent can be an infectivity resistant, for example antibiotic, anti-inflammatory compound, antihistaminic, anticholinergic agent, antiviral agent, antimitotics, peptide, protein, enzyme, nucleic acid (RNA or DNA), peptide nucleic acid(PNA), plasmid, gene, antisense oligonucleotide, RNA interfering, ribozyme, micromolecule, diagnostic agent, immunosuppressant, virus, antibacterial, other microorganisms or eukaryotic cell with specific bond ability or activity (for example by the chemotherapy of targeting).

Activating agent can be imported drug delivery system with the form of powder, solution, suspension or for example cyclodextrin or any other suitable compound are compound with solubilizing agent.

Can use some activating agents of describing herein with the form of prodrug.With regard to the segmented intestine targeted prodrug of having studied widely of different activities composition (for example steroid and nonsteroidal antiinflammatory drug and spasmolytic).These systems act on the ability of prodrug with the activity form of release of active ingredients based on the enzyme that is produced by colonic microflora.

Prodrug can be based on the effect of antibacterial azo reductase, so that the available drug delivery system of describing herein is with activating agent targeting colon, form activating agent with the reaction by prodrug and antibacterial azo reductase, this provides guarantees the double mechanism of medicament administration to colon.The representative chemical drugs that is used to form such prodrug is described in for example people (1972) The role of intestinal bacteria in the metabolism ofsalicylazosulfapyridin such as Peppercorn M.A., The Journal of Pharmacology andExperimental Therapeutics, 181,555 and 64,240.

Another method is to use antibacterial hydrolytic enzyme for example glycosidase and polyase (FriendD.R. (1995) Glycoside prodrugs:novel pharmacotherapy forcolonic diseases, S.T.P.Pharma Sciences, 5,70; People (1984) A colon-specific drug-delivery system based on drugglycosides and the glycosidases of colonic bacteria such as Friend D.R., Journalof Medicinal Chemistry, 27,261; People (1985) Drugglycosides:potential prodrugs for colon-specific drugdelivery such as Friend D.R., Journal of Medicinal Chemistry, 28,51; With people (1992) Drug glycosides in oral colon-specific drugdelivery such as Friend D.R., Journal of Controlled Release, 19,109).Therefore prodrug is by for example using people (1996) In vitro evaluation of Biphenylyl Acetic Acid-beta-Cyclodextrin conjugates as colon-targeting prodrugs:drugrelease behavior in rat biological media such as steroid coupling sugar (glucose, galactose, cellobiose, glucosan (dextrane) (International Application No. WO 90/09168)), cyclodextrin Hirayama F., Journal of Pharmacyand Pharmacology, 48,27) develop.

A) the antibiotic reagent of deactivation

In one embodiment, activating agent be can be in colon the antibiotic enzyme of deactivation.Can use the antibiotic any reagent of deactivation.

When antibiotic is beta-Lactam antibiotic, can use beta-lactamase.Selected enzyme is that beta-lactamase L1 is (from the Zn that depends on that has a liking for maltose oligotrophy Zymomonas mobilis ²⁺Beta-lactamase) be selected from a series of beta-lactamases be used for by the best features of the application of targeting because its feature shows.In addition, proved that it has the advantages of excellent stability feature.The feature of the different beta-lactamases of being estimated has been described hereinafter.

Except beta-lactamase L1 enzyme discussed above, also exist many kinds to be known as the dependent enzyme of metal.When expectation is administered to this fermentoid through port clothes the patient and uses, must carefully avoid making enzyme in stomach or epigaster, to be digested.Therefore, the drug delivery system of describing herein can be advantageously used in and send this metalloid dependent enzyme.The cation that is used for cross-linked pectin comprises the cation that enzyme relies on.

A representative enzyme is beta-lactamase L1, from the Zn that depends on that has a liking for maltose oligotrophy Zymomonas mobilis ²⁺Beta-lactamase, it is selected from a series of beta-lactamases, is used for by the best features of the application of targeting because its feature shows.In addition, proved that it has the advantages of excellent stability feature.The feature of the different beta-lactamases of being estimated has been described hereinafter.

When antibiotic from other-during the antibiotic of kind, can use this type of antibiotic enzyme of deactivation or other molecules.Such example is to use Erythromycin esterase. deactivation macrolide antibiotic.

A representative Erythromycin esterase. is by people ((1985) " Plasmid mediated susceptibility to intestinal microbialantagonisms in Escherichia coli, " Infect.Immun.49 (3): 751) (its content is integrated with this paper by reference) disclosed Erythromycin esterase. such as Andremont A..

When antibiotic is quinolinones, activating agent can be can the deactivation quinolinones activating agent.Representative reagent comprises by Chen, the disclosed reagent of people such as Y ((1997) " Microbicidal models ofsoil metabolisms biotransformations of danofloxacin, " Journalof Industrial Microbiology and Biotechnology 19:378).

Available these combination of agents treatment patients.

Representative beta-lactamase and they are shown in table 1 to the different antibiotic effect.

Table 1

Antibiotic	?FEZ-1*?K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)	??L-1(wt)**??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)
							Penicillin
Benzylpcnicillin	??70	??590	??0.11	??600	??38	??16
							Ampicillin	??＞5.5	??＞5000	??0.011	??520	??55	??9.5
Carbenicillin	??35	??1600	??0.023
							Piperacillin	??50	??4200	??0.012
The azlocillin
							The mezlocillin
Ticarcillin	??＞65	??＞5000	??0.013
							Temocillin
							Cephalosporin
Cefalorne (Cephaloridin)	??16	??1000	??0.016
							Cephalothin	??300	??120	??2.5	??82	??8.9	??9.2
Cefoxitin				??1	??3	??0.33
							Cefuroxime
Cefotaxime	??165	??70	??2.4	??270	??10	??27
							??Ceftazidin
Cefepime (Cefepim)	??＞6	??＞1000	??0.006
							Cefpirome (Cefpirom)
Nitrocefin	??90	??100	??0.9	??41	??4	??10

Antibiotic	?FEZ-1*?K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)	??L-1(wt)**??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)
							Latamoxef	??3	??18	??0.17
							Carbapenem
Imipenum	??＞200	??＞1000	??0.2	??370	??57	??6.5
							Meropenem	??45	??85	??0.5	??157	??15	??10
Biapenem	??70	??＞1000	??0.07	??134	??32	??4.2
Monobactam
							Aztreonam
Carumonam
Inactivator based on mechanism
							??(Mechanism-??Based??Inactivator)
Sulbactam
							Tazobactam Sodium	??40	??700	??1.06
Clavulanic acid	??＜0.01	??＞1000	??＜0.00001	??11	??22	??0.5

* (people such as Mercuri, Antimicrob.Agents.Chemother.2001 Apr; 45 (4): 1254-1262)

* (people such as Carenbauer, BMC Biochem.2002; 3:4.Epub 2002 Feb.13; Frere, 2005, unpub data)

Table 1 (continuing)

Antibiotic	??IMP-1***??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)	??VIM-2****??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)
							Penicillin

Antibiotic	??IMP-1***??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)	??VIM-2****??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)
							Benzylpcnicillin	??320	??520	??0.62	??56	??49	??1.114
Ampicillin	??950	??200	??4.8	??125	??90	??1.4
							Carbenicillin			??0.02	??185	??205	??0.9
Piperacillin			??0.72	??300	??125	??2.4
							The azlocillin				??200	??200	??1
The mezlocillin				??200	??125	??1.4
							Ticarcillin	??1.1	??740	??0.0015	??180	??125	??1.6
Temocillin		??＞2000	??＜0.0001	??7.7	??390	??0.002
Cephalosporin
							Cefalorne	??53	??22	??2.4	??140	??50	??2.8
Cephalothin	??48	??21	??2.4	??130	??11	??12
							Cefoxitin	??16	??8	??2	??15	??13	??1.2
Cefuroxime	??8	??37	??0.22	??8	??20	??0.4
							Cefotaxime	??1.3	??4	??0.45	??70	??12	??5.8
??Ceftazidin	??8	??44	??0.18	??3.6	??72	??0.05
							Cefepime	??7	??11	??0.66	??＞40	??＞400	??0.1
Cefpirome	??9	??14	??0.64	??180	??180	??1
							Nitrocefin	??63	??27	??2.3	??770	??18	??43
Latamoxef				??90	??55	??1.6
Carbapenem

Antibiotic	??IMP-1***??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)	??VIM-2****??K cat(S -1)	??K m(μM)	??K cat/K m??(μM/s -1)
							Imipenum	??46	??39	??1.2	??34	??9	??3.8
Meropenem	??50	??10		??5	??2	??2.5
							Biapenem	??160	??28	??6	??8.5	??15	??0.55
							Monobactam
Aztreonam	??＞0.01	??＞1000	??＜0.0001	??＜0.01	??＞1000	??＜0.0001
							Carumonam	??＞0.01	??＞1000	??＜0.0001
							Inactivator based on mechanism
Sulbactam				??23	??320	??0.072
							Tazobactam Sodium				??28	??875	??0.032
Clavulanic acid

* * (people 2003 such as Murphy, Antimicrob.Ag.Chemother.2003 Feb, 47 (2): 582-7; People such as Laraki, Antimicrob.Ag.Chemother.1999 Apr., 43 (4): 902-6)

* * * (people such as Docquier, J Antimicrob.Chemother.2003 Feb., 51 (2): 257-266)

B) reagent of treatment colon cancer

When drug delivery system is used for the treatment of colon cancer, can use the antitumor agent of any kind.Antitumor agent can be an antiproliferative for example, the reagent that is used for dna modification or reparation, the DNA synthetic inhibitor, the agent of DNA/RNA transcriptional regulatory, RNA processes inhibitor, influence protein expression, synthetic and stable reagent, influence the reagent of the ability of protein positioning or their their physiological actions of performance, the reagent of interferencing protein-protein or protein-nucleic acid interaction, disturb the reagent that works by RNA, the receptors bind molecule of any chemical property (comprising micromolecule and antibody), by the toxin of targeting, zymoexciter, enzyme inhibitor, the Gene regulation agent, the HSP-90 inhibitor, disturb the molecule of microtubule or other cytoskeleton components or cell adhesion and motion, the reagent and the treatment adjuvant (therapy adjunct) that are used for phototherapy.

Representative antiproliferative comprises N-acetyl group-D-sphingol (C ₂Ceramide), apigenin, berberine hydrochloride, clodronate disodium salt (dichloro Medronate disodium salt (dichloromethylenediphosphonic acid disodium salt)), aloe-emodin (loe-emodine), emodin, HA 14-1, N-hexanoyl-D-sphingol (C ₆Ceramide), 7b-hydroxy cholesterol, 25-hydroxy cholesterol, hyperforine, parthenolide and rapamycin.

The representative reagent that is used for dna modification and reparation comprises aphidicolin, Bleomycin Sulphate, carboplatin, carmustine, chlorambucil, cyclophosphamide monohydrate, cyclophosphamide monohydrate

Cisplatin (cis-diammineplatinum (II) dichloride) (cisplatin), esculetin (esculetin), melphalan, methoxamine hydrochloride, ametycin, mitoxantrone dihydrochloride, oxaliplatin and streptozotocin.

The representative DNA synthetic inhibitor comprises (±) methotrexate (methotrexate), 3-amino-1,2,4-phentriazine 1,4-dioxide, aminopterin, cytosine b-D-furan galactoside (Ara-C), cytosine b-D-furan galactoside (Ara-C) hydrochlorate, 2-fluoroadenine-9-b-D-furan galactoside (dephosphorylation fludarabine (Fludarabinedes-phosphate), F-ara-A), 5-fluoro-5 '-BrdU, 5-fluorouracil, ganciclovir, hydroxyurea, Ismipur and 6-thioguanine.

Representative DNA/rna transcription regulator comprises actinomycin D, daunorubicin hydrochloride, 5,6-dichloro benzimidazole 1-b-D-furan type riboside, doxorubicin hydrochloride, homoharringtonine and idarubicin hydrochloride.

Representative zymoexciter and inhibitor comprise Forskolin, the DL-aminoglutethimide, apicidin, the Bowman-Birk inhibitor, butein, (S)-(+)-camptothecine, curcumin, (-)-deguelin, (-)-depudecin, doxycycline hydrochloride, etoposide, formestane, the fostriecin sodium salt, bristle element (hispidin), 2-imino group-1-imidazoline acetic acid (circular muscle acid), oxamflatin, the 4-benzenebutanoic acid, roscovitine, sodium valproate, Trichostatin A, tyrphostin AG 34, tyrphostin AG 879, the urinary trypsin inhibitor fragment, valproic acid (2-valproic acid) and XK469.

Representative Gene regulation agent comprise 5-azepine-2 '-deoxycytidine, 5-azacytidine, vitamin D3 (Vitamin D3), ciglitizone, cyproterone acetate, 15-deoxidation-D ^12,14-prostaglandin J ₂, epitestosterone, flutamide, ammonium glycyrrhizinate (glycyrrhizin), 4-hydroxy-tamoxifen, mifepristone, procamide, RALOXIFENE HCL, complete-trans-retinene (axerophthal), tretinoin (retinoic acid), 9-be suitable-tretinoin, 13-be suitable-tretinoin, tretinoin be right-hydroxyanilines (p-hydroxyanilide), retinol (vitamin A), zitazonium, zitazonium citrate, TTA and troglitazone.

Representative HSP-90 inhibitor comprises 17-(allyl amino)-17-de-methoxy lattice moral mycin and geldanamycin.

Representative microtubule inhibitor comprises Colchicine, Dolastatin 15, nocodazole, taxanes and paclitaxel, podophyllotoxin, rhizomycin, vinblastine sulfate, leucocristine sulfate and vindesine sulfate and vinorelbine (nvelbine) two tartrates especially.

The representative reagent that is used to carry out phototherapy comprises photosensitive porphyrin ring, hypericin, 5-bergapten, 8-methoxyposoralen, psoralen and ursodeoxycholic acid.

Representative reagent as the treatment adjuvant comprises amifostine, 4-amino-1,8-naphthalimide, brefeldin A, cimetidine, fosfomycin disodium salt (phosphomycindisodium salt), leuprorelin (leuprorelin) acetate, luteinising hormone-releasing hormo (LH-RH) acetate, agglutinin, papaverin hydrochloride, Pi Feisong-a, (-)-scopolamine hydrobromide and thapsigargin.

Reagent can also be anti-VEGF (VEGF) reagent, and such reagent is known in this area.Several antibody and micromolecule are used for clinical trial at present or have proved by suppressing VEGF work for example Avastin (Bevacizumab), SU5416, SU11248 and BAY 43-9006.But described reagent is growth factor receptors EGF receptor (Iressa or gefitinib, and tower Western method or Erlotinib), Erb-B2 receptor (Trastuzumab or Herceptin), other receptors (for example Rituximab or Rituxan/ Mabthera), tyrosine kinase, nonreceptor tyrosine kinase, cell serine/threonine kinase (comprising map kinase) and its imbalance various other protein (for example little/Ras family and big/heterotrimeric G protein) of facilitating tumor to generate for example of antibiosis growth factor receptor style such as EGF/Erb-B family also.Several antibody of these molecules of targeting and micromolecule are at present in the different development phase (comprising that approval is used for the treatment of or clinical trial).

In the most frequently used antitumor agent in that use at present or the clinical trial some comprise paclitaxel, docetaxel, zitazonium, vinorelbine, gemcitabine, cisplatin, etoposide, hycamtin, irinotecan, Anastrozole, Rituximab, Herceptin, fludarabine, cyclophosphamide, lucky trastuzumab (gentuzumab), carboplatin, interferon and doxorubicin.The most frequently used anticarcinogen is a paclitaxel, its use separately or with other chemotherapeutics for example: 5-FU, doxorubicin, vinorelbine, cyclophosphamide and cisplatin are used in combination.

Can provide combination treatment by two or more of above-claimed cpd are made up.

C) reagent of treatment Crohn disease

There are several Therapeutic Method that are used for the treatment of Crohn disease.Most of people at first treat with the medicine that contains aminosalicylic acid (material that help controls inflammation).Sulfasalazine is the medicine of normal use in these medicines.Can not use other medicines that contains aminosalicylic acid, be commonly referred to 5-ASA reagent, for example An Sake (Asacol), olsalazine sodium or Pentasa from its patient that maybe can not tolerate it that is benefited.Usually using corticosteroid controls inflammation.

Immunosuppressant also is used for the treatment of Crohn disease.The most frequently used prescription is Ismipur and related drugs azathioprine.Immunosuppressant facilitates the immunoreation of inflammation to work by blocking-up.

The patient can with these combination of agents for example the combination of corticosteroid and immunosuppressive drug treat.

