CN101090720A - Nanoparticulate compositions of tubulin inhibitor compounds - Google Patents
Nanoparticulate compositions of tubulin inhibitor compounds Download PDFInfo
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- CN101090720A CN101090720A CN 200580037827 CN200580037827A CN101090720A CN 101090720 A CN101090720 A CN 101090720A CN 200580037827 CN200580037827 CN 200580037827 CN 200580037827 A CN200580037827 A CN 200580037827A CN 101090720 A CN101090720 A CN 101090720A
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- indol
- pyridin
- acetaldehyde amide
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Abstract
The present invention is directed to novel pharmaceutical compositions comprinsing nano- and micro-particulate formulations of poorly water soluble tubulin inhibitors of the indole chemical class, preferably N-substituted indol-3-glyoxyamides, and more preferably N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylic acid amide (D-24851), also known as ''Indibulin'', and methods of making and using such compositions for the treatment of anti-tumor agent resistant cancers and other diseases.
Description
The present invention relates to nanometer and micron particle preparation, manufacture method and the using method of indole Antitubulin.Preferred indole Antitubulin comprises indole-3-acetaldehyde amide that N-replaces, and more preferably, N-(pyridin-4-yl)-[1-(4-benzyl chloride base)-indol-3-yl] glyoxamides (D-24851) is also referred to as " Indibulin ".Although the particulate composition of indole Antitubulin can pass through prepared in various methods, preferable methods is included in the surfactant existence and separates out the Antitubulin chemical compound down in aqueous medium, form pre-suspended substance, apply energy then and distribute in suspended substance, to obtain required nanoparticle size.This compositions is used for various treatments, is preferred for treating the cancer and the other diseases of anti-anticarcinogen.
Background of invention
A. about the background of the nano-particle of poorly soluble medicine
Its quantity of preparation poorly soluble or not soluble drug constantly increases in aqueous solution.This medicine is a kind of challenge for the injection type of preparation parenteral.Yet insoluble medicine can provide tangible stability advantages when being mixed with the suspended substance of submicron particles in aqueous medium in water.For safety with use these preparations effectively, accurate control particle diameter.Particle diameter usually must be less than 7 microns, by capillary tube, and can not cause thromboembolism (people such as Allen, 1987 with safely; Davis and Taube, 1978; People such as Schroeder, 1978; People such as Yokel, 1981).
Carry not that a kind of technology of soluble drug is documented in United States Patent (USP) 2,745, in 785.This patent disclosure a kind of preparation be suitable for the lamellar of parenteral or the method for tabular benzylpenicillin crystal (N, N '-dibenzyl ethylenediamine salt).This method may further comprise the steps: by adding the dissolubility that entry reduces benzylpenicillin, from formamide solution recrystallization benzylpenicillin.' 785 patents also provide can use wetting agent such as lecithin, emulsifying agent, surfactant, defoamer, high fatty acid partial ester, its polyoxyalkylene derivative and the aralkyl Aethoxy Sklerol of Sorbitol or the cosmocillin granule of its salt coating.' 785 patents also disclose under pressure and have made the benzylpenicillin micronization with gas shock, form about 5～20 microns crystal.
United States Patent (USP) 5,118, disclosed another kind of technology has been put down in writing a kind of method for preparing nano-particle in 528.This method may further comprise the steps: (1) prepares the liquid phase of material in solvent that can be added with one or more surfactants or solvent mixture, (2) second liquid phase of preparation non-solvent or non-solvent mixture, non-solvent can be miscible with solvent or solvent mixture that described material is used, and (3) are stirred down solution (1) and (2) are added to together; And (4) remove undesired solvent, obtains the colloidal suspension of nano-particle.' 528 patent disclosures noenergy supply and the granule that makes less than 500nm.Patent has been illustrated especially, ' 528 does not need to use high-energy equipment such as ultrasonic disruption instrument and homogenizer.