(trade name Remicade) is used for the treatment of the nullvalent moderate of standard treatment (aminosalicylic acid material, corticosteroid, immunosuppressant) to serious Crohn disease be used for the treatment of open drain fistula (draining fistulas) FDA Food and Drug Administration's approved medicine infliximab.Infliximab is anti-tumor necrosis factor α (TNF-α) antibody.This reagent and other anti-TNF-α reagent can be used for removing TNF-α from colon, thus prevention of inflammation, and no-trump TNF-α clears out of the side effect that colon may cause from blood flow.

Usually diarrhea be can also use, diphenoxylate, loperamide and codeine comprised.

D) reagent of treatment ulcerative colitis

The reagent that is used for the treatment of ulcerative colitis is identical with the reagent part that is used for the treatment of Crohn disease.Example comprises aminosallcylic acid ester/salt that help controls inflammation, and contains the medicine of 5-amino salicylate (5-ASA), for example sulfasalazine, olsalazine, aminosalicylic acid and balsalazide.They also comprise for example for example azathioprine and 6-sulfydryl-purine (6-MP), cytokine, interleukin and lymphokine of prednisone and hydrocortisone and immunomodulator of corticosteroid.Cyclosporin A can make with 6-MP or azathioprine and be used for treating active serious ulcerative colitis.Also can use anti-TNF-α reagent, thiazolidinediones or glitazone (glitazones) comprise rosiglitazone and pioglitazone.

E) reagent of treatment constipation/irritable bowel syndrome

Stimulant laxative, permeability aperient (osmotic laxatives) are used in constipation (for example relevant with irritable bowel syndrome constipation) usually, and for example lactulose and MiraLax, stool softener (stool softener) (for example mineral oil or docusate sodium), extender (for example Metamucil (Metamucil) or bran) are treated.Reagent for example Zelnorm (being also referred to as tegaserod) can be used for treating IBS with constipation.In addition, anticholinergic agent for example

With Found to help to alleviate the enterospasm of IBS.

F) protein and peptide medicine

If drug delivery system can be used for Orally administered be degraded and may must intramuscular or intravenous protein and the peptide used.

The example that is used for protein of the present invention and peptide comprises:

Thyroliberin (ACTH) peptide includes but not limited to, ACTH, people, ACTH1-10, ACTH 1-13, people: ACTH 1-16, people, ACTH 1-17, ACTH 1-24, people, ACTH 4-10, ACTH 4-11, ACTH 6-24, ACTH 7-38, people, ACTH 18-39, people, ACTH, rat, ACTH 12-39, rat, beta cell opsonin (ACTH 22-39), biotinyl-ACTH 1-24, people, biotinyl-ACTH 7-38, people, corticostatin (corticostatin), people, corticostatin, rabbit, [Met (O2) ⁴, DLys ⁸, Phe ⁹] ACTH 4-9, people, [Met (O) ⁴, DLys ⁸, Phe ⁹] ACTH 4-9, people, N-acetyl group, ACTH1-17, people and ebiratide.

The adrenomedullin peptide includes but not limited to, adrenomedullin, adrenomedullin 1-52, people, adrenomedullin 1-12, people, adrenomedullin 13-52, people, adrenomedullin 22-52, people, the former 45-92 of adrenomedullin, people, the former 153-185 of adrenomedullin, people, adrenomedullin 1-52, pig, adrenomedullin former (N-20), pig, adrenomedullin 1-50, rat, adrenomedullin 11-50, rat and proAM-N20 (terminal 20 peptides of the former N-of adrenomedullin), rat.

The allatostatin peptide includes but not limited to, allatostatin I, allatostatin II, allatostatin III and allatostatin IV.

Pancreas opsonin (amylin) peptide includes but not limited to; acetyl group-pancreas opsonin 8-37; the people; acetylation pancreas opsonin 8-37; rat; AC 187 pancreas opsonin antagonisies; AC253 pancreas opsonin antagonist; AC625 pancreas opsonin antagonist; pancreas opsonin 8-37; the people; pancreas opsonin (IAPP); cat; pancreas opsonin (insulinoma or island amyloid polypeptide IAPP)); pancreas opsonin amide; the people; pancreas opsonin 1-13 (diabetes associated peptide 1-13); the people; pancreas opsonin 20-29 (IAPP 20-29); the people; AC625 pancreas opsonin antagonist; pancreas opsonin 8-37; the people; pancreas opsonin (IAPP); cat; the pancreas opsonin, rat; pancreas opsonin 8-37, rat; biotinyl-pancreas opsonin; rat and biotinyl-pancreas opsonin amide, the people.

Amyloid-beta-protein fragments peptide includes but not limited to, Alzheimer beta-protein 12-28 (SP17), amyloid-beta-protein 25-35, amyloid-beta/A4-amyloid protein precursor 328-332, amyloid-beta/A4 amyloid protein precursor (APP) 319-335, amyloid-beta-albumen 1-43, amyloid-beta-albumen 1-42, amyloid-beta-albumen 1-40, amyloid-beta-protein 10-20, amyloid-beta-4 protein 22-35, Alzheimer beta-protein (SP28), beta-amyloid peptide 1-42, rat, beta-amyloid peptide 1-40, rat, amyloid beta 1-11, amyloid beta 31-35, amyloid beta 32-35, amyloid beta 35-25, amyloid beta/A4 amyloid protein precursor 96-110, amyloid beta precursor protein 657-676, amyloid beta 1-38, [Gln ¹¹]-Alzheimer beta-protein, [Gln ¹¹]-amyloid beta 1-40, [Gln ²²Non--A β component (NAC) of]-amyloid beta 6-40, Alzheimer amyloid, P3, (A β 17-40) Alzheimer amyloid-beta-peptide and SAP (serum amyloid shape albumen P component) 194-204.

Angiotensin peptides includes but not limited to, A-779, Ala-Pro-Gly-Angiotensin II, [Ile ³, Val ⁵]-Angiotensin II, the anti-peptide of Angiotensin II I, angiogenin fragment 108-122, angiogenin fragment 108-123, tonin inhibitor, angiotensin I, people, tonin substrate, hypertensin 1 1-7, people, blood vessel press down peptide (angiopeptin); Angiotensin II, people, the anti-peptide of Angiotensin II, Angiotensin II 1-4, people, Angiotensin II 3-8, people, Angiotensin II 4-8, people, Angiotensin II 5-8, people, Angiotensin II I ([Des-Asp ¹]-Angiotensin II), people, Angiotensin II I inhibitor ([Ile ⁷]-Angiotensin II I), angiotensin-convertion enzyme inhibitor (yellowfin sturgeon (Neothunnus macropterus)), [Asn ¹, Val ⁵]-angiotensin I, Goosefiss, [Asn ¹, Val ⁵, Asn ⁹]-angiotensin I, salmon, [Asn ¹, Val ⁵, Gly ⁹]-angiotensin I, Anguillar japonica, [Asn ¹, Val ⁵]-angiotensin I 1-7, Anguillar japonica, Goosefiss, salmon, [Asn ¹, Val ⁵]-Angiotensin II, biotinyl-angiotensin I, people, biotinyl-Angiotensin II, people, biotinyl-Ala-Ala-Ala-Angiotensin II, [Des-Asp ¹]-angiotensin I, people, [right-the aminobenzene alanine ⁶]-Angiotensin II, feritin substrate (proangiotensin 1-13), people, preangiotensinogen 1-14 (feritin substrate tetradecapeptide), people, feritin substrate tetradecapeptide (proangiotensin 1-14), pig, [Sar ¹]-Angiotensin II, [Sar ¹]-Angiotensin II 1-7 amide, [Sar ¹, Ala ⁸]-Angiotensin II, [Sar ¹, Ile ⁸]-Angiotensin II, [Sar ¹, Thr ⁸]-Angiotensin II, [Sar ¹, Tyr (Me) ⁴]-Angiotensin II (Sarmesin), [Sar ¹, Val ⁵, Ala ⁸]-Angiotensin II, [Sar ¹, Ile ⁷]-Angiotensin II I, synthetic tetradecapeptide feritin substrate (No.2), [Val ⁴]-Angiotensin II I, [Val ⁵]-Angiotensin II, [Val ⁵]-angiotensin I, people, [Val ⁵]-angiotensin I, [Val ⁵, Asn ⁹]-angiotensin I, bull frog and [Val ⁵, Ser ⁹]-angiotensin I, fowl.

Antibiotic peptide includes but not limited to, Ac-SQNY, bactenecin, cattle, CAP37 (20-44), carbormethoxycarbonyl-DPro-DPhe-OBzl, CD36 peptide P139-155, CD36 peptide P 93-110, attacin A-melittin T1249 [CA (1-7) M (2-9) NH2], cecropin B, free acid, CYS (Bzl) 84CD fragment 81-92, sozin (people) HNP-2, skin bacteriostatic peptide, immunostimulating peptide, people, lactoferricin, cattle (BLFC) and MAGAININ MSI-344 introns.

Can cause enhanced immunoreactive antigenic polypeptide enhance immunity reaction and/or cause immune effecting reaction disease and/or diseases induced reagent, described disease and/or diseases induced reagent include but not limited to adenovirus, anthrax, bordetella pertussis (Bordetellapertussus), botulism, bovine rhinotracheitis, branhamella catarrhalis (Branhamella catarrhalis), dog hepatitis, canine distemper, chlamydia, cholera, ball sporozoite bacterium (coccidiomycosis), cowpox, cytomegalovirus, dengue fever, the dengue fever toxoplasmosis, diphtheria, encephalitis, enterotoxigenic escherichia coli, Epstein-Barr virus, equine encephalitis, contagious equine abortion, equine influenza, horse pneumonia, equine rhinoviruses, escherichia coli, the cat leukemia, banzi virus, globulin, the Type B hemophilus influenza, hemophilus influenza (Haemophilus influenzae), Hemophilus pertussis (Haemophilus pertussis), helicobacter pylori (Helicobacter pylon), haemophilus, hepatitis, hepatitis virus A, hepatitis virus B, hepatitis virus C, herpesvirus, HIV, HIV-1 virus, HIV-2 virus, HTLV I, HTLV II, HTLV III, influenza, Japanese encephalitis, the kind of Klebsiella, invade lung legionella (Legionella pneumophila), leishmania, leprosy, Lyme disease, the malaria immunogen, measles, meningitis, meningococcus, A group meningitis cocci polysaccharide, C group meningitis cocci polysaccharide, mumps, mumps virus, mycobacteria, mycobacterium tuberculosis (Mycobacterium tuberculosis), Neisseria gonorrhoeae, Diplococcus gonorrhoeae (Neisseria gonorrhoeae), Neisseria meningitidis (Neisseriameningitidis); Ovine blue tongue, the Medulla caprae seuovis inflammation, human papillomavirus, parainfluenza, paramyxovirus, the bacillus pertussis extracellular toxin, the plague, streptococcus pneumoniae, Pneumocystis carinii (Pneumocystiscarinii), pneumonia, poliovirus, the kind of Proteus, Pseudomonas aeruginosa (Pseudomonas aeruginosa), rabies, respiratory syncytial virus, rotavirus, rubella, Salmonella, schistosomicide, shigella dysenteriae, simian immunodeficiency virus, variola, staphylococcus aureus (Staphylococcus aureus), the kind of staphylococcus, streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus pyogenes (Streptococcuspyogenes), the kind of Streptococcus, clostridium difficile (Clostridium difficile), the kind of fusobacterium, swine flue, tetanus, Tyreponema pallidum (Treponema pallidum), typhoid fever, cowpox, varicella zoster virus and vibrio cholera (Vibrio cholerae).

Antimicrobial peptide includes but not limited to, buforin I, buforin II, attacin A, cecropin B, attacin P1, pig, gaegurin 2 (Ranarugosa (schlegel). (Ranarugosa)), gaegurin 5 (Ranarugosa (schlegel).), indole bacterium peptide (indolicidin), protegrin-(PG)-I, MAGAININ MSI-344 1 and MAGAININ MSI-344 2 and T-22[Tyr ^5,12, Lys ⁷]-poly-phemusin II peptide.

The apoptosis related peptides includes but not limited to, Alzheimer beta-protein (SP28), the calpain inhibitor peptide, capsase-1 inhibitor V, capsase-3, substrate IV, caspase-1 inhibitor I, cell is permeable, caspase-1 inhibitor VI, caspase-3 substrate III, fluorescence, caspase-1 substrate V, fluorescence, caspase-3 inhibitor I, cell is permeable, caspase-6 ICE inhibitor III, [Des-Ac, biotin]-ICE inhibitor III, IL-1B invertase (ICE) inhibitor II, IL-1B invertase (ICE) substrate IV, MDL 28170 and MG-132.

Atrial natriuretic peptide includes but not limited to, α-ANP (α-chANP), chicken, anantin, ANP 1-11, rat, ANP 8-30, the frog, ANP 11-30, the frog, ANP-21 (fANP-21), the frog, ANP-24 (fANP-24), the frog, ANP-30, the frog, ANP fragment 5-28, the people, dog, ANP-7-23, the people, ANP fragment 7-28, the people, dog, α-atrium natriuresis polypeptide 1-28, people, dog, A71915, rat, atrial natriuretic peptide 8-33, rat, atrium natriuresis polypeptide 3-28, the people, atrium natriuresis polypeptide 4-28, the people, dog, atrium natriuresis polypeptide 5-27, the people, atrium natriuresis aeptide (ANP), Anguillar japonica, atrial natriuretic peptide I, rat, rabbit, mice, atrial natriuretic peptide II, rat, rabbit, mice, atrial natriuretic peptide III, rat, rabbit, mice, atrial natriuretic peptide (rANF), rat, auriculin A (rat ANF 126-149), auriculin B (rat ANF 126-150), β-ANP (1-28, dimer, antiparallel), β-rANF 17-48, biotinyl-α-ANP 1-28, the people, dog, biotinyl-atrial natriuretic peptide (biotinyl-rANF), rat, cardiodilatin (cardiodilatin) 1-16, the people, C-ANF 4-23, rat, Des-[Cys ¹⁰⁵, Cys ¹²¹]-atrial natriuretic peptide 104-126, rat, [Met (O) ¹²] ANP 1-28, people, [Mpr ⁷, DAla ⁹] ANP 7-28, amide, rat, the former 104-116 of preceding ANF, people, the former 26-55 of preceding ANF (proANF 1-30), people, the former 56-92 of preceding ANF (proANF 31-67), people, the former 104-123 of preceding ANF, people, [Tyr ⁰]-atrial natriuretic peptide I, rat, rabbit, mice, [Tyr ⁰]-atrial natriuretic peptide II, rat, rabbit, mice, [Tyr ⁰The former 104-123 of]-preceding ANF, people, urine sodium element (urodilatin) (CDD/ANP 95-126), ventricle natriuretic peptide (VNP), Anguillar japonica and ventricle natriuretic peptide (VNP), Squaliobarbus ourriculus.

Bag cell peptide includes but not limited to, α bag cell peptide, α-bag cell peptide 1-9, α-bag cell peptide 1-8, α-bag cell peptide 1-7, β-bag cytokine and γ-bag cytokine.

Bombesin includes but not limited to, α-s1 casein 101-123 (milk), biotinyl-bombesin, bombesin 8-14, bombesin, [Leu ¹³-psi (CH2NH) Leu ¹⁴]-bombesin, [D-Phe ⁶, Des-Met ¹⁴]-bombesin 6-14 buserelin, [DPhe ¹²] bombesin, [DPhe ¹², Leu ¹⁴]-bombesin, [Tyr ⁴]-bombesin and [Tyr ⁴, DPhe ¹²]-bombesin.

Bone GLA peptide (BGP) includes but not limited to, bone GLA albumen, bone GLA albumen 45-49, [Glu ¹⁷, Gla ^21,24]-Bone Gla protein 1-49, people, myclopeptide-2 (MP-2), Bone Gla protein 1-49 people, Bone Gla protein 37-49, people and [Tyr ³⁸, Phe ^42,46] bone GLA albumen 38-49, the people.

Kallidin I includes but not limited to, [Ala ^2,6, des-Pro ³]-Kallidin I, Kallidin I, Kallidin I (bowfin. garfish), bradykinin potentiating peptide, Kallidin I 1-3, Kallidin I 1-5, Kallidin I 1-6, Kallidin I 1-7, Kallidin I 2-7, Kallidin I 2-9, [DPhe ⁷] Kallidin I, [Des-Arg ⁹]-Kallidin I, [Des-Arg ¹⁰]-Lys-Kallidin I ([Des-Arg ¹⁰]-kallidin), [D-N-Me-Phe ⁷]-Kallidin I, [Des-Arg ⁹, Leu ⁸]-Kallidin I, Lys-Kallidin I (kallidin), Lys-[Des-Arg ⁹, Leu ⁸]-Kallidin I ([Des-Arg ¹⁰, Leu ⁹]-kallidin), [Lys ⁰-Hyp ³]-Kallidin I, ovokinin, [Lys ⁰, Ala ³]-Kallidin I, Met-Lys-Kallidin I, peptide K12 bradykinin potentiating peptide, [(pCl) Phe ^5,8]-Kallidin I, T-kassinin kinin (Ile-Ser-Kallidin I), [Thi ^5,8, D-Phe ⁷]-Kallidin I, [Tyr ⁰]-Kallidin I, [Tyr ⁵]-Kallidin I, [Tyr ⁸]-Kallidin I and kallikrein.

Brain natriuretic peptide (BNP) includes but not limited to that BNP 32, dog, BNP sample peptide, Anguillar japonica, BNP-32, people, BNP-45, mice, BNP-26, pig, BNP-32, pig, biotinyl-BNP-32, pig, BNP-32, rat, biotinyl-BNP-32, rat, BNP-45 (BNP51-95, the 5K cardiac natriuretic peptides), rat and [Tyr ⁰]-BNP 1-32, the people.

The C-peptide includes but not limited to, C-peptide and [Tyr ⁰]-C-peptide, the people.

C-type natriuretic peptide (CNP) includes but not limited to, C-type natriuretic peptide, chicken, C type natriuretic peptide-22 (CNP-22), pig, rat, people, C-type natriuretic peptide-53 (CNP-53), people, C-type natriuretic peptide-53 (CNP-53), pig, rat, C-type natriuretic peptide-53 (pig, rat) 1-29 (CNP-53 1-29), the former 1-27 of preceding CNP, rat, the former 30-50 of preceding CNP, pig, rat, blood vessel sodium peptide (vasonatrin peptide) are (VNP) and [Tyr ⁰]-C-type natriuretic peptide-22 ([Tyr ⁰]-CNP-22).

Calcitonin polypeptide includes but not limited to, biotinyl-calcitonin, people, biotinyl-calcitonin, rat, biotinyl-calcitonin, salmon, calcitonin, chicken, calcium element, Anguillar japonica, calcitonin, people, calcitonin, pig, calcitonin, rat, calcitonin, salmon, calcitonin 1-7, people, calcitonin 8-32, salmon, katacalcin (PDN-21) (C-procalcitonin) and N-proCT (amino-terminal procalcitonin cutting peptide), people.

Calcitonin-gene-related peptide (CGRP) includes but not limited to; acetyl group-α-CGRP19-37, the people; α-CGRP 19-37, the people; α-CGRP 23-37; the people; biotinyl-CGRP; the people; biotinyl-CGRP II, the people; biotinyl-CGRP, rat; β-CGRP; rat; biotinyl-β-CGRP; rat; CGRP, rat; CGRP, the people; the terminal contiguous peptide (adjacent peptide) of calcitonin C-; CGRP 1-19; the people; CGRP 20-37; the people; CGRP8-37, the people; CGRP II, the people; CGRP; rat; CGRP 8-37; rat; CGRP 29-37, rat; CGRP 30-37, rat; CGRP 31-37; rat; CGRP 32-37; rat; CGRP 33-37, rat; CGRP 31-37, rat; ([Cys (Acm) ^2,7]-CGRP, elcatonin, [Tyr ⁰]-CGRP, people, [Tyr ⁰]-CGRP II, people, [Tyr ⁰]-CGRP 28-37, rat, [Tyr ⁰]-CGRP, rat and [Tyr ²²]-CGRP 22-37, rat.

The CART peptide includes but not limited to, CART, people, CART 55-102, people, CART, rat and CART 55-102, rat.

The cheese deltorphin delta includes but not limited to, β-cheese deltorphin delta, people, β-cheese deltorphin delta 1-3, β-cheese deltorphin delta 1-3, amide, β-cheese deltorphin delta, cattle, β-cheese deltorphin delta 1-4, cattle, β-cheese deltorphin delta 1-5, cattle, β-cheese deltorphin delta 1-5, amide, cattle, β-cheese deltorphin delta 1-6, cattle, [DAla ²]-β-cheese deltorphin delta 1-3, amide, cattle, [DAla ², Hyp ⁴, Tyr ⁵]-β-cheese deltorphin delta 1-5 amide, [DAla ², DPro ⁴, Tyr ⁵]-β-cheese deltorphin delta 1-5, amide, [DAla ², Tyr ⁵]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ^2,4, Tyr ⁵]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ², (pCl) Phe ³]-β-cheese deltorphin delta, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-4, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-5, cattle, [DAla ²]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ², Met ⁵]-β-cheese deltorphin delta 1-5, cattle, [DPro ²]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-6, cattle, [DPro ²]-β-cheese deltorphin delta 1-4, amide, [Des-Tyr ¹]-β-cheese deltorphin delta, cattle, [D Ala ^2,4, Tyr ⁵]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ², (pCl) Phe ³]-β-cheese deltorphin delta, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-4, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-5, cattle, [DAla ²]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ², Met ⁵]-β-cheese deltorphin delta 1-5, cattle, [DPro ²]-β-cheese deltorphin delta 1-5, amide, cattle, [DAla ²]-β-cheese deltorphin delta 1-6, cattle, [DPro ²]-β-cheese deltorphin delta 1-4, amide, [Des-Tyr ¹]-β-cheese deltorphin delta, cattle and [Val ³]-β-cheese deltorphin delta 1-4, amide, cattle.

Chemotactic Peptide includes but not limited to, sozin 1 (people) HNP-1 (human neutrophil peptide-1) and N-formoxyl-Met-Leu-Phe.

Cholecystokinin (CCK) peptide includes but not limited to; caerulin; cholecystokinin; CCK-PZ; CCK-33; the people; cholecystokinin octapeptide 1-4 (non-sulfuric acidization) (CCK26-29; not Sulfated); cholecystokinin octapeptide (CCK 26-33); cholecystokinin octapeptide (non-sulfuric acidization) (CCK 26-33; not Sulfated); cholecystokinin seven peptides (CCK 27-33); cholecystokinin tetrapeptide (CCK 30-33); CCK-33; pig; CR 1 409; the cholecystokinin antagonist; CCK flank peptide (not Sulfated); N-acetyl group cholecystokinin; CCK 26-30; Sulfated; N-acetyl group cholecystokinin; CCK 26-31; Sulfated; N-acetyl group cholecystokinin; CCK 26-31, non-sulfuric acidization; preceding former fragment V-9-M of CCK and proglumide.

The colony stimulating factor peptide includes but not limited to, colony stimulating factor (CSF), GM-CSF, M-CSF and G-CSF.

Corticotropin-releasing factor (CRF) peptide includes but not limited to, astressin, alpha-helix CRF 12-41, biotinyl-CRF, sheep, biotinyl-CRF, people, rat, CRF, cattle, CRF, people, rat, CRF, sheep, CRF, pig, [Cys ²¹]-CRF, people, rat, CRF antagonist (alpha-helix CRF 9-41), CRF 6-33, people, rat, [DPro ⁵]-CRF, people, rat, [D-Phe ¹², Nle ^21,38]-CRF 12-41, people, rat, acidophil Chemotactic Peptide, [Met (O) ²¹]-CRF, sheep, [Nle ²¹, Tyr ³²]-CRF, ovine, the former 125-151 of preceding CRF, people, sauvagine, the frog, [Tyr ⁰]-CRF, people, rat, [Tyr ⁰]-CRF, sheep, [Tyr ⁰]-CRF 34-41, sheep, [Tyr ⁰]-urocortin, urocortin amide, people, urocortin, rat, urotensin I (white catostomid mullet (Catostomus commersoni)), urotensin I I and urotensin I I (the lake frog).

Hydrocortisone stabilize proteins (cortistatin) peptide includes but not limited to, hydrocortisone stabilize proteins 29, hydrocortisone stabilize proteins 29 (1-13), [Tyr ⁰]-hydrocortisone stabilize proteins 29, former (pro-cortistatin) 28-47 of hydrocortisone stabilize proteins and the former 51-81 of hydrocortisone stabilize proteins.

Cell factor peptide includes but not limited to, tumor necrosis factor (TNF-α) and tumor necrosis factor-β (TNF-β).Interleukin includes but not limited to IL-1 α, IL-1 β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 and IL-13.The interleukin peptide includes but not limited to, interleukin-1 ' beta ' 165-181, rat and interleukin 8 (IL-8, CINC/gro), rat.Chemotactic factor includes but not limited to RANTES, MCP-1, MI P-1 α, MIP-1 β.

Dermorphin includes but not limited to, dermorphin and dermorphin analog 1-4.

Dynorphin includes but not limited to, big dynorphin (prodynorphin 209-240), pig, biotinyl-dynorphin A (biotinyl-prodynorphin 209-225), [DAla ², DArg ⁶]-dynorphin A 1-13, pig, [D-Ala ²]-dynorphin A, pig, [D-Ala ²]-dynorphin A amide, pig, [D-Ala ²]-dynorphin A 1-13, amide, pig, [D-Ala ²]-dynorphin A 1-9, pig, [DArg ⁶]-dynorphin A 1-13, pig, [DArg ⁸]-dynorphin A 1-13, pig, [Des-Tyr ¹]-dynorphin A 1-8, [D-Pro ¹⁰]-dynorphin A 1-11, pig, dynorphin A amide, pig, dynorphin A 1-6, pig, dynorphin A 1-7, pig, dynorphin A 1-8, pig, dynorphin A 1-9, pig, dynorphin A 1-10, pig, dynorphin A 1-10 amide, pig, dynorphin A 1-11, pig, dynorphin A 1-12, pig, dynorphin A 1-13, pig, dynorphin A 1-13 amide, pig, DAKLI (dynorphin A-analog κ part), DAKLI-biotin ([Arg ^11,13]-dynorphin A (1-13)-Gly-NH (CH2) 5NH-biotin), dynorphin A2-17, pig, dynorphin 2-17, amide, pig, dynorphin A 2-12, pig, dynorphin A 3-17, amide, pig, dynorphin A 3-8, pig, dynorphin A 3-13, pig, dynorphin A 3-17, pig, dynorphin A 7-17, pig, dynorphin A 8-17, pig, dynorphin A 6-17, pig, dynorphin A 13-17, pig, dynorphin A (prodynorphin 209-225), pig, dynorphin B 1-9, [MeTyr ¹, MeArg ⁷, D-Leu ⁸]-dynorphin 1-8 buserelin, [(nMe) Tyr ¹] dynorphin A 1-13, amide, pig, [Phe ⁷]-dynorphin A 1-7, pig, [Phe ⁷]-dynorphin A1-7, amide, pig and prodynorphin 228-256 (dynorphin B 29) (proenkephalin), pig.

Endorphins includes but not limited to; α-Xin-endorphins, pig, β-Xin-endorphins, Ac-beta-endorphin, camel; cattle; sheep, Ac-beta-endorphin 1-27, camel, cattle; sheep, Ac-beta-endorphin; people, Ac-beta-endorphin 1-26, people, Ac-beta-endorphin 1-27, people, Ac-γ-endorphins (Ac-β-lipotropin 61-77), acetyl group-alpha-endorphin, alpha-endorphin (β-lipotropin 61-76), α-Xin-endorphins analog, α-Xin-endorphins 1-7, [Arg ⁸]-α-Xin-endorphins 1-8, beta-endorphin (β-lipotropin 61-91), camel, cattle, sheep, beta-endorphin 1-27, camel, cattle, sheep, beta-endorphin, horse, beta-endorphin (β-lipotropin 61-91), the people, beta-endorphin (1-5)+(16-31), the people, beta-endorphin 1-26, the people, beta-endorphin 1-27, the people, beta-endorphin 6-31, the people, beta-endorphin 18-31, the people, beta-endorphin, pig, beta-endorphin, rat, β-lipotropin 1-10, pig, β-lipotropin 60-65, β-lipotropin 61-64, β-lipotropin 61-69, β-lipotropin 88-91, biotinyl-beta-endorphin (biotinyl-β-lipotropin 61-91), biotin complex of yeast .-beta-endorphin, the people, γ-endorphins (β-lipotropin 61-77), [DAla ²]-α-Xin-endorphins 1-2, amide, [DAla ²]-β-lipotropin 61-69, [DAla ²]-γ-endorphins, [Des-Tyr ¹]-beta-endorphin, people, [Des-Tyr ¹]-γ-endorphins (β-lipotropin 62-77), [Leu ⁵]-beta-endorphin, camel, cattle, sheep, [Met ⁵, Lys ⁶]-α-Xin-endorphins 1-6, [Met ⁵, Lys ^6,7]-α-Xin-endorphins 1-7 and [Met ⁵, Lys ⁶, Arg ⁷]-α-Xin-endorphins 1-7.

Endothelin includes but not limited to, endothelin-1 (ET-1), endothelin-1[biotin-Lys ⁹], endothelin-1 (1-15), people, endothelin-1 (1-15), amide, people, Ac-endothelin-1 (16-21), people, Ac-[DTrp ¹⁶]-endothelin-1 (16-21), people, [Ala ^3,11]-endothelin-1, [Dpr1, Asp ¹⁵]-endothelin-1, [Ala ²]-endothelin-3, people, [Ala ¹⁸]-endothelin-1, people, [Asn ¹⁸]-endothelin-1, people, [Res-701-1]-endothelin B receptor antagonist, Suc-[Glu ⁹, Ala ^11,15]-endothelin-1 (8-21), terminal six peptides of IRL-1620, endothelin-C-, [D-Val ²²]-big endothelin-1 (16-38), the people, endothelin-2 (ET-2), the people, dog, endothelin-3 (ET-3), the people, rat, pig, rabbit, biotinyl-endothelin-3 (biotinyl-ET-3), before former-endothelin-1 (94-109), pig, BQ-518, BQ-610, BQ-788, the endothelium-dependent relaxation antagonist that relaxes, FR139317, IRL-1038, JKC-301, JKC-302, PD-145065, PD 142893, sarafotoxin S6a (Israel's poisonous snake cave viper (atractaspis engaddensis)), sarafotoxin S6b (Israel's poisonous snake cave viper), sarafotoxin S6c (Israel's poisonous snake cave viper), [Lys ⁴]-sarafotoxin S6c, sarafotoxin S6d, big endothelin-1, the people, biotinyl-big endothelin-1, the people, big endothelin-1 (1-39), pig, big endothelin-3 (22-41), amide, the people, big endothelin-1 (22-39), rat, big endothelin-1 (1-39), cattle, big endothelin-1 (22-39), cattle, big endothelin-1 (19-38), the people, big endothelin-1 (22-38), the people, big endothelin-2, the people, big endothelin-2 (22-37), the people, big endothelin-3, the people, big endothelin-1, pig, big endothelin-1 (22-39) (preceding former-endothelin-1 (74-91)), big endothelin-1, rat, big endothelin-2 (1-38), the people, big endothelin-2 (22-38), the people, big endothelin-3, rat, biotinyl-big endothelin-1, people and [Tyr ¹²³]-preceding be former-endothelin (110-130), and amide, people.

ETa receptor antagonist peptide includes but not limited to, [BQ-123], [BE18257B], [BE-18257A]/[W-7338A], [BQ-485], FR139317, PD-151242 and TTA-386.

ETb receptor antagonist peptide includes but not limited to, [BQ-3020], [RES-701-3] and [IRL-1720].

Enkephalin includes but not limited to; adrenorphin; free acid, amidorphin (proenkephalin A (104-129)-NH2), cattle, BAM-12P (bovine adrenal medullary substance dodecapeptide), BAM-22P (bovine adrenal medullary substance two dodecapeptides), benzoyl-Phe-Ala-Arg, enkephalin, [D-Ala ², D-Leu ⁵]-enkephalin, [D-Ala ², D-Met ⁵]-enkephalin, [DAla ²]-Leu-enkephalin, amide, [DAla ², Leu ⁵, Arg ⁶]-enkephalin, [Des-Tyr ¹, DPen ^2,5]-enkephalin, [Des-Tyr ¹, DPen ², Pen ⁵]-enkephalin, [Des-Tyr ¹]-Leu-enkephalin, [D-Pen ^2,5]-enkephalin, [DPen ², Pen ⁵]-enkephalin, enkephalinase substrate, [D-Pen ², pCI-Phe ⁴, D-Pen ⁵]-enkephalin, Leu-enkephalin, Leu-enkephalin, amide, biotinyl-Leu-enkephalin, [D-Ala ²]-Leu-enkephalin, [D-Ser ²]-Leu-enkephalin-Thr (Δ-receptor peptide) (DSLET), [D-Thr ²]-Leu-enkephalin-Thr (DTLET), [Lys ⁶]-Leu-enkephalin, [Met ⁵, Arg ⁶]-enkephalin, [Met ⁵, Arg ⁶]-enkephalin-Arg, [Met ⁵, Arg ⁶, Phe ⁷]-enkephalin, amide, Met-enkephalin, biotinyl-Met-enkephalin, [D-Ala ²]-Met-enkephalin, [D-Ala ²]-Met-enkephalin, amide, Met-enkephalin-Arg-Phe, Met-enkephalin, amide, [Ala ²]-Met-enkephalin, amide, [DMet ², Pro ⁵]-enkephalin, amide, [DTrp ²]-Met-enkephalin, amide, metorphinamide (adrenorphin), peptide B, cattle, 3200 dalton's adrenal gland peptide E; cattle, peptide F, cattle, preproenkephalin B186-204, people, spinorphin; cattle and thiorphan (D, L, 3-sulfydryl-2-benzyl propiono-glycine).