United States Patent (USP) 4,826,689 disclose and have a kind ofly prepared the particulate method of uniform-dimension from water-insoluble drug or other organic compound.At first, the SOLID ORGANIC chemical compound that dissolving is fit in organic solvent, and can use the non-solvent dilute solution.Then, the injection aqueous is separated out liquid, separates out to have basically the evenly non-accumulative granule of average diameter.Granule is separated with organic solvent.Depend on organic compound and required particle diameter, can change the parameters such as ratio, charge velocity, stir speed (S.S.) and volume of temperature, non-solvent and organic solvent according to this invention.This method has formed metastable medicine, and it is that thermokinetics is unsettled, and finally changes into more stable crystalline state.Medicine is retained in metastable state, and wherein free energy is between original drug solution and the stable crystal formation.' 689 patent disclosures utilize crystallisation inhibitors (for example, polyvinylpyrrolidone) and surfactant (for example, poly-(oxygen ethylene)-altogether-oxypropylene)) precipitation enough is stablized to be separated by centrifugal, membrane filtration or reverse osmosis.
United States Patent (USP) 5,091,188; 5,091,187 and 4,725,442 disclose (a) with natural or synthetic phospholipid painting medicine granule or (b) dissolved substance and forming with natural or semisynthetic phospholipid stable emulsion in the lipophilic carriers that is fit to.A shortcoming of these technology is that they depend on the quality of medicine material, and does not openly change the raw material form and make material be step frangible, easier form processing.
The another kind of technology that is provided for the insoluble pharmaceutical preparation of parenteral delivery is documented in United States Patent (USP) 5,145, in 684.' 684 patent disclosures in the presence of surface modifier wet grinding soluble drug not, so that the drug particles of average effective particle diameter less than 400nm to be provided.Surface modifier is adsorbed on the surface of drug particles, presents in an amount at least sufficient to prevent to be condensed into larger particle.
The another kind that is provided for the insoluble pharmaceutical preparation of parenteral delivery attempts being documented in United States Patent (USP) 5,922, in 355.' 355 patent disclosures by using the mixture of surface modifier and phospholipid, use such as sonicated then, homogenize, grinding, Micro Fluid, separate out or technology such as recrystallization reduces particle diameter, the not nanometer size particles of soluble drug is provided.In ' 355 patents, openly do not change processing conditions to make the crystal of more frangible form.
United States Patent (USP) 5,780,062 discloses the not short grained method of soluble drug of a kind of preparation, comprise (1) dissolved substance in mixable first solvent of water, (2) medicine is second solution for preparing polymer and amphiprotic substance in insoluble basically aqueous second solvent therein, thereby form the solution that first and second steps are mixed in polymer/amphiprotic substance complex and (3), separate out the agglomerate of medicine and polymer/amphiprotic substance complex.
United States Patent (USP) 5,858,410 disclose a kind of medicinal nano suspended substance that is suitable for parenteral.' 410 patents have been put down in writing a kind of method that makes dispersive at least a solid-state therapeutical active compound in the solvent carry out high pressure homogenizing in piston-clearance-type homogenizer.Measure according to photon correlation spectroscopy (PCS), the particulate average diameter that forms is 10nm～1000nm, in total amount greater than 5 microns granule ratio less than 0.1% (by Coulter enumerator mensuration distributed number), do not change into molten mass in advance.Jet grinding before homogenizing is disclosed among the embodiment of ' 410 patents.The use of solvent is hindered, and forms excessive crystal because this use makes.
United States Patent (USP) 4,997,454 disclose a kind of particulate method of making uniform-dimension from solid chemical compound.This method may further comprise the steps: dissolved solid chemical compound in the solvent that is fit to, liquid is separated out in injection then, thereby separates out the granule of even average diameter basically of non-cohesion.Make granule and separated from solvent then.' 454 patents are not advocated to form the crystalline state granule, because in precipitation process, crystal may dissolve and recrystallization, thereby has widened particle size distribution range.' 454 patents encourage to capture the granule of meta particulate form in precipitation process.
United States Patent (USP) 5,605,785 disclose a kind of method that forms the nanometer amorphous dispersions of photographic compound.The method of this formation nanometer amorphous dispersions comprises any known emulsification method that is used to produce the decentralized photo with amorphous granular.
U.S.2002/0127278A1 discloses a kind of particulate method of organic compound for preparing submicron-scale.
United States Patent (USP) 6,607,784 disclose a kind of particulate method of organic compound for preparing submicron-scale, its dissolubility in mixable first solvent of water is than big in aqueous second solvent, this method may further comprise the steps: (i) be dissolved with organic compounds in mixable first solvent of water, form solution, (ii) make the solution and second solvent, obtain pre-suspended substance; And (iii) apply energy to pre-suspended substance, form the granule of average effective particle diameter 400nm～2 microns.
B. about the background of indole derivatives and its purposes as anticarcinogen
The open 2002/0091124A1 of the U.S. discloses indole and assorted indole derivatives and as the purposes of anticarcinogen.
United States Patent (USP) 6,008,231; 6,232,327 and 6,693,119 disclose indole-3-acetaldehyde amide that N-replaces, preparation method and be used for the treatment of cancer, asthma, the purposes of Sensitive disease and as the purposes of immunosuppressant.This chemical compound is particularly suitable for treating the tumor of anti-anticarcinogen, metastatic carcinoma (comprise metastatic carcinoma development and diffusion), and to the tumor of angiogenesis inhibitor sensitivity, perhaps anti-anticarcinogen and to the tumor of angiogenesis inhibitor sensitivity.
The open 2003/0195244A1 of the U.S. discloses benzazolyl compounds and it is used for the treatment of the purposes of cancer and angiogenesis associated conditions.The preparation or the purposes of this derivates nanometer granular preparation are not disclosed in 2003/0195244A1.
The open 2004/0033267A1 of the U.S. discloses the Nanoparticulate compositions that comprises angiogenesis inhibitor.
C. about the background of Antitubulin
In mitosis, the DNA of cell is replicated, and splits into two new cells then.This chromosome that will newly duplicate is divided into two processes that form cells and relates to and spin the Duo fiber, and the long-chain formation of the less protein subunit of microtubule by being known as tubulin itself with the microtubule structure.Spin the Duo microtubule and be connected, and a chromosome that duplicates is moved to a side of somatoblast with the chromosome that duplicates.Do not have these microtubules, cell division is impossible.Referring to, Cancerquest (2003): " other apy of Cancer Treatments-Chem "
Www.cancerquest.org/index.cfm7page=520Or similar network address.
Therefore, microtubule is the most important subcellular fraction target of anticancer chemotherapy, because they are present in all cells, and for (for example transportation in the cell of mitosis, interkinesis and cell maintenance function, the maintenance of development and cell shape, cell mobility, and molecule may distribute on cell membrane) be necessary.May separate out and isolate and intervene cell cycle by making tubulin with the interactional chemical compound of tubulin, thereby interrupt the multiple important biomolecule function that depends on the subcellular organelle of microtubule class.Therefore, this chemical compound may suppress to come from the propagation of the tumor cell line of various organs potentially.Referring to, for example, people such as Bacher, (2001) Pure Appl.Chem.73:9459-1464 and Rowinsky ﹠amp; Donehower (1991) Pharm α c.Ther.52:35-84.
The anti-mitosis medicine of one class marked feature and clinical use is a natural origin, that is, and and taxanes (paclitaxel, Ramulus et folium taxi cuspidatae terpene), vinca alkaloids (vincristine, vinblastine, Herba Catharanthi Rosei) and podophyllotoxin/colchicine.These medicaments or suppress the polymerization of tubulin (vinca alkaloids/Colchicine) or prevent that microtubule (taxane) from decomposing.The major defect of taxane and vinca alkaloids is, the neurotoxicity that the microtubule function in the aixs cylinder of carrying owing to pharmaceutical intervention mediation neuron vesicle develops.
Ebomycin A and B and analog thereof show high cell toxicity and good microtubule stability.These natural products are separated from slime bacteria at first.Compare with taxane, unique ability and good solubility that they suppress the tumor cell line of anti-the taxol are great advantage.Yet the complicated chemical constitution and the restricted use and the chemical sproof formation of natural origin have often limited the potentiality of these natural products.
The feature of other natural products or derived analogs is that dissolubility or ability strengthen, but chemical constitution is still complicated.
D. about the background of Indibulin
New synthesized micromolecule chemical entities combines with tubulin, but is not the substrate of striding membrane pump, and the function of also nonintervention aixs cylinder microtubule will strengthen the therapeutic index of treatment malignant tumor greatly.
A series of synthetic and the bonded molecules of tubulin are just estimated before clinical or in the clinical commitment at present.Synthetic compound wherein, N-(pyridin-4-yl)-[1-(4-benzyl chloride base)-indol-3-yl] glyoxamides is called D-24851, is also referred to as " Indibulin ".