Liver is joined protein B, its analog and antagonist.

The fibronectin peptide includes but not limited to PF4 (58-70), people, echiststin (echistatin) (phoorsa (Echis carinatus)), E, P, L selects albumen conserved region, fibronectin analog, fibronectin binding protein, fibrinopeptide A, people, [Tyr ⁰]-fibrinopeptide A, people, fibrinopeptide B, people, [Glu ¹]-fibrinopeptide B, people, [Tyr ¹⁵]-fibrinopeptide B, the fine former beta chain fragment of the blood of people, 24-42, separate inhibitive factor, FN-C/H-1 (fibronectin heparin binding fragment), FN-C/H-V (fibronectin heparin binding fragment), heparin binding peptide, laminin pentapeptide in conjunction with fine former inhibitor peptide, fibronectin related peptides (collagen binding fragment), the blood fibrinolytic of blood, amide, Leu-Asp-Val-NH2 (LDV-NH2), the people, cattle, rat, chicken, necrofibrin, people, necrofibrin, rat and platelet membrane glycoprotein IIB peptide 296-306.

Galanin includes but not limited to, galanin, the people, galanin 1-19, the people, the preceding former 1-30 of galanin, the people, the preceding former 65-88 of galanin, the people, the preceding former 89-123 of galanin, the people, galanin, pig, galanin 1-16, pig, rat, galanin, rat, biotinyl-galanin, rat, the preceding former 28-67 of galanin, rat, galanin 1-13-Kallidin I 2-9, amide, M40, galanin 1-13-Pro-Pro-(Ala-Leu) 2-Ala-amide, C7, galanin 1-13-spantide-amide, GMAP 1-41, amide, GMAP 16-41, amide, GMAP25-41, amide, galantide and intestinal-kassinin.

The gastrin peptide includes but not limited to, gastrin, chicken; Gastric inhibitory polypeptide (GIP), the people; Gastrin I, the people; Biotinyl-gastrin I, the people; Big gastrin-1, the people; Gastrin releasing peptide, the people; Gastrin releasing peptide 1-16, the people; Gastric inhibitory polypeptide (GIP), pig; Gastrin releasing peptide, pig; Biotinyl-gastrin releasing peptide, pig; Gastrin releasing peptide 14-27, pig, people; Little gastrin, rat; Pentagastrin; Gastric inhibitory polypeptide 1-30, pig; Gastric inhibitory polypeptide 1-30, amide, pig; [Tyr ⁰]-gastric inhibitory polypeptide 23-42, the people; And gastric inhibitory polypeptide, rat.

Glucagon-like peptide includes but not limited to, [Des-His ¹, Glu ⁹]-glucagon, extendin-4, glucagon, people; Biotinyl-glucagon, the people; Glucagon 19-29, the people; Glucagon 22-29, the people; Des-His ¹-[Glu ⁹]-glucagon, amide; Glucagon-like peptide 1, amide (preceding Proglucagon 72-107, amide); Glucagon-like peptide 1 (preceding Proglucagon 72-108), the people; Glucagon-like peptide 1 (7-36) (preceding Proglucagon 78-107, amide); Glucagon-like peptide II, rat; Biotinyl-glucagon-like-peptide-1 (7-36) (biotinyl-preceding Proglucagon 78-107, amide); Glucagon-like peptide 2 (preceding Proglucagon 126-159), the people; Oxyntomodulin/glucagon 37; And valosin (peptide VQY), pig.

Gn-RH related peptides (GAP) includes but not limited to, Gn-RH related peptides 25-53, people; Gn-RH related peptides 1-24, the people; Gn-RH related peptides 1-13, the people; Gn-RH related peptides 1-13, rat; The promoting sexual gland hormone release peptide, folliculus, people; [Tyr ⁰]-GAP ([Tyr ⁰]-Gn-RH precursor peptide 14-69), people; And (POMC) precursor 27-52 of proopiomelanocortin (proopiomelanocortin), pig.

Growth factor peptides includes but not limited to, cell growth factor, epidermal growth factor, tumor growth factor, TGF-α, the people, TGF-α is from other mammalian species TGF-β, α-TGF 34-43, people EGF (epidermal growth factor), acid fibroblast growth factor, basic fibroblast growth factor, basic fibroblast growth factor 13-18, basic fibroblast growth factor 120-125, brain source property acid fibroblast growth factor 1-11, brain source property basic fibroblast growth factor 1-24, brain source property acid fibroblast growth factor 102-111, [Cys (Acm ^20,31)]-epidermal growth factor 20-31, egfr peptide 985-996, insulin-like growth factor (IGF)-I, chicken, IGF-I, rat, IGF-I, people, Des (1-3) IGF-I, people, R3 IGF-I, people, R3 IGF-I, people, long R3 IGF-I, people, adjuvant peptide analog, subtract appetite peptide, Des (1-6) IGF-II, people, R6 IGF-II, people, IGF-I analog, IGF I (24-41), IGF I (57-70), IGF I (30-41), IGFII, IGF II (33-40), [Tyr ⁰]-IGF II (33-40), hepatocyte growth factor, the mid-term factor, mid-term factor 60-121, people, N-acetyl group, α-TGF 34-43, methyl ester, rat, nerve growth factor (NGF), mice, platelet-derived growth factor, platelet-derived growth factor antagonist; .Erb-B the part of the receptor of family.

Growth hormone peptide includes but not limited to, growth hormone (hGH), people, growth hormone 1 GH1-43, people, growth hormone 6-13, people, somatotropin releasing factor, people, somatotropin releasing factor, cattle, somatotropin releasing factor, pig, somatotropin releasing factor 1-29, amide, rat, somatotropin releasing factor (growth hormone pro-releasing factor), people, biotinyl-somatotropin releasing factor, people, somatotropin releasing factor 1-29, amide, people, [D-Ala ²]-somatotropin releasing factor 1-29, amide, people, [N-Ac-Tyr ¹, D-Arg ²]-GRF 1-29, amide, [His ¹, Nle ²⁷]-somatotropin releasing factor 1-32, amide, somatotropin releasing factor 1-37, people, somatotropin releasing factor 1-40, people, somatotropin releasing factor 1-40, amide, people, somatotropin releasing factor 30-44, amide, people, somatotropin releasing factor, mice, somatotropin releasing factor, sheep, somatotropin releasing factor, rat, biotinyl-somatotropin releasing factor, rat, GHRP-6 ([His ¹, Lys ⁶]-GHRP), sea sand Rayleigh (growth hormone discharges six peptides) and [D-Lys ³]-GHRP-6.

GTP-is conjugated protein to include but not limited to [Arg with its fragment peptide ⁸The conjugated protein fragment of GTP-of the conjugated protein fragment Gs α of]-GTP-, G 'beta ' family, the conjugated protein fragment of GTP-of G γ family, the conjugated protein fragment of GTP-, the conjugated protein fragment of G α, GTP-, Go α a and b, the conjugated protein fragment of GTP-, the conjugated protein fragment of Gs α and GTP-, G α i1, G α i2, G α i3, the conjugated protein fragment of GTP-, the conjugated protein fragment of Golf α, GTP-, the conjugated protein fragment of Gz α, GTP-, Gq α.

The guanosine peptide includes but not limited to, guanosine peptide, people, guanosine peptide, rat and urine guanosine peptide (uroguanylin).

The inhibin peptide includes but not limited to, inhibin, cattle, inhibin, α-subunit 1-32, people, [Tyr ⁰]-inhibin, α-subunit 1-32, people, refining inhibin-sample peptide, people, [Tyr ⁰]-refining inhibin-sample peptide, people, inhibin, α-subunit 1-32, pig and [Tyr ⁰]-inhibin, α-subunit 1-32, pig.

Interferon polypeptide includes but not limited to, the interferon-alpha classification (for example, α 1, α 2, α 2a, α 2b, α 2c, α 2d, α 3, α 4, α 4a, α 4b, α 5, α 6, α 74, α 76, α A, α B, α C,, α C1, α D, α E, α F, α G, α G, α H, α I, α J1, α J2, α K, α L), the interferon beta classification (for example, β 1a), any analog of interferon gamma classification (for example, γ 1a, γ 1b), interferon ε, interferon-tau, interferon ω or interferon ω.The various analog of IFN-are described in people such as Pechenov " Methodsfor preparation of recombinant cytokine proteins V.mutantanalogues of human interferon-gamma with higher stability andactivity " Protein Expr.Purif.24:173-180 (2002), it integrates with this paper in full by reference with it, is used to instruct the preparation and the detection of interferon analogue.

Insulin peptide includes but not limited to, insulin, people, insulin, pig, IGF-I, people, insulin-like growth factor II (69-84), proinsulin-like growth factor II (68-102), people, proinsulin-like growth factor II (105-128), people, [Asp ^B28]-insulin, people, [Lys ^B28]-insulin, people, [Leu ^B28]-insulin, people, [Val ^B28]-insulin, people, [Ala ^B28]-insulin, people, [Asp ^B28, Pro ^B29]-insulin, people, [Lys ^B28, Pro ^B29]-insulin, people, [Leu ^B28, Pro ^B29]-insulin, people, [Val ^B28, Pro ^B29]-insulin, people, [Ala ^B28, Pro ^B29]-insulin, people, [Gly ^A21]-insulin, people, [Gly ^A21Gln ^B3]-insulin, people, [Ala ^A21]-insulin, people, [Ala ^A21Gln ^B3]-insulin, people, [Gln ^B3]-insulin, people, [Gln ^B30]-insulin, people, [Gly ^A21Glu ^B30]-insulin, people, [Gly ^A21Gln ^B3Glu ^B30]-insulin, people, [Gln ^B3Glu ^B30]-insulin, people, B22-B30 insulin, people, B23-B30 insulin, people, B25-B30 insulin, people, B26-B30 insulin, people, B27-B30 insulin, people, B29-B30 insulin, the A chain of people, insulin human and the B chain of insulin human.

The laminin peptide includes but not limited to, laminin, α 1 (I)-CB3 435-438, rat and laminin binding inhibitors.

The leptin peptide includes but not limited to, leptin 93-105, people, leptin 22-56, rat, Tyr-leptin 26-39, people and leptin 116-130, amide, mice.

Leucokinin includes but not limited to, leucomyosuppressin (LMS), leucopyrokinin (LPK), leucokinin I, leucokinin II, leucokinin III, leucokinin IV, leucokinin VI, leucokinin VII and leucokinin VIII.

The luteinizing hormone releasing hormone peptide includes but not limited to, antide, Gn-RH II, chicken, luteinizing hormone releasing hormone (LH-RH) (GnRH), biotinyl-LH-RH, cetrorelix (D-20761), [D-Ala ⁶]-LH-RH, [Gln ⁸]-LH-RH (chicken LH-RH), [DLeu ⁶, Val ⁷] LH-RH 1-9, buserelin, [D-Lys ⁶]-LH-RH, [D-Phe ², Pro ³, D-Phe ⁶]-LH-RH, [DPhe ², DAla ⁶] LH-RH, [Des-Gly ¹⁰]-LH-RH, buserelin, [D-Ala ⁶, Des-Gly ¹⁰]-LH-RH, buserelin, [DTrp ⁶]-LH-RH, buserelin, [D-Trp ⁶, Des-Gly ¹⁰]-LH-RH, buserelin (deslorelin), [DSer (But) ⁶, Des-Gly ¹⁰]-LH-RH, buserelin, buserelin, leuprorelin, LH-RH 4-10, LH-RH 7-10, LH-RH, free acid, LH-RH, Lampetra japonica (Martens)., LH-RH, salmon, [Lys ⁸]-LH-RH, [Trp ⁷, Leu ⁸] LH-RH, free acid and [(t-Bu) DSer ⁶, (Aza) Gly ¹⁰]-LH-RH.

Mastoparan includes but not limited to, mastoparan, mas7, mas8, mas 17 and mastoparan X.

Mastoparan includes but not limited to, mastoparan HR-1 and mastoparan HR-2.

Melanotropin (MSH) peptide includes but not limited to [Ac-Cys ⁴, DPhe ⁷, Cys ¹⁰] α-MSH 4-13, amide, alpha-Melanocyte stimulating hormone, α-MSH, free acid, β-MSH, pig, biotinyl-alpha-Melanocyte stimulating hormone, biotinyl-[Nle ⁴, D-Phe ⁷] alpha-Melanocyte stimulating hormone, [Des-acetyl group]-α-MSH, [DPhe ⁷]-α-MSH, amide, y-1-MSH, amide; [Lys ⁰]-γ-1-MSH, amide, MSH release inhibiting factor, amide, [Nle ⁴]-α-MSH, amide, [Nle ⁴, D-Phe ⁷]-α-MSH, N-acetyl group, [Nle ⁴, DPhe ⁷] α-MSH 4-10, amide, β-MSH, people and γ-MSH.

Morphiceptin (Morphiceptin) peptide includes but not limited to, morphiceptin (β-cheese deltorphin delta 1-4 amide), [D-Pro ⁴]-morphiceptin and [N-MePhe ³, D-Pro ⁴]-morphiceptin.

The motilin peptide includes but not limited to, motilin, dog, motilin, pig, biotinyl-motilin, pig and [Leu ¹³]-motilin, pig.

Neuropeptide includes but not limited to, Ac-Asp-Glu, the excited peptide-1 (ACEP-1) (Achatina fulica (Ferussae).) of Achates spiral shell heart, lipotropin (AKH) (locust), lipotropin (Heliothis zea and maduca sexta), alytensin, tabanus atratus lipotropin (Taa-AKH), lipotropin II (Locustamigratoria (Linnaeus)), lipotropin II (desert locust), lipotropin III (AKH-3), lipotropin G (AKH-G) (two speckle Xi), allatotropin (AT) (maduca sexta), allatotropin 6-13 (maduca sexta), APGW amide (lymnaea stagnalis), buccalin, cerebellin, [Des-Ser ¹]-cerebellin, melanism are induced neuropeptide (U.S. Blatta seu periplaneta, periplaneta americana), Crustacean acts on peptide (CCAP), Crustacean erythrocyte, DF2 (the former crayfish of Ke Shi), diazepam (diazepam) the binding inhibitors fragment of heart (cardioactive), people, diazepam binding inhibitors fragment (ODN), salivary gland 11 peptides (eledoisin) related peptides, FMRF amide (Mollusca heart excitor nerve peptide), Gly-Pro-Glu (GPE), people, granuliberin R, an activator neuropeptide, [His ⁷]-melanism is induced neuropeptide, walkingstick hypertrehalosaemic factor II, tabanus atratus hypertrehalosemic hormone (Taa-HoTH), the isoguvacine hydrochlorate, bicuculline methiodide, piperidines-4-sulfonic acid, the connection peptides of proopiomelanocortin (POMC), cattle, connection peptides, rat, KSAYMRF amide (saprophitic nematode), kassinin, kinetensin (kinetensin), levitide, litorin, LUQ 81-91 (California, USA sea hare), LUQ 83-91 (California, USA sea hare), myoactive peptide I (Periplanetin CC-1) (neuro hormone D), myoactive peptide II (Periplanetin CC-2), myomodulin, the neuronal specificity peptide, neuron specific enolase 404-443, rat, neuropeptide FF, neuropeptide K, pig, NEI (the former 131-143 of preceding MCH) neuropeptide, rat, NGE (the former 110-128 of preceding MCH) neuropeptide, rat, NF1 (the former crayfish of Ke Shi), PBAN-1 (silkworm (Bombyx mori)), Hez-PBAN (Heliothis zea), SCPB (from the cardioactive peptide of sea hare (aplysia)), secretoneurin, rat, uperolein, urechistachykininI, urechistachykinin II, xenopsin related peptides I, xenopsin-related peptides II, pedal peptide (Pep), sea hare, peptide F1, Lobster, phyllomedusin, hornet Venenum apis, proctolin, pipinin, Ro I (oxya chinensis (LubberGrasshopper), blunt locust (Romalea microptera)), Ro II (oxya chinensis, blunt locust), SALMF amide 1 (S1), SALMF amide 2 (S2) and SCPA.