D-24851 is a kind of synthetic micromolecule indole Antitubulin, has remarkable vitro and vivo antitumor activity.It makes the microtubule instability in tumor cell and the cell-free system.It is not overlapping with the tubulin-binding site of unstable agent vincristine of the microtubule of marked feature or colchicine that the binding site of D-24851 seems.In addition, this molecular selectivity is blocked the cell cycle progress of metaphase of cell division.
External, D-24851 brings into play tangible active anticancer for various malignant tumor (for example, prostate, brain, breast, pancreas, and colon).In animal, D-24851 demonstrates high anti-tumor in vivo and renders a service.Based on its mechanism of action, expect that it is a target with all types of solid tumors.Also expection shows asthma, antiallergic, immunosuppressant and immunoregulation effect.In zoopery, do not find nervous symptoms so far.Rodentine clinical before the experiment in, chemical compound has fabulous toleration to efficient dosage.Another advantage that further develops is, compares with other tubulins-inhibition chemical compound, and it is easy to synthesize.
Other tubulins of indole chemical classes suppress chemical compound and also have been identified the potential drug candidate that has the similar action pattern as to Indibulin, include but not limited to D-64131, the 2-(hetero) aryl indole derivatives, be documented in " New Small-Molecule Tubulin Inhibitors ", Pure Appl.Chem., Vol.73, No.9 is in 2001.
Summary of the invention
The present invention relates to the particulate composition of indoles Antitubulin.Preferred compositions comprises the aqueous suspension with the nano-particle of the indoles Antitubulin of at least a surfactant coating, and described surfactant is selected from ionic surface active agent, non-ionic surface active agent, zwitterionic surfactant, biologically-derived surfactant, aminoacid and derivant thereof and combination thereof.
Described compositions can be administered to animal, and is particularly human.The method that gives that described compositions is relevant with it provides multiple advantage, comprises the ability that described compositions is carried by parenteral or orally give, reduces toxicity and increases bioavailability.In addition, because granule of the present invention (for example, nano-particle) constituted a high proportion of antitublin, therefore nanoparticle suspension body of the present invention contains the excipient of obvious low concentration, as surfactant or other solubilizing agents, the medicament solubilising that other situations then need a large amount of excipient to make to give.The excipient level reduces makes activating agent dosage obviously higher (because excipient low concentration, so the complication that excipient causes descends).In addition, the preferred suspended substance of the present invention contains a small amount of solvent to there not being solvent, thereby makes activating agent dosage bigger, has reduced the solvent toxicity to the experimenter simultaneously.
When preparation of the present invention is provided, can avoid multiple shortcoming of the prior art.These shortcomings comprise toxicity, to the ineffectivity of multidrug resistance (MDR) tumor, and low absorption rate, the bioavailability of difference and complicated chemical constitution (make to synthesize and become difficult).
The invention still further relates to the method for the particulate composition of making Antitubulin, comprise the granule of at least a Antitubulin chemical compound of preparation and at least a surfactant of choosing wantonly, and the granule that preparation obtains in the drug administration carrier that is fit to.Preferable methods relates to the aqueous class nanoparticle suspension body that preparation is used for the Antitubulin that parenteral gives.
The invention still further relates to treatment mammal-preferred people experimenter's method, by treating the microtubulin-resisting suspended substance of effective dose.Preferably, that the compositions that gives will provide will be anticancer, asthma, antiallergic, immunosuppressant or immunoregulatory activity.Most preferred method relates to the Indibulin nanoparticle suspension body that is used for the treatment of cancer.
Will clearer other advantages of the present invention and each side by reading following detailed description of the present invention.
Description of drawings
Fig. 1 is the figure that intravenous injection compositions 4 and 5 compares the D-24851 blood plasma level afterwards;
Fig. 2 shows that vein gives to Canis familiaris L.-Di 1 day (compositions 4) the mean plasma concentration figure of D-24851;
Fig. 3 shows that vein gives to Canis familiaris L.-Di 27 days (compositions 4) the mean plasma concentration figure of D-24851;
Fig. 4 illustrates method " A ", a kind of method for optimizing of making particle suspension; And
Fig. 5 schematically shows method " B ", a kind of method for optimizing of making particle suspension.