Neuropeptide tyrosine (NPY) peptide includes but not limited to [Leu ³¹, Pro ³⁴]-neuropeptide tyrosine, people, neuropeptide F (expansion moniezia (Moniezia expansa)), B1BP3226 NPY antagonist, two (31/31 ') { [Cys ³¹, Trp ³², Nva ³⁴] NPY 31-36}, neuropeptide tyrosine, people, rat, neuropeptide tyrosine 1-24 amide, people, biotinyl-neuropeptide tyrosine, [D-Tyr ^27,36, D-Thr ³²]-NPY 27-36, Des 10-17 (ring 7-21) [Cys ^7,21, Pro ³⁴]-NPY, C2-NPY, [Leu ³¹, Pro ³⁴] neuropeptide tyrosine, people, neuropeptide tyrosine, free acid, people, neuropeptide tyrosine, free acid, pig, the former 68-97 of preceding NPY, people, N-acetyl group-[Leu ²⁸, Leu ³¹] NPY 24-36, neuropeptide tyrosine, pig, [D-Trp ³²]-neuropeptide tyrosine, pig, [D-Trp ³²] NPY 1-36, people, [Leu ¹⁷, DTrp ³²] neuropeptide tyrosine, people, [Leu ³¹, Pro ³⁴]-NPY, pig, NPY 2-36, pig, NPY 3-36, people, NPY 3-36, pig, NPY 13-36, people, NPY 13-36, pig, NPY16-36. pig, NPY 18-36, pig, NPY 20-36, NFY 22-36, NPY 26-36, [Pro ³⁴]-NPY 1-36, people, [Pro ³⁴]-neuropeptide tyrosine, pig, PYX-1, PYX-2, T4-[NPY (33-36)] 4 and Tyr (OMe) ²¹]-neuropeptide tyrosine, the people.

The neurotrophic factor peptide includes but not limited to, glial cell derived neurotrophic factor (GDNF), Brain Derived Neurotrophic Factor (BDNF) and ciliary neurotrophic factor (CNTF).

The part of Notch receptor includes but not limited to Δ-sample-1, Δ-sample-2, Δ-sample-3, Δ-sample-4, Jagged-1 and Jagged-2 albumen and its fragment.

The appetite peptide includes but not limited to, appetite peptide A, appetite peptide B, people, appetite peptide B, rat, mice.

The opioid peptide includes but not limited to, alpha-casein fragment 90-95, BAM-18P, casomokinin L, caseidin (casoxin) D, crystal, DALDA, dermenkaphaline (deltorphin) (monkey Rhacophorus (Phylomedusa sauvagei)), [D-Ala ²]-deltorphin I, [D-Ala ²]-deltorphin II, interior morphine peptide-1, interior morphine peptide-2, kyotorphin, [DArg ²]-kyotorphin, morphine tolerance peptide, morphine modulating peptide, C-terminal fragment, morphine are regulated neuropeptide (A-18-F-NH2), nociceptin [orphanin FQ] (ORL1 agonist), TIPP, Tyr-MIF-1, Tyr-W-MIF-1, valorphin, LW-blood morphine-like peptide-6, people, Leu-valorphin-Arg and Z-Pro-D-Leu.

The oxytocin peptide includes but not limited to, [Asu ⁶]-oxytocin, oxytocin, biotinyl-oxytocin, [Thr ⁴, Gly ⁷]-oxytocin and tocinoi cacid ([Ile ³]-pressinoicacid).

PACAP (pituitary adenylate cyclase activating peptide) peptide includes but not limited to, PACAP 1-27, people, sheep, rat, PACAP (1-27)-Gly-Lys-Arg-NH2, people, [Des-Gln ¹⁶]-PACAP 6-27, people, sheep, rat, PACAP 38, the frog, PACAP27-NH2, the people, sheep, rat, biotinyl-PACAP27-NH2, people, sheep, rat, PACAP 6-27, people, sheep, rat, PACAP 38, the people, sheep, rat, biotinyl-PACAP 38, people, sheep, rat, PACAP 6-38, the people, sheep, rat, PACAP27-NH2, the people, sheep, rat, biotinyl-PACAP27-NH2, people, sheep, rat, PACAP 6-27, people, sheep, rat, PACAP38, the people, sheep, rat, biotinyl-PACAP38, the people, sheep, rat, PACAP6-38, people, sheep, rat, PACAP 3816-38, people, sheep, rat, PACAP38 31-38, the people, sheep, rat, PACAP38 31-38, the people, sheep, rat, PACAP related peptides (PRP), people and PACAP related peptides (PRP), rat.

The pancreastatin peptide includes but not limited to, chromostatin, cattle, pancreastatin (hPST-52) (Chromogranin A 250-301, amide), pancreastatin 24-52 (hPST-29), people, Chromogranin A 286-301, amide, people, pancreastatin, pig, biotinyl-pancreastatin, pig, [Nle ⁸]-pancreastatin, pig, [Tyr ⁰, Nle ⁸]-pancreastatin, pig, [Tyr ⁰]-pancreastatin, pig, other gland chalone 1-19 (Chromogranin A 347-365), pig, pancreastatin (Chromogranin A 264-314-amide, rat, biotinyl-pancreastatin (biotinyl-Chromogranin A 264-314-amide, [Tyr ⁰]-pancreastatin, rat, pancreastatin 26-51, rat and pancreastatin 33-49, pig.

Pancreatic polypeptide includes but not limited to, pancreatic polypeptide, birds, pancreatic polypeptide, people, the acid of C-fragment pancreatic polypeptide, people, C-fragment pancreatic polypeptide amide, people, pancreatic polypeptide (wood frog), pancreatic polypeptide, rat and pancreatic polypeptide, salmon.

Pth peptide includes but not limited to, [Asp ⁷⁶]-parathyroid hormone 39-84, people, [Asp ⁷⁶]-parathyroid hormone 53-84, people, [Asn ⁷⁶]-parathyroid hormone 1-84, hormone, [Asn ⁷⁶] parathyroid hormone 64-84, people, [Asn ⁸, Leu ¹⁸]-parathyroid hormone 1-34, people, [Cys ^5,28]-parathyroid hormone 1-34, people, the pernicious factor 1-40 of hypercalcemia, [Leu ¹⁸]-parathyroid hormone 1-34, people, [Lys (biotinyl) ¹³, Nle ^8,18, Tyr ³⁴]-parathyroid hormone 1-34 amide, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 1-34 amide, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 3-34 amide, cattle, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 1-34, people, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 1-34 amide, people, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 3-34 amide, people, [Nle ^8,18, Tyr ³⁴]-parathyroid hormone 7-34 amide, cattle, [Nle ^8,21, Tyr ³⁴]-parathyroid hormone 1-34 amide, rat, parathyroid hormone 44-68, the people, parathyroid hormone 1-34, cattle, parathyroid hormone 3-34, cattle, parathyroid hormone 1-31 amide, the people, parathyroid hormone 1-34, the people, parathyroid hormone 13-34, the people, parathyroid hormone 1-34, rat, parathyroid hormone 1-38, the people, parathyroid hormone 1-44, the people, parathyroid hormone 28-48, the people, parathyroid hormone 39-68, the people, parathyroid hormone 39-84, the people, parathyroid hormone 53-84, the people, parathyroid hormone 69-84, the people, parathyroid hormone 70-84, the people, [Pro ³⁴]-peptide YY (PYY), people, [Tyr ⁰The pernicious factor 1-40 of]-hypercalcemia, [Tyr ⁰]-parathyroid hormone 1-44, people, [Tyr ⁰]-parathyroid hormone 1-34, people, [Tyr ¹]-parathyroid hormone 1-34, people, [Tyr ²⁷]-parathyroid hormone 27-48, people, [Tyr ³⁴]-parathyroid hormone 7-34 amide, cattle, [Tyr ⁴³]-parathyroid hormone 43-68, people, [Tyr ⁵², Asn ⁷⁶]-parathyroid hormone 52-84, people and [Tyr ⁶³]-parathyroid hormone 63-84, the people.

Parathyroid hormone (PTH) related peptides includes but not limited to PTHrP ([Tyr ³⁶]-PTHrP1-36 amide), chicken, hHCF-(1-34)-NH2 (body fluid hypercalcemic factor), people, PTH associated protein 1-34, people, biotinyl-PTH associated protein 1-34, people, [Tyr ⁰]-PTH associated protein 1-34, people, [Tyr ³⁴]-PTH associated protein 1-34 amide, people, PTH associated protein 1-37, people, PTH associated protein 7-34 amide, people, PTH associated protein 38-64 amide, people, PTH associated protein 67-86 amide, people, PTH related protein 10 7-111, the people, rat, mice, PTH-related protein 10 7-111 free acid, PTH related protein 10 7-138, people and PTH related protein 10 9-111, the people.

Peptide T peptide includes but not limited to, peptide T, [D-Ala ¹]-peptide T and [D-Ala ¹]-peptide T amide.

The prolactin antagonist release peptide includes but not limited to, prolactin antagonist release peptide 31, people, prolactin antagonist release peptide 20, people, prolactin antagonist release peptide 31, rat, prolactin antagonist release peptide 20, rat, prolactin antagonist release peptide 31, cattle and prolactin antagonist release peptide 20, cattle.

Peptide YY (PYY) peptide includes but not limited to, PYY, people, PYY 3-36, people, biotinyl-PYY, people, PYY, pig, rat and [Leu ³¹, Pro ³⁴]-PYY, the people.

The feritin peptide substrate includes but not limited to, acetyl group, proangiotensin 1-14, people, proangiotensin 1-14, pig, feritin substrate tetradecapeptide, rat, [Cys ⁸]-feritin substrate tetradecapeptide, rat, [Leu ⁸]-feritin substrate tetradecapeptide, rat and [Val ⁸]-feritin substrate tetradecapeptide, rat.

Secretin (secretin) peptide includes but not limited to, secretin, dog, secretin, chicken, secretin, people, biotinyl-secretin, people, secretin, pig and secretin, rat.

Somatostatin (Somatostatin) (GIF) peptide includes but not limited to, BIM-23027, biotinyl-somatostatin, biotinylated hydrocortisone stabilize proteins 17, people, hydrocortisone stabilize proteins 14, rat, hydrocortisone stabilize proteins 17, people, [Tyr ⁰]-hydrocortisone stabilize proteins 17, people, hydrocortisone stabilize proteins 29, rat, [D-Trp ⁸]-somatostatin, [DTrp ⁸, DCys ¹⁴]-somatostatin, [DTrp ⁸, Tyr ¹¹]-somatostatin, [D-Trp ¹¹]-somatostatin, NTB (Naltriben), [Nle ⁸]-somatostatin 1-28, press down growth peptide (SMS 201-995), prosomatostatin1-32, pig, [Tyr ⁰]-somatostatin, [Tyr ¹]-somatostatin, [Tyr ¹]-somatostatin 28 (1-14), [Tyr ¹¹]-somatostatin, [Tyr ⁰, D-Trp ⁸]-somatostatin, somatostatin, somatostatin antagonist, somatostatin-25, somatostatin-28, somatostatin-28 (1-12), biotinyl-somatostatin-28, [Tyr ⁰]-somatostatin-28, [Leu ⁸, D-Trp ²², Tyr ²⁵]-somatostatin-28, biotinyl-[Leu ⁸, D-Trp ²², Tyr ²⁵]-somatostatin-28, somatostatin-28 (1-14) and somatostatin analogs, RC-160.

P material peptide includes but not limited to, G protein antagonist-2, Ac-[Arg ⁶, Sar ⁹, Met (O2) ¹¹]-P material 6-11, [Arg ³]-P material, Ac-Trp-3, two (trifluoromethyl) benzyl esters of 5-, Ac-[Arg ⁶, Sar ⁹, Met (O2) ¹¹]-P material 6-11, [D-Ala ⁴]-P material 4-11, [Tyr ⁶, D-Phe ⁷, D-His ⁹]-P material 6-11 (sendide), biotinyl-P material, biotinyl-NTE[Arg ³]-P material, [Tyr ⁸]-P material, [Sar ⁹, Met (O2) ¹¹]-P material, [D-Pro ², D-Trp ^7,9]-P material, [D-Pro ⁴, 0-Trp ^7,9]-P material 4-11, P material 4-11, [DTrp ^2,7,9]-P material, [(dehydrogenation) Pro ^2,4, Pro ⁹]-P material, [dehydrogenation-Pro ⁴]-P material 4-11, [Glp ⁵, (Me) Phe ⁸, Sar ⁹]-P material 5-11, [Glp ⁵, Sar ⁹]-P material 5-11, [Glp ⁵]-P material 5-11, seven-P material (P material 5-11), six-P material (P material 6-11), [MePhe ⁸, Sar ⁹]-P material, [Nle ¹¹]-P material, eight-P material (P material 4-11), [pGlu ¹]-six-P material ([pGlu ⁶]-P material 6-11), [pGlu ⁶, D-Pro ⁹]-P material 6-11, [(pNO2) Phe ⁷Nle ¹¹]-P material, five-P material (P material 7-11), [Pro ⁹]-P material, GR73632, P material 7-11, [Sar ⁴]-P material 4-11, [Sar ⁹]-P material, septide ([pGlu ⁶, Pro ⁹]-P material 6-11), spantide I, spantide II, P material, P material, cod, P material, Squaliobarbus ourriculus, P substance antagonist, P material-Gly-Lys-Arg, P material 1-4, P material 1-6, P material 1-7, P material 1-9, ten-P material (P material 2-11), nine-P material (P material 3-11), P material tetrapeptide (P material 8-11), P material tripeptides (P material 9-11), P material, free acid, P material methyl ester and [Tyr ⁸, Nle ¹¹] the P material.

Tachykinin includes but not limited to, [Ala ⁵, β-Ala ⁸] neurokinin A 4-10, salivary gland 11 peptides, locustatachykinin I (Lom-TK-I) (Locustamigratoria (Linnaeus)), locustatachykinin II (Lom-TK-II) (Locustamigratoria (Linnaeus)), neurokinin A 4-10, neurokinin A (neuromedin L, the K material), neurokinin A, cod and Squaliobarbus ourriculus, biotinyl-neurokinin A (biotinyl-neuromedin L, biotinyl-K material), [Tyr ⁰]-neurokinin A, [Tyr ⁶]-K material, FR64349, [Lys ³, Gly ⁸-(R)-gamma-lactams-Leu ⁹]-neurokinin A 3-10, GR83074, GR87389, GR94800, [β-Ala ⁸]-neurokinin A 4-10, [Nle ¹⁰]-neurokinin A 4-10, [Trp ⁷, β-Ala ⁸]-neurokinin A 4-10, neurokinin B (neuromedin K), biotinyl-neurokinin B (biotinyl-neuromedin K), [MePhe ⁷]-neurokinin B, [Pro ⁷]-neurokinin B, [Tyr ⁰]-neurokinin B, neuromedin B, pig, biotinyl-neuromedin B, pig, neuromedin B-30, pig, neuromedin B-32, pig, neuromedin B receptor antagonist, neuromedin C, pig, neuromedin N, pig, neuromedin (U-8), pig, neuromedin (U-25), pig, Neuromedin U, rat, neuropeptide-γ (γ-preprotachykinin 72-92), PG-KII, phyllolitorin, [Leu ⁸]-phyllolitorin (monkey Rhacophorus), physalaemin, physalaemin 1-11, scyliorhinin II, amide, spiny dogfish, senktide, selective neurokinin B receptor peptide, [Ser ²]-neuromedin C, β-preprotachykinin 69-91, people, β-preprotachykinin 111-129, people, king crab antibacterial peptide I, xenopsin and xenopsin 25 (xenin 25), people.

Throtropin releasing hormone (TRH) peptide includes but not limited to biotinyl-throtropin releasing hormone, [Glu ¹]-TRH, His-Pro-diketopiperazine, [3-Me-His ²]-TRH, pGlu-Gln-Pro-amide, pGlu-His, [Phe ²]-TRH, the former 53-74 of preceding TRH, the former 83-106 of preceding TRH, the former 160-169 of preceding TRH (Ps4, TRH-strengthens peptide), the former 178-199 of preceding TRH, throtropin releasing hormone (TRH), TRH, free acid, TRH-SH Pro and TRH precursor peptide.

Toxin peptide includes but not limited to, ω-agatoxin (agatoxin) TK, agelenin, (Aranea, Caulis et Folium Polygalae Tenuifoliae spider (Agelena opulenta)), apamin (Apis, Apis mellifera (Apis mellifera)), calcicudine (CaC) (green mamba Serpentis, the green mamba in East Africa), calcium snake venom (calciseptine) (black mamba Serpentis (black mamba), black mamba (Dendroaspis polylepis polylepis)), charybdotoxin (ChTX) (Scorpio, Leiurus quinquestriatus var.hebraeus), catilan, conotoxin GI (ocean Limax, the killer cone shell), conotoxin GS (ocean Limax, the killer cone shell), conotoxin M I (ocean frock cone shell), alpha-conotoxin EI, the Testudinis cone shell, alpha-conotoxin SIA, alpha-conotoxin Im1, alpha-conotoxin SI (cone shell, the fine rule cone shell), small-conotoxin GIIIB (ocean Limax, the killer cone shell), omega-conotoxin GVIA (ocean Limax, the killer cone shell), omega-conotoxin M VI IA (frock cone shell), omega-conotoxin M VII C (frock cone shell), omega-conotoxin SVIB (cone shell, the fine rule cone shell), the endotoxin inhibitor, geographutoxin I (GTX-I) (mu-conotoxin GIIIA), iberiotoxin (IbTX) (Scorpio, Buthust amulus), short skin charybdotoxin (Kaliotoxin) 1-37, short skin charybdotoxin (Scorpio, north African Scorpio (Androct-onusmauretanicus mauretanicus)), mastoparan (MCD-peptide, peptide 401), margatoxin (MgTX) (Scorpio, Mexico wood scorpion), neurotoxin NSTX-3 (pupua newguinean spider, people's face Aranea), PLTX-II (Aranea, Plectreurystristes), scyllatoxin (leiurotoxin I) and actinocongestin (stichodactylatoxin) are (ShK), diphtheria toxin, diphtherotoxin, ricin A, the Pseudomonas aeruginosa exotoxin A.