Fig. 6 be comparison in Rat AH 13 tumor models D-24851 nanoparticle suspension body (compositions 4) dosage correlation and the figure of contrast solution.
Fig. 7 shows D-24851 nanoparticle suspension body (compositions 4) the plasma concentration figure afterwards that gives various dose at the rat medium-sized vein,
Fig. 8 shows at the rat medium-sized vein to give D-24851 nanoparticle suspension body (compositions 4) afterwards at the plasma concentration figure of the 1st day and the 15th day.
The specific embodiment
Although the present invention has multiple multi-form embodiment, below will concentrate on the preferred embodiment of the invention, should be appreciated that these embodiments should be considered to explain principle of the present invention, and be not intended to limit broad aspect of the present invention.
In this application, use following several definition to describe the present invention.
" pact " should be understood by those of ordinary skills and to a certain degree variation arranged in using its context.If in using its context, the use of this term is unclear to those of ordinary skills, so " pact " will be used in reference to reach particular range add or deduct 10%.
At the pharmacokinetics performance of pharmaceutical composition, " bioavailability " is usually used in describing the interior performance of body of preparation in the art.The parameter (or bioavailability) that is usually used in describing performance in the body of preparation in the art is C
Max, the Cmax of activating agent in blood; T
Max, drug dose arrives C
MaxAfter the used time; And AUC (area under curve), the measuring of the medicine total amount that the patient absorbs.Therefore, at nanoparticle suspension body of the present invention, for given indole Antitubulin of the present invention, " improved bioavailability " refers to that the preparation outside this nanoparticle suspension body ratio nano particulate composition has improved performance (for example, improved C
Max, T
Max, AUC or other performance standards).With respect to the multiple dosage of other preparations that contain same medicine, this improved bioavailability also is applicable to the multiple dosage of nanoparticle suspension body of the present invention.Depend on administered agents dosage, the patient who is given and patient's disease severity to be treated, can increase or reduce C
Max, T
Max, AUC or other performance standard values are to obtain improved bioavailability.For example, if for the C of given medicine
MaxNeed reduce to improve the effectiveness (that is, effect and safety) of medicine, so when giving nanoparticle suspension body of the present invention, with contain same medicine other give preparation and compare C
MaxReduce to have improved bioavailability.Equally, if T
MaxNeed to increase to improve the effectiveness of medicine, the nanoparticle suspension body of the present invention of this parameter increase will have improved bioavailability so.
At surfactant or other excipient of granule (for example, nanometer or micron particle) compositions, " coating " refers near this chemical compound is present in particle surface or its.Can coat partially or completely with this chemical compound with this chemical compound " coating " particle, and this chemical compound can partly be entrained in the particle, perhaps not be entrained in the particle.
" frangible " refers to the frangible and easier more particle of small-particle that is broken into.
" micron suspended substance " refers to the suspended substance of micron particle, and unless otherwise prescribed, " micron particle " refers to the about 200nm of mean diameter～about 5 microns activating agent particle.
" nanoparticle suspension body " refers to the suspended substance of nanoparticle, and unless otherwise prescribed, " nanoparticle (nanoparticle) " and " nano-particle (nanoparticulate) " refers to the about 15nm of mean diameter～about 2 microns activating agent particle." particle suspension body " refers to the particle suspension body that various sizes distribute.
Among the present invention, " particle diameter " or " size " (at particle) measured based on the volume weight average particle diameter, according to well known to a person skilled in the art that conventional grain diameter measurement technology measures.This technology comprises for example sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugal, light microscope method or electron microscope method.
" pre-suspended substance " refers to it can is amorphous, hypocrystalline or crystalline solid dispersion, and its size fully is not reduced to required scope and/or needs energy input to come the stabilization of solid dispersion.
" poorly water-soluble " refers to that the water solubility of chemical compound is less than about 10mg/ml.
At stable drug particle, " stable " refer to that the Antitubulin granule does not have remarkable flocculation or coagulation or otherwise increases particle diameter.
" slow release " showed and given nanoparticle suspension body of the present invention, wherein the valid density of the active pharmaceutical ingredient in giving the back blood flow was kept in the long relatively time, or kept the longer time than the valid density behind other preparations that contain identical active pharmaceutical ingredient.