Immunotoxin is the toxin covalently bound with antibody, described antibody is as the system (homing system) that goes back to the nest, and particularly described toxin targeting wished the system that goes back to the nest of those cells that the antibody (polyclone or monoclonal) of the molecule that carries on the cell surface by anti-institute targeting or component is removed.Toxin (including but not limited to above-mentioned toxin) can be used for this effect.The invention of describing in the present patent application can be used for sending this type of immunotoxin to colon.In some cases, antibody can substitute with the micromolecule that is used for similarly the selected cell mass of toxin targeting.

Vasoactive intestinal peptide (VIP/PHI) includes but not limited to, VIP, and the people, pig, rat, sheep, VIP-Gly-Lys-Arg-NH2, biotinyl-PHI (biotinyl-PHI-27), pig, [Glp ¹⁶] VIP 16-28, pig, PHI (PHI-27), pig, PHI (PHI-27), rat, PHM-27 (PHI), the people, the preceding former 81-122 of VIP, the people, the preceding former 111-122 of VIP/PHM, the preceding former 156-170 of VIP/PHM, biotinyl-PHM-27 (biotinyl-PHI), the people, vasoactive intestinal contractor (endothelin-β), vasoactive 28-peptide, chicken, vasoactive intestinal peptide, Cavia porcellus, biotinyl-VIP, the people, pig, rat, vasoactive intestinal peptide 1-12, people, pig, rat, vasoactive intestinal peptide 10-28, the people, pig, rat, vasoactive intestinal peptide 11-28, the people, pig, rat, sheep, vasoactive intestinal peptide (cod, cod (Gadus morhua)), vasoactive intestinal peptide 6-28, the vasoactive peptide antagonists, vasoactive peptide antagonists ([Ac-Tyr ¹, D-Phe ²]-GHRF 1-29 amide), vip receptor antagonist (4-Cl-D-Phe ⁶, Leu ¹⁷]-VIP) and vip receptor binding inhibitors, L-8-K.

Vasopressin (ADH) peptide includes but not limited to vasopressin, [Asu ^1,6, Arg ⁸]-vasopressin, vasotocin, [Asu ^1,6, Arg ⁸]-vasotocin, [Lys ⁸]-vasopressin, pressinoic acid, [Arg ⁸]-deaminize vasopressin is removed Aminoacetamide, [Arg ⁸]-vasopressin (AVP), [Arg ⁸]-vasopressin is removed Aminoacetamide, biotinyl-[Arg ⁸]-vasopressin (biotinyl-AVP), [D-Arg ⁸]-vasopressin, deaminize-[Arg ⁸]-vasopressin, deaminize-[D-Arg ⁸]-vasopressin (DDAVP), [deaminize-[D-3-(3 '-pyridine radicals-Ala)]-[Arg ⁸]-vasopressin, [1-(β-sulfydryl-β, β-cyclopentamethylene propanoic acid), 2-(O-methyl) tyrosine]-[Arg ⁸]-vasopressin, vasopressin metabolite neuropeptide [pGlu ⁴, Cys ⁶], vasopressin metabolite neuropeptide [pGlu ⁴, Cys ⁶], [Lys ⁸]-deaminize vasopressin is removed Aminoacetamide, [Lys ⁸]-vasopressin, [Mpr ¹, Val ⁴, DArg ⁸]-vasopressin, [Phe ², Ile ³, Orn ⁸]-vasopressin ([Phe ², Orn ⁸]-vasotocin), [Arg ⁸]-vasotocin and [d (CH2) 5, Tyr (Me) ², Orn ⁸]-vasotocin.

The virus related peptides includes but not limited to fluorescence people CMV protease substrate, HCV core protein 59-68, HCV NS4A protein 18-40 (JT strain system); HCV NS4A protein 21-34 (JT strain system), hepatitis B virus receptors bind fragment, hepatitis B virus pro-S zone 120-145, [Ala ¹²⁷]-hepatitis B virus pro-S zone 120-131, herpesvirus inhibitor 2, HIV envelope protein fragment 254-274, HIV gag fragment 129-135, HIV substrate, P18 peptide, peptide T, [3,5 two iodo-Tyr ⁷] peptide T, R15K HIV-1 peptide for inhibiting, T20, T21, V 3-decapetide P 18-110 and virus replication peptide for inhibiting.

The protein of Wnt family and its fragment.

Although described some analog, fragment and/or the analog fragment of each peptide species in the above, but (it keeps the whole of specific polypeptide or some are active should to understand other analog, fragment and/or analog fragment, or on the contrary its as antagonist, thereby stop the effect of specific polypeptide) also can be used for embodiment of the present invention.Analog can obtain by the whole bag of tricks, and this is understood by those skilled in the art.For example, in the polypeptide some aminoacid can be with other amino acid replacements the remarkable ability that mutually combines of loss and structure (for example antigen binding domain of antibody or the binding site on the substrate molecule).Because the interaction ability and the character of polypeptide drugs determine its biological function activity, therefore can in aminoacid sequence, carry out some aminoacid sequence displacement, yet this displacement keeps having the polypeptide of similar quality or giving this analog antagonistic activity on the contrary, and described antagonistic activity disturbs or block the effect of natural product.In addition, micromolecule (no matter whether being to intend peptide, natural or synthetic) may be able to substitute above-mentioned protein and peptide and have the activity of similar receptors bind with them.On the contrary, this micromolecular can or disturb the activity of above-mentioned protein and peptide by the blocking-up of different mechanism, and described mechanism includes but not limited to, stops the interaction of they and their corresponding receptor (cognate receptor).In addition, many above-mentioned albumen are as the inhibitor of signal transduction path.Embodiment of the present invention are that chemical molecular (any other natural or synthetic molecule of peptide, plan peptide or any chemical property) is as the activator of these signal transduction paths or the purposes of inhibitor.This tactful example is to use the inhibitor of gamma-secretase to suppress the Notch signal transduction path, or using the interactional inhibitor between the white and Tcf transcription factor of beta-catenin to suppress the white approach of Wnt-beta-catenin, these two pathways all participate in colorectal carcinoma.

G) oligonucleotide reagent

Activating agent can also be preventative to be used for, oligonucleotide (comprising oligoribonucleotide, oligodeoxyribonucleotide and its derivant) form of appeasing property or therapeutic purpose (comprising the cancer for example gene therapy and the treatment of colon cancer) exists.

Oligonucleotide is the polymer that is called the recurring unit of nucleotide generically.Not modified (naturally occurring) nucleotide has three components: (1) contains the heterocyclic base of nitrogen, it is connected by one of its nitrogen-atoms and (2) 5-five carbofurans (pentofuranosyl) sugar and 5 ' or the phosphoric acid of 3 ' carbon atom esterification of (3) and described sugar.When being integrated into oligonucleotide chain, the phosphoric acid of first nucleotide also passes through the sugar of the vicinity of the adjacent nucleotide of 3 '-5 ' phosphide key (phosphate linkage) esterification to the second.Nucleotide is the nucleoside that further comprises with the covalently bound phosphate group of the sugar moieties of nucleoside.In forming oligonucleotide, phosphate group is covalently bound mutually with adjacent nucleoside, thereby forms the linear polymerization chemical compound.The end separately of this linear polymerization structure can further connect, thereby forms loop configuration, yet in description of the present invention, open linear structure is normally preferred.

Oligonucleotide can comprise nucleotide sequence, and described sequence is enough to influence the specific hybrid with specific nucleic acid on homogeneity and number.Usually be described as " antisense " with this class oligonucleotide of a part of specific hybrid of the sense strand of gene.In description of the present invention, " hybridization " is meant and can be Watson-Crick, Hoogsteen or the reverse hydrogen-bonded hydrogen bonding of Hoogsteen between the complementary nucleotide.For example, adenine and thymine is paired complementary base by the formation of hydrogen bond." complementation " as used herein, is meant accurate paired ability between two nucleotide.For example, if the nucleotide on some site of oligonucleotide can with the nucleotide hydrogen bonding on the same loci of DNA or RNA molecule, this oligonucleotide and this DNA or RNA are considered to complementary mutually on this site so.When the corresponding site of sufficient amount in each molecule each other can hydrogen-bonded nucleotide be occupied, this oligonucleotide and this DNA or RNA were complementary mutually.

Term " oligonucleotide " is meant the oligomer or the polymer of ribonucleic acid (RNA) or DNA (deoxyribonucleic acid) (DNA) or its analogies.This term comprises the oligonucleotide that is connected to form by (main chain) between naturally occurring base, sugar and covalency sugar and has the oligonucleotide that there is part in intimate non-natural.They can be strand or two strands.Usually, the oligonucleotide length that is formulated in the compositions of the present invention can be for about 8 to about 100 nucleotide, more preferably length about 10 to about 50 nucleotide and most preferably length about 10 to about 25 nucleotide.

The oligonucleotide that is formulated in the compositions of the present invention comprises antisense compounds and the active oligonucleotide of other biological.The detailed description of the modification of antisense oligonucleotide and some expectations is found in people such as DeMesmaeker (Ace.Chem.Res., 1995,28,366).

As used herein, antisense compounds comprises antisense oligonucleotide, antisense peptide nucleic acid (PNA), siRNA, bob clamping structure RNA, ribozyme and external guide sequence (EGS).In the antisense regulation and control of messenger RNA (mRNA), the hybridization of antisense compounds and its mRNA target is disturbed the normal effect of mRNA and is caused the adjusting of its function in cell.The function for the treatment of interferential mRNA comprise all vital functionss (vital function) for example the montage of the actual translations of RNA to the transhipment in protein translation site, protein from RNA, RNA with the turnover that produces one or more mRNA kinds, mRNA and degraded and even the independently catalytic activity that can be undertaken by RNA possibly.This type of disturbs the population effect of mRNA function is the adjusting of protein expression, wherein " adjustings " be meant the increase (stimulation) or the minimizing (inhibition) of protein expression.In description of the present invention, inhibition is the preferred form that gene expression is regulated.

Antisense compounds can be brought into play their effect by many modes.Such mode is the RNA enzyme P of the endogenous nuclease for example eukaryotic RNA enzyme H of antisense mediation or prokaryotic cell to the orientation of target nucleic acid (people such as Chiang, J.Biol.Chem., 1991,266,18162; People such as Forster, Science, 1990,249,783).

The sequence of recruiting RNA enzyme P is called external guide sequence (therefore being abbreviated as " EGS ") people such as (, Proc.Natl.Acad.Sci.USA, 1997,94,8468) Guerrier-Takada.Another mode comprises the composite part with nuclease covalently bound to the oligonucleotide with antisense sequences, rather than depends on the recruitment of endogenous nuclease.Composite part with nuclease includes but not limited to (people such as Haseloff, Nature, 1988,334,585 such as enzymatic RNA, lanthanide ion complex; People such as Baker, J.Am.Chem.Soc, 1997,119,8749).

As used herein, term " antisense compounds " comprises that also ribozyme, synthetic RNA molecule and its derivant of catalysis high degree of specificity endoribonuclease reaction is (common, referring to, the United States Patent (USP) 5 that belongs to people such as Haseloff, 543,508 and belong to people's such as Goodchild United States Patent (USP) 5,545,729).

In addition, term " antisense compounds " comprises the RNA (or DNA of this type of RNA that encodes) that causes regulator gene to be expressed by the RNA interference mechanism.This quasi-molecule includes but not limited to short interfering rna, it is made up of the double-stranded RNA that is less than 50 base pairs, length is generally 21 or 29 nucleotide, be added with other chemical moleculars at their arbitrary end and (comprise deoxyribonucleotide, natural or modified), and disturb the bob clamping structure RNA work (or cause the dna molecular that produces in their the external or body, comprise the plasmid and the virus of any character) by RNA.This is also included within and causes the interferential any strand of RNA or double-stranded DNA or RNA molecule in the cell.

Antisense compounds (1) length that is formulated in the compositions of the present invention can be for about 8 to about 100 nucleotide, more preferably length about 10 is to about 30 nucleotide, (2) be strand or double-stranded, (3) by the extremely next needed nucleotide sequence of gene expression that comprises the people since mammal of targeting, (4), when when expressing the cells contacting of target gene, regulate its expression.Owing to the biologic activity by the gene outcome of target gene coding, the adjusting of its expression has the result of the expectation that specific preventative, appeasing property and/or therapeutic effects are provided.

Understand in this area, but the base sequence of oligonucleotide or other antisense compounds needn't with target nucleic acid sequence 100% complementation of its specific hybrid.Expect therein under the bonded condition of specificity when existence is enough to avoid oligonucleotide and non-target sequence (promptly measure in vivo or the situation of therapeutic treatment under, under physiological condition, or under the situation of external test, under condition determination) during the complementary degree of non-specific binding, antisense compounds can with its target nucleic acid specific hybrid.

The active oligonucleotide of other biological comprises aptamers and molecule bait.As used herein, described term is meant any such oligonucleotide (comprising peptide nucleic acid(PNA) or PNA), described oligonucleotide (1) give have this animal that needs provide preventative, appeasing property or therapeutic effects and (2) by non-antisense mechanism promptly by except working by certain methods with nucleic acid hybridization.

The title aptamers is provided by people such as Ellington (Nature, 1990,346,818), refer to non-nucleic acid ligands for example peptide, protein and micromolecule for example medicine and dyestuff are adaptive, thereby with significant specificity nucleic acid molecules bonded with it.Because these ligands specifics are in conjunction with character, the nucleic acid that can be categorized as aptamers and oligonucleotide can easily carry out purification via affinity chromatograph by the pillar that fixed part is carried in use or separate.Aptamers can be the short relatively nucleic acid nucleic acid to hundreds of nucleotide sizes.For example, reported length and be 155 nucleotide and with good selectivity and dyestuff for example Cibacron Blue and Reactive Blue 4 bonded RNA aptamers (people such as Ellington, Nature, 1990,346,818).Though at first the RNA molecule is called aptamers, but the term that uses among the present invention also refers to show and bonded any nucleic acid of micromolecule ligand specificity or oligonucleotide, include but not limited to, DNA, RNA, DNA derivant and conjugate, RNA derivant and conjugate, modified oligonucleotide, chimeric oligonucleotide and gapmers (referring to, for example, the United States Patent (USP) of announcing on June 4th, 1,996 5,523 that belongs to people such as Ecker, 3B9, it integrates with this paper by reference).

The molecule bait be on the simulation nucleic acid with the factor short double-strandednucleic acid in the site of protein bound (comprising) for example through designing " folding back " itself single-chain nucleic acid.So described factor of bait expection competitive inhibition; That is, because described factor molecule is in conjunction with excessive bait, thus reduce with concentration corresponding to the bonded factor in cell site of bait, thus therapeutic, appeasing property or preventative effect produced.The method of identifying and make up bait molecule is described in the United States Patent (USP) 5,716,780 that for example belongs to people such as Edwards.

The biological activity oligonucleotide of another kind of type is the RNA-DNA hybrid molecule that can instruct the gene conversion of endogenous nucleic acid people such as (, Science, 1996,273,1386) Cole-Strauss.

Preferred modified oligonucleotide main chain comprises, for example, thiophosphate, the chirality thiophosphate, phosphorodithioate, phosphotriester, the aminoalkyl phosphotriester, methyl and other alkyl phosphates comprise 3 '-alkylidene phosphate ester and chiral phosphorus acid esters, phosphinate (phosphinate), phosphoramidate comprises 3 '-amino phosphoramidate and aminoalkyl phosphoramidate, the sulfo-amino phosphate ester, the alkylthio phosphate ester, the alkylthio phosphotriester with have normal 3 '-5 ' boranophosphate of being connected, the analog of 2 of these materials '-5 ' connection and those materials with reversed polarity (wherein adjacent nucleoside unit is connected such, 3 '-5 ' become 5 '-3 ' or 2 '-5 ' become 5 '-2 ').Also comprise various salt, blended salt and free acid form.

Any aforementioned biological activity oligonucleotide can be formulated into drug delivery system of the present invention and unify and be used for preventative or the therapeutic purpose.Oligonucleotide can by for example with cation lipid for example Lipoplexe or cationic polymer for example Polyplexe is compound stablizes.

H) diagnostic agent

Medical imaging is that the Noninvasive or the non-surgery of internal organs or pathological changes (process) manifests.Representative method of diagnosis comprises X-ray, nuclear magnetic resonance (MRI), radionuclide or nuclear medicine and ultrasonic.

Radionuclide is by dissipation excess energy (parent) nuclear that (this process launch by the energy of particle or electromagnetic radiation form carry out) decay that becomes stable (daughter).Fluoroscopy (Fluoroscopy) is to detect the fluorescence examination of γ or X-ray, and it provides the real time imaging of the organ in the running by using for example PCTA of contrast agent with the television camera imaging.The computerized axial tomography of CAT-(Computed axial tomography)-utilize the little difference of tissue radiation photographic density to produce image.Usually the barium coloclysis of GI series is studied with the radiography that carries out large intestine colon and rectum the colon imaging under using.

Technetium is a radioactive label commonly used.Other radio-labelled compounds comprise iodine radioactive label, for example sulphuric acid ¹³¹Iobenguane, ¹²³Sodium iodide, ¹³¹Sodium iodide and indium labelling are for example ¹¹¹In radioactive label, indium chloride and satumomab pendetide indium.Image-forming contrast medium comprises iron content contrast agent for example ferumoxides and tree-shaped gadolinium (dentritic gadolinium).

The present invention can be used for reagent is delivered to colon, and described reagent makes it possible to or help manifest structure, damage, cell with molecule in definite cell surface or the cell by any imaging technique (include but not limited to radiography, radial fault photography (radio-tomography), nuclear magnetic resonance (MRI), ultrasonic, positron emission tomography (positron emission tomography) (PET scanning) or use the imaging technique of any other form of the radio magnetic wave of any wavelength).For example, available radionuclide is the micromolecule of the structure of cell surface of 99 mtc labeleds identification colon cancer cell or antibody and use it for and detect tumor cell and different big or small metastasis for example, comprises micro metastasis.

II. be used to prepare the method for pectin beads

Can use method known to those skilled in the art to prepare pectin beads, described method comprises and is blended in activating agent in the pectin solution and makes for example divalent zinc (for example divalent zinc that exists with the form of the zinc acetate solution) gelation of pectin anionicsite and bivalent cation.

Usually carry out gelation like this, promptly pass through solution, suspension or the dispersion of stirring active agent (being beta-lactamase L1 in one embodiment) and pectin, adjust the pH of solution if desired, this solution dropwise is added under stirring condition carries out gelation in the zinc acetate solution then.In some embodiments, when activating agent is not subjected to the adverse effect of other metal ions, can use bivalence or trivalent metal ion except zinc.

The suitable technique that is used for pectin solution is dropwise added zinc acetate solution is known to those skilled in the art; It comprises from the multi nozzle of Nisco Engineering AG (multi-nozzle) system and produces other correlation techniques of drop from pectin solution.

Pectin drips and experiences gelation process ideally to obtain best encapsulation yield and release efficiency subsequently in the predetermined time.

The concentration of pectin solution advantageously about 4 is to about 10% (w/v), and preferably approximately 4 to about 7%, and metal cation for example zinc acetate solution advantageously is about 2 to about 20% (w/v), and preferably approximately 5 to about 15%.More preferably, pectin solution is about 5% (w/v), and zinc acetate solution is about 12% (w/v).

Advantageously under about 6 pH, at room temperature, under slow stirring condition, for example stir pectin beads in the zinc acetate solution at metal cation, carry out about at least 12 minutes until about 20 hours, preferably approximately 20 minutes to about 2 hours.

Recyclable then beadlet, rinsing in aquae destillata, the electrical conductivity until rinsing solution reaches platform ideally.Preferably carry out at least twice rinsing or in successive process, carry out rinsing in rinsing solution so that the amount of the residual zinc acetate that reclaims is reduced to minimum.

Collect beadlet then, and can use method known to those skilled in the art to comprise that the incubation case of heating or fluidization make its experience dry run through rinsing.

Usually with beadlet at about 20 to about 40 ℃ temperature dry about 30 minutes to about 24 hours, preferably in about 35 ℃ of following dried overnight.Preferably carry out dry weight and reach platform until beadlet.

Thereby the pin that can use suitable internal diameter forms the pectin that is added to zinc acetate solution and drips and adjust particulate diameter subtly.Bead diameter is preferably between about 600 and 1500 μ m.

When activating agent was beta-lactamase L1, the encapsulation yield was generally 50 to 100% (measuring according to enzymatic activity).

III. comprise the formation of the drug delivery system of pectin beads

Can collect pectin beads, and itself and appropriate excipients are made up, be formulated as multiple oral drugs delivery system.For example, can be with the combination of beadlet and solid excipient, make tablet then or be included in the capsule.

Also can be with the pectin beads and the liquid/gel excipient composition of depolymerized pectin beadlet not, and mixture/dispersion can be integrated into for example soft gelatin capsule (gel-cap) of capsule.

If want, available suitable enteric coating peridium patch agent or capsule are not degraded by stomach with help.PH in the stomach is 1 to 3 progression, but it increases in small intestinal and colon, reach value (people (1996) Current Applications ofPolysaccharides in Colon Targeting such as Hovgaard L. near 7, Critical Reviews inTherapeutic Drug Carrier Systems, 13,185).By wrapping by them with the polymer (described polymer is soluble but solvable in neutrality or alkaline pH in acid pH) that depends on pH, the drug delivery system that exists with forms such as tablet, gelatine capsule, spheroides can arrive colon and not be exposed to these variations (people such as Kinget is referring to above-mentioned quoted passage (op.cit)) of pH.Be most commonly used to the derivant that this purpose polymers is a methacrylic acid at present

L and S (people (1993) such as Ashford M., Anin vivo investigation of thesuitability of pH-dependent polymers for colonic targeting, International Journal of Pharmaceutics, 95,193 and 95,241; With people (1997) Acrylic polymers for colon-specific drugdelivery such as David A., S.T.P.Pharma Sciences, 7,546) and nearer since

FS.

With the treatment of the disease (at this disease administered compound) that is suitable for providing enough degree or the effective dose drug administration delivery system of prevention.The effective dose of this compounds is usually less than and causes the required threshold concentration of any appreciable side effect.Can treat some diseases therein and avoid administered compound in the treatment window (therapeutic window) of some side effect.Ideally, the effective dose of the chemical compound of describing herein is enough to the effect of expectation is provided in colon but is not enough to (that is, not in sufficiently high level) other places in vivo provides the side effect of not expecting.

Most preferably, effective dose is in low-down concentration, observes ceiling effect this moment and takes place, and have minimum side effect, and this colonic delivery by targeting by activating agent comes optimization.Above-mentioned effective dose has been represented the dosage of using as single dosage or use as one or more dosage of using usually in 24 hours.

IV. the method for using the drug delivery system described to treat herein

To can be used for treating for its colonic delivery be suitable those patient's condition and disease type to the drug delivery system of Miao Shuing herein.In one embodiment, disease is the disease that the development of the resistance of the change of antibiotic exposure (for example diarrhoea), symbiosis flora and bacterial antibiotic is caused by colon.In this embodiment, drug delivery system comprises the antibiotic reagent of deactivation, can be with the treatment effective dose to using, just using and maybe will use effective ingredient with the patient that one or more antibiotic are treated.

When the metal dependent enzyme is except deactivation during the enzyme the antibiotic enzyme, can uses such enzyme and treat particular disorder by this class enzyme treatment.

In another embodiment, to suffering from patient's drug administration delivery system of colon cancer.In this embodiment, drug delivery system comprises one or more antitumor agents, with the treatment effective dose patient who suffers from colon cancer is used described system.Selectively, cancer can be present in intravital another position, and drug delivery system can be used for walking around the degraded of its some antitumor agent of following of harmonization of the stomach, thereby needing to avoid intramuscular or intravenous to use these reagent.

In another embodiment, to suffering from for example patient's drug administration delivery system of Crohn disease, ulcerative colitis, irritable bowel syndrome, diarrhoea or constipation of colonic disorders.In this embodiment, drug delivery system comprises treats or prevents the reagent of these diseases, and can be with the treatment effective dose to suffering from patient's administration system of such disease.

In another embodiment, drug delivery system be used to use based on peptide or activity of proteins agent for example insulin, antibody etc. or based on the therapeutic agent of oligonucleotide for example antisense or RNA disturb therapy so that reagent is not degraded by stomach.In this embodiment, drug delivery system comprises these reagent based on proteins/peptides/oligonucleotide, and can be with the patient administration system of treatment effective dose to treating with these reagent, and need not to use these reagent by subcutaneous or intravenous injection.

In other embodiments, drug delivery system can be used for diagnostic agent is applied to colon.In this embodiment, drug delivery system comprises diagnostic agent, image-forming contrast medium (imaging contrast agent) for example, and with the diagnosis effective dose to patient's (described patient will experience diagnostic assay to diagnose colonic disorders) administration system.

By will be further understood that the present invention with reference to following indefiniteness embodiment.

Embodiment 1: be used for the sensitivity of beta-lactamase L1, quantitatively and the exploitation of specific assay

The hydrolysis of Nitrocefin is to be used for that quantitative penicillinase is active knows technology.Yet common type is in single pipe and is not suitable for the analysis of a large amount of samples.Present embodiment has been described the exploitation and the suitability condition (fitfor purpose qualification) of this algoscopy of carrying out in 96 hole micro plate formats.

By the Nitrocefin dried powder is dissolved in the stock solution that obtains Nitrocefin in the dimethyl sulfoxide (DMSO) with the concentration of 10mM.Stock solution is stored in-20 ℃ and dilutes 100 times down and before soon in the 50mM sodium phosphate buffer that contains 0.1mg/ml bovine serum albumin (BSA) (Hepes buffer) pH 7.0, using.The selection of buffer is described in the table 1.

In the Nitrocefin of 180 μ l dilution, add 20 μ l solution to be analyzed.Be used in 37 ℃ of absorptances of using Multiskan Ascent (Thermo Labsystems) card reader to measure in per 30 seconds down and measure the kinetics of Nitrocefin hydrolysis at the 492nm place.

Use Excel Adds In Cellula (Prism Technologies, CambridgeUK) slope calculations (difference of absorptance/second).

In each solubilising buffer with beta-lactamase L1 (Eurogentec, Belgium, be determined as about 10mg/mL by μ BCA algoscopy) dilution 500x, 1000x, 2000x and 4000x, and add the solution that 20 μ l contain enzyme in the buffer of the Nitrocefin by containing 100 μ M to 180 μ l and come initial action.

At 10mM Hepes, detect the activity of beta-lactamase L1 in the 145mM NaCl pH of buffer 7.4.Detect EDTA to the interference of metal dependent enzyme with to the needs of carrier protein (bovine serum albumin is abbreviated as BSA).As illustrated in the table 2, should avoid EDTA (it can be used for external solubilising beadlet to measure their content).Comprising of BSA or other carrier proteins is useful.

Table 2: be used for the selection that the active quantitative buffer of beta-lactamase L1 is formed

As illustrated in the table 2, EDTA disturbs the enzymatic determination of activity, and BSA strengthens the recovery of enzymatic activity.

Embodiment 2: the unstability of beta-lactamase L1 in original pectin mixture and the effect of metal counter ion counterionsl gegenions

With 0.3ml beta-lactamase L1 (Eurogentec, Belgium, being determined as about 10mg/mL by μ BCA algoscopy) (the amidated pectin (Unipectine) of low methoxylated, Texturant Systems cat#OG175C) mix for 6% pectin solution for preparing in water with 10g; Do not adjust the pH of pectin solution.

At room temperature under the condition that stirs (200rpm), use the pin of peristaltic pump and 0.8mm internal diameter that pectin/beta-lactamase L1 mixture is dropwise added to the beaker that 40ml calcium chloride (6%) is housed in 2 minutes time.

So that after free and the bonded calcium ion balance,, and in the water of 200ml purification, clean beadlet 3 times at further incubation to remove excessive free calcium by the filtered and recycled beadlet.In this stage, beadlet is called " beadlet of gelation ".

Under 37 ℃ in baking oven dry beadlet 2 hours, thereby produce exsiccant beadlet.

Obtain 2x5 drips and drips sample with 2x15 and measure initial beta-lactamase L1 activity in the exit of pin.Also prepare nonprotein beadlet as negative control.

At Zn ion (0.1mM ZnCl ₂) exist and non-existent situation under the enzymatic activity (Nitrocefin hydrolysis) of quantitative beta-lactamase L1, described in embodiment 1.

As illustrated in the table 3, in beta-lactamase L1/ pectin mixture, do not find enzymatic activity, but containing Zn ^{+ 2}Buffer in recovered significant activity in the beadlet measured.

Table 3: the deactivation of beta-lactamase L1 in the pectin solution that non-pH-adjusts

Embodiment 3: the effect that is used for the pH of the optimization of metal ion of gelation pectin and pectin solution

In order to measure the effect of pectin solution parameter and zinc ion, compare the experiment of 4 kinds of preparations.According to factorial design Design Expert 6.0.10, Stat-Ease, Minneapolis sets up design.Detect two parameters:

(a) pH:4.0 of pectin solution and 7.0.

(b) metal cation in the gelling water-bath: Ca ²⁺(CaCl ₂) or Zn ²⁺(zinc acetate is abbreviated as ZnAc)

Prepare beadlet as described in example 2 above.Yet because the stability of pectin reduces with the increase of pH, the concentration of pectin solution is reduced to 4% from 6%.

The encapsulation yield is measured by the enzymatic activity of measuring beta-lactamase L1, described in embodiment 1.

At 1% pectase (from the pectase of microorganism Aspergillus aculeatus (Aspergillus aculeatus), Pectinex SP-L Ultra (SIGMA, France) under existence or the non-existent situation, 5 beadlet are dissolved in 20ml 10mM Hepes under 4 ℃, 145mM NaCl, 0.1mg/mlBSA among the pH 7.4, spend the night.

In 20ml 10mM Hepes, 145mM NaCl prepares positive control among the 0.1mg/ml BSA pH 7.4 by dilution and the beta-lactamase L1 that should be included in same amount in 5 beadlet.As illustrated in the table 4, when pectin solution is in pH 4.0, no matter be used for what the agglomerative cation of pectin is, beta-lactamase L1 be inactivated (4.3% residual activity in calcium and 3.8% residual activity in zinc), yet, after pectin solution is buffered to pH 7.0, keep almost completely activity (in the calcium 86.7% and zinc in 64.0%).

Table 4: be used for the effect (beta-lactamase active recovery) of the pH of agglomerative cation and pectin to stability

Embodiment 4: preparation is used for the mensuration of vital parameter of the beta-lactamase L1 that colon-specific sends and the optimization of these parameters

Detect 5 parameters:

(a) concentration of pectin solution (low methoxylated amidated pectin (Unipectine), Texturant Systems, cat# OG175C): 4% and 5% (w/v)

(b) be used for agglomerative cation: Ca ²⁺Or Zn ²⁺

(c) with polymine (PEI) solution (PEI, high molecular, the second bag quilt of the gelation beadlet that anhydrous (SIGMA-ALDRICH, France)) carries out

(d) pH:7 of PEI solution and 11 (solution that initial non-pH-adjusts).

(e) dissolving of beadlet, be determined at 1% pectase exist with non-existent situation under the enzymatic activity that encapsulates.

Table 5 has been summarized experimental design

Table 5: the optimized experimental design that is used to relate to the vital parameter of beta-lactamase L1 preparation

To repeat these 16 experiments (32 results) in duplicate.

Repeated experiments (run) 13 (34 results).

The pH of the pectin solution with 4% and 5% is adjusted to 7.0.Yet after measured, the pH of 5% pectin solution is unsettled and is reduced to pH 5.4 when experiment finishes.Therefore also 5% pectin solution is adjusted to pH 8.5 to compare.

At last, use 48 results of factorial design analysis.

Prepare beadlet as described in example 2 above, except the gelling time in the cation water-bath was reduced to 10 minutes from 20 minutes, to allow experimental period arrangement flexibly.

Measuring enzymatic activity (hydrolysis of Nitrocefin as described in example 1 above) before, 1% pectase exist and non-existent situation under sample (5 beadlet) spent the night under 4 ℃ be dissolved in 20ml 10mM Hepes, 145mM NaCl is among the 0.1mg/ml BSA pH 7.4.

Table 6 has been summarized the experimental result that is obtained.

Table 6: be used for the vital parameter that optimization relates to beta-lactamase L1 preparation

Whole results of experimental design

Table 6 (continuing): be used for whole results of experimental design that optimization relates to the vital parameter of beta-lactamase L1 preparation

The optimum preparation of using following parameters to obtain beta-lactamase L1 has been highlighted in simple univariate statistics analysis (Simple mono-variate statisticalanalysis) (yield of the continuous minimizing of encapsulation sorting):

(a) 5% concentration of pectin (when pH 5.4, maxima solubility)

(b) be neutralized to the pectin solution of at least 5.4 pH

(c) should use zinc ion

(d) polymer of available other types is further estimated second coating

(e) pectase should be used for the quantitatively beta-lactamase L1 of preparation.

Embodiment 5: improve the stability of beadlet in mimic intestinal medium (SIM) that comprises beta-lactamase L1 by increasing zinc ion concentration and exsiccant persistent period

Preparation comprises the beadlet of beta-lactamase L1 as described in example 4 above.Detect ever-increasing zinc acetate concentration (6,8,10 and 12%).Relatively has or do not have the other coating of PEI.

The drying of beadlet also increased to from 2 hours spends the night.

Removing the efficient of the excessive cleaning that is used for agglomerative metal ion also monitors by the electrical conductivity of measuring water rinse solution.

As illustrated in fig. 1, in cleaning, 3 water obtain effectively to clean behind the cleaning beadlet.

Illustrational as institute in the table 7, higher zinc acetate concentration has increased the stability of beadlet in SIM (mimic intestinal medium, US Pharmacopeia 26) that comprises beta-lactamase L1, yet PEI second coating reduces their stability.

Table 7: zinc acetate concentration and PEI second coating are to the influence of the stability of beadlet in SIM that comprises beta-lactamase L1

+: stable beadlet

-: dissolved beadlet

Y: have PEI second coating

N: do not have PEI second coating

Embodiment 6: zinc concentration and drying time are to the effect of the stability of beadlet in mimic intestinal medium (SIM)

Preparation comprises the beadlet of beta-lactamase L1 as described above, and carries out gelation (referring to embodiment 5) with 6 or 12% zinc acetate solution.

The influence of drying time also by 35 ℃ (for industrialization purposes, preferably to 37 ℃ temperature) down dry beadlet detected in 2,4 and 16 hours.Only in 12% zinc solution gelation and dry to surpass 4 hours beadlet be stable in SIM after 5 hours at 37 ℃ of following incubations.Measure the stability (in 37 ℃ under carry out 5 hour) of beadlet in SIM, the results are shown in table 8.

Table 8: beadlet carries out 5 hours stability under 37 ℃ in mimic intestinal medium.

Numeral number of beads of complete appearance still in solution.

Clean back: 10mM Hepes, further incubation among the 145mM NaCl (stock solution) at mimic colon medium (SCM).Before being about to use, add 1% pectase, 0.1mg/ml BSA; Use NaOH 1M that the initial beta-lactam enzymatic activity (Nitrocefin hydrolysis) that pH is adjusted to pH 6.0,63% is resumed.

Embodiment 7: gelling time, rinse method and drying time are to the influence of the active recovery of beta-lactamase L1

Use is from the beadlet of the multi nozzle systems produce different batches of Nisco Engeneering AG.Beadlet is experienced different gelling times, rinse method and time and drying means type and time.

Clearly, be less than 20 hours and, obtain preferred package efficient and enzymatic activity when gelling time when carrying out rinsing when removing the residual zinc acetate from beadlet.The results are shown among Fig. 2.

Embodiment 8: be used for the sensitivity of beta-lactamase L1, quantitatively and the exploitation of specific assay method

The hydrolysis of CENTA is the active technology of knowing of quantitative beta-lactamase that is used for.Yet common type is in single pipe and is not suitable for analyzing a large amount of samples.Present embodiment has been described the exploitation and the suitability condition of this algoscopy of carrying out in 96 hole micro plate formats.

By being dissolved in the water with the concentration of 25mM, the CENTA dried powder obtains the stock solution of CENTA; Its five equilibrium with 25 μ l is stored down in-20 ℃.By contain 50 μ m ZnCl at following mensuration buffer: 10ml ₂30mM Hepes pH of buffer 7.5 in dilution 22 μ 1 CENTA stock solution measure mixing, thereby produce the CENTA concentration of 110 μ M.About measuring, the solution that 20 μ l to be determined is comprised enzyme is added in the mensuration mixture of 180 μ l, thereby uses the final concentration of 100 μ M CENTA in mensuration.Be used in 37 ℃ of absorptances of using Multiskan Ascent (Thermo Electron Corporation) card reader to measure in per 9 seconds down and measure the kinetics of CENTA hydrolysis in the 405nm place.Use AscentSoftware for Multiskan Ascent version 2.6 slope calculations (difference of absorptance/second).

In measuring buffer with beta-lactamase L1 (Eurogentec, Belgium, be determined as about 10mg/mL by μ BCA algoscopy) be diluted to 0.2,0.5,1.0 and 2.0 μ g/ml, and add the solution that 20 μ l contain enzyme in the mixture and come initial action by measuring to 180 μ l.As shown in figure below, in 3 were independently measured, it was linear measuring for the enzyme concentration in this scope.Standard deviation is less than 10%.

Embodiment 9. beta-lactamase L1 never wrap the beadlet of quilt and have or do not have the release of beadlet that HPMC wraps the Eudragit bag quilt of quilt in advance.

The a collection of pectin beads that comprises beta-lactamase L1 of preparation under following condition: by by the pin of 0.5mm internal diameter with 5% the reorganization beta-lactamase L1 (Eurogentec that contains the 300mg/l purification, Belgium) pectin solution dropwise is added to 12% ZnAc, 2H ₂Form beadlet in the O water-bath.The gelation beadlet is 90 minutes in the zinc acetate water-bath, collects beadlet, and water cleans and reaches stabilised platform (showing that rinsing is best) until electrical conductivity of water, carries out drying in 35 ℃ at last under vacuum.The exsiccant beadlet that obtains has the diameter of 0.8-1.25mm, average weight 0.6mg, and every mg beadlet comprises about 5 to 6 μ g beta-lactamase L1.Do not wrap, or use Glatt GPC 1.1 bags by them with top spray (Top spray) according to the following prescription (formulas) shown in the table 9 by them.

Table 9

Raw material	Amount (g) batches 83	Amount (g) batches 100	Amount (g) batches 82	Amount (g) batches 99	Amount (g) batches 81	Amount (g) batches 97
							??Eudragit?L?30D-55	??1600.0	??149.5	??300.0	??31.9
??Eudragit?NE?30D			??700.0	??74.4

Raw material	Amount (g) batches 83	Amount (g) batches 100	Amount (g) batches 82	Amount (g) batches 99	Amount (g) batches 81	Amount (g) batches 97
							??Eudragit?FS?30D					??800.0	??85.0
GMS (glyceryl monostearate)	??24.0	??2.2	??15.0	??1.6	??12.0	??1.3
							Sodium hydroxide	??28.8	??2.7	??30.4	??1.9		??1.5
Tween 80 (polysorbate) 33% aqueous solution	??48.0	??2.2	??18.0	??1.6	??14.4	??1.3
							Triethyl citrate	??1107.2	??94.5	??4.50	??67.2	??10.0	??25.2
Water	??1600.0	??149.5	??565.7	??1600.0	??505.6	??85.0
							Wrap quilt in advance with 5%HPMC	Not	Be	Not	Be	Not	Be

Use and the identical materials that is used for Eudragit bag quilt, carry out the pre-bag quilt of beadlet with HPMC.

The scanning electron micrograph (SEM) of the beadlet of Eudragit bag quilt is shown in Fig. 4.The transverse section shows the relative thickness of Eudragit coating.

In order to assess the release of beta-lactamase L1, under blended condition gently under 37 ℃ in the 50mM Hepes pH of buffer 7.4 that contains 0.1M NaCl and 100PG/ml pectase (SigmaAldrich) from microorganism Aspergillus aculeatus beadlet incubation bag quilt and that do not wrap quilt.On the different time, take out medium, and use the Nitrocefin algoscopy of describing among the embodiment 1 it to be measured with regard to the beta-lactam enzymatic activity.

Use the beadlet bag quilt and that do not wrap quilt to measure release dynamics, the results are shown in Fig. 5.

Embodiment 10: the antibiotic efficient of L1 extracorporeal hydrolysis of release

In order to assess when the beadlet of bag quilt arrives colon, whether they in fact can the hydrolysis antibiotic, with they incubations 1 hour in mimic stomach medium (0.1N HCl) continuously, under 37 ℃ in mimic intestinal medium (the phosphoric acid Na/K pH of buffer 6.8 that contains 0.1M NaCl of 50mM) incubation 3 hours, containing the specified time quantum of incubation in the pectase (SigmaAldrich) of 100PG/ml from microorganism Aspergillus aculeatus and the mimic colon medium of 2mg/ml amoxicillin (50mM Hepes pH of buffer 7.4,0.1M NaCl) at last.Take out medium and measure the amount of residual amoxicillin by HPLC and UV absorption process in different time.Use Bio-Diss III device (Varian) to carry out described method.Only incubation does not wrap the beadlet of quilt in having the mimic colon medium of pectase and amoxicillin.

The results are shown in Fig. 6.

Embodiment 11: comprise the influence of the beadlet of beta-lactamase L1 to the appearance of the bacterial resistance in the piglets of handling with the amoxicillin.

Do not handle or, carried out 7 days with the oral processing in the 20mg/kg amoxicillin every day piglets in 6 to 7 ages in week.In the animal of handling half accepted the antibiotic of daily dose and is filled with 5%HPMC to wrap gelatine capsule quilt and wrap the 320mg pectin beads that contains beta-lactamase L1 of quilt with 40%Eudragit L30D-55 (batch 100) in advance; Second half accepts the placebo pectin beads of similar bag quilt.Beginning to handle preceding 3 days and every day in 7 days processing is collected feces, total inclusions and amoxicillin resistance intestinal bacteria with regard to them on the MacConkey agar plate that contains 0 or 100 μ g/ml amoxicillin are analyzed it.As shown in Figure 7, the feces of untreated animal contains the amoxicillin tolerant bacteria (＜5%) of minimum scale, yet this ratio increases fast in the animal of handling with the amoxicillin, reaches 50 to 80% value after 7 days.On the contrary, accept to contain the beadlet of beta-lactamase and the animal of amoxicillin is only showed the of short duration and limited increase of antibiotic-resistant bacteria.Present embodiment show the Eudragit bag contain beta-lactamase L1 by pectin beads use altogether the protection piglets avoid by handle with the amoxicillin animal the infringement of appearance of inductive antibiotic-resistant bacteria.

All patents disclosed herein and publication are integrated with this paper in full by reference with it.According to foregoing detailed description of the present invention, change of the present invention and variation are obvious to those skilled in the art.

Claims (39)

1. the drug delivery system that is used for the Orally administered and colonic delivery of preventive, therapeutic agent or diagnostic agent, it comprises the pectin beads that contains preventive, therapeutic agent or diagnostic agent, and wherein said pectin and metal cation are crosslinked and with the methacrylic acid-alkyl acrylate copolymer that is used for enteric coating for example

The polymer coating beadlet.

2. the drug delivery system of claim 1, wherein said reagent is cancer therapy drug.

3. the drug delivery system of claim 1, wherein said reagent is antiinflammatory.

4. the drug delivery system of claim 1, wherein said reagent is protein or peptide.

5. the drug delivery system of claim 1, wherein said reagent are or comprise nucleic acid.

6. the drug delivery system of claim 1, wherein said reagent are virus, antibacterial or fungus.

7. the drug delivery system of claim 1, wherein said reagent is diagnostic agent.

8. the drug delivery system of claim 1, wherein said reagent is immunomodulator.

9. the drug delivery system of claim 1, wherein said reagent blocking-up or the activity of regulating receptor in the colon.

10. the drug delivery system of claim 1, wherein said reagent deactivation can be regulated the active other treatment agent of receptor in colon.

11. the drug delivery system of claim 1, the wherein said reagent antibiotic in can the deactivation colon.

12. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is beta-lactamase.

13. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is from the beta-lactamase L1 that has a liking for maltose oligotrophy Zymomonas mobilis.

14. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is Erythromycin esterase..

15. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is the antibiotic enzyme of deactivation quinolinones.

16. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is the enzyme of deactivation fluoroquinolone antibiotic.

17. the drug delivery system of claim 11, wherein the antibiotic reagent of deactivation is the enzyme of deactivation glycopeptide antibiotic.

18. the drug delivery system of claim 1, wherein methacrylic acid-alkyl acrylate copolymer for example Polymer is selected from the methacrylic acid-alkyl acrylate copolymer with acidity or basic group, for example has acidity or basic group

The polymer of the release that depends on pH of L, S, FS and E polymer, permission active component.

19. the drug delivery system of claim 1, wherein methacrylic acid-alkyl acrylate copolymer for example

Polymer is selected from the methacrylic acid-alkyl acrylate copolymer with alkalescence or neutral group, for example has basic group

RL and RS polymer and have neutral group

NE polymer, the polymer that allows active component to discharge when not relying on the swelling control of pH.

20. the drug delivery system of claim 1 is wherein described in the claim 18 and 19

The mixture of type of polymer is used to guarantee the protection of active component and suitable sending.

21. the drug delivery system of claim 1, wherein said metal cation is a zinc cation.

22. each drug delivery system in the claim 1 to 21, its form with tablet, pill, capsule or soft gelatin capsule exists.

23. the antibiotic method of deactivation in patient's colon, it is included in before the administration of antibiotics, during or afterwards the patient is used in the claim 11 to 21 each compositions.

24. be used for the drug delivery system of delivery of metal dependent enzyme, it comprises the pectin beads of package metals dependent enzyme, wherein also the metal cation that described enzyme relied on is used for cross-linked pectin, and methacrylic acid-alkyl acrylate copolymer that wherein said pectin beads is used for enteric coating for example

Polymer wraps quilt.

25. the drug delivery system of claim 23, wherein said metal dependent enzyme are from the beta-lactamase L1 that has a liking for maltose oligotrophy Zymomonas mobilis.

26. the drug delivery system of claim 23, wherein said methacrylic acid-alkyl acrylate copolymer for example

Polymer is selected from the methacrylic acid-alkyl acrylate copolymer with acidity or basic group, for example has acidity or basic group

The polymer of the release that depends on pH of L, S, FS and E polymer, permission active component.

27. the drug delivery system of claim 23, wherein said methacrylic acid-alkyl acrylate copolymer for example

Polymer is selected from the methacrylic acid-alkyl acrylate copolymer with alkalescence or neutral group, for example has basic group

RL and RS polymer and have neutral group

The NE polymer allows active component to discharge when not relying on the swelling control of pH.

28. the drug delivery system of claim 23, wherein methacrylic acid-alkyl acrylate copolymer of describing in the claim 25 and 26 for example The mixture of the kind of polymer is used to guarantee the protection of active component and suitable sending.

29. be used for the oral drugs delivery system that the colon of active component discharges, it comprises:

A) can treat colonic disorders activating agent and

B) comprise the drug delivery system of pectin beads, wherein said pectin and zinc ion are crosslinked, and methacrylic acid-alkyl acrylate copolymer that beadlet is used for enteric coating for example

Polymer wraps quilt.

30. the drug delivery system of claim 29, wherein said disease is Crohn disease or ulcerative colitis, and described activating agent is selected from aminosallcylic acid ester/salt, comprise 5-aminosalicylic acid medicine, corticosteroid, immunomodulator, cyclosporin A, TNF α, thiazolidinediones and the glitazone of (5-ASA).

31. the drug delivery system of claim 30, wherein said immunomodulator is selected from cytokine, lymphokine and interleukin.

32. the method for treatment Crohn disease or ulcerative colitis, this method comprise that the patient to its treatment of needs uses in the claim 30 and 31 of effective dose each drug delivery system.

33. the drug delivery system of claim 29, wherein said disease is a colon cancer, and described activating agent is selected from antiproliferative, the reagent that is used for dna modification or reparation, the DNA synthetic inhibitor, the agent of DNA/RNA transcriptional regulatory, RNA processes inhibitor, influence protein expression, synthetic and stable reagent, influence the reagent of the ability of protein positioning or their their physiological actions of performance, the reagent of interferencing protein-protein or protein-nucleic acid interaction, disturb the reagent that works by RNA, the receptors bind molecule of any chemical property (comprising micromolecule and antibody), by the toxin of targeting, zymoexciter, enzyme inhibitor, the Gene regulation agent, the HSP-90 inhibitor, disturb the molecule of microtubule or other cytoskeleton components or cell adhesion and motion, the reagent and the treatment adjuvant that are used for phototherapy.

34. the method for treatment colon cancer, this method comprises the drug delivery system of the patient of its treatment of needs being used the claim 33 of effective dose.

35. the drug delivery system of claim 29, wherein said disease are irritable bowel syndrome or constipation, and described activating agent is selected from stimulant laxative, permeability aperient, stool softener, extender, Zelnorm (tegaserod) and anticholinergic agent.

36. the method for treatment irritable bowel syndrome or constipation, this method comprises the drug delivery system of the patient of its treatment of needs being used the claim 35 of effective dose.

37. the drug delivery system of claim 29, wherein said system is as diagnostic agent, and the reagent of encapsulation is diagnostic agent.

38. the drug delivery system of claim 37, wherein said diagnostic agent are selected from the chemical compound and the gas of radiolabeled chemical compound, radip-opaque.

39. the method for the disease in the diagnosis colon, this method comprises:

A) to the patient of its diagnosis of needs use in the claim 36 or 37 of effective dose each drug delivery system and

B) detect diagnostic agent.

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