" treatment effective dose " refers to provide the drug dose that improves effect to the experimenter who gives usually.Should be emphasized that, because the variation of morbid state and individual reaction, under specific circumstances, " the treatment effective dose " that gives the particular subject present composition is always not effective for the described disease of treatment, even this dosage is thought " treatment effective dose " by those skilled in the art.Be also to be understood that under specific circumstances, in parenteral or oral agents, measure drug dose, or in blood or blood plasma, measure levels of drugs.
" toleration " refer to individual accept to give continuously, the ability of bolus agent, multiple dose or more heavy dose of nanoparticle suspension body of the present invention (containing active pharmaceutical ingredient) of giving than other preparations by identical active pharmaceutical ingredient, be not harmful to or unwanted effect, perhaps reduce with respect to harmful for the effect that gives these other preparations of class in the individuality or unwanted effect, no matter and be continuously, bolus agent or multiple dose scheme give this preparation.
Chemical compound/particle
Following term has the implication in the description of the present invention:
Term " free hydroxyl " refers to the OH base.Term " sense modify hydroxyl " refers to functionalised the OH base that forms following material: ether, alkyl wherein, aryl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, acyl group alkyl, alkynyl, or heteroaryl replacement hydrogen; Ester, wherein acyl substituted hydrogen; Carbamate, wherein aminocarbonyl replaces hydrogen; Or carbonic ester, wherein aryloxy group-, heteroaryloxy-, alkoxyl-, cycloalkyloxy-, the heterocycle alkoxyl-, alkene oxygen base-, cyclenes oxygen base-, heterocycle alkene oxygen base-, or alkynyloxy group-carbonyl substituted hydrogen.Preferred part comprises OH, OCH
2C (O) CH
3, OCH
2C (O) C
2H
5, OCH
3, OCH
2CH
3, OC (O) CH
3, and OC (O) C
2H
5
Term " free amino group " refers to NH
2Term " amino that sense is modified " refers to functionalised the NH that forms following material
2Base: aryloxy group-, heteroaryloxy-, alkoxyl-, cycloalkyloxy-, the heterocycle alkoxyl-, thiazolinyl-, cycloalkenyl group-, heterocycloalkenyl-, alkynyl-, or hydroxyl-amino, wherein the group that is fit to replaces a hydrogen; One of aryl-, heteroaryl-, alkyl-, cycloalkyl-, Heterocyclylalkyl-, thiazolinyl-, cycloalkenyl group-, heterocycloalkenyl-, the acyl group alkyl, or alkynyl-amino, wherein the group of Shi Heing replaces one or two hydrogen; Amide, wherein hydrogen of acyl substituted; Carbamate, wherein aryloxy group-, heteroaryloxy-, alkoxyl-, cycloalkyloxy-, the heterocycle alkoxyl-, thiazolinyl-, cycloalkenyl group-, heterocycloalkenyl-, or hydrogen of alkynyl-carbonyl substituted; Or urea, wherein aminocarbonyl replaces a hydrogen.These combinations that replace forms also fall in the amino definition that sense modifies and comprise within the scope of the invention, for example one of them hydrogen by alkyl replace, the NH of another hydrogen alkoxy carbonyl substituted
2Preferred part comprises NH
2, NHCH
3, NHC
2H
5, N (CH
3)
2, NHC (O) CH
3, NHOH, and NH (OCH
3).
Term " free mercapto " refers to the SH base.Term " sense modify mercapto " refers to functionalised the SH base that forms following material: thioether, alkyl wherein, aryl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, alkynyl, acyl group alkyl, or heteroaryl replacement hydrogen; Or thioesters, wherein acyl substituted hydrogen.Preferred part comprises SH, SC (O) CH
3, SCH
3, SC
2H
5, SCH
2C (O) C
2H
5, and SCH
2C (O) CH
3
Term " acyl group " representative is by having the two keys that are attached on the oxygen atom and being attached to the group that the single bonded carbon atom on another carbon atom couples together.
Term " alkyl " comprises the aliphatic alkyl of saturated straight or branched, and promptly they do not contain carbon-carbon double bond.Alkyl can insert one or more hetero atoms, as oxygen, nitrogen or sulfur, can replace with other groups, and as halogen, hydroxyl, aryl, cycloalkyl, aryloxy group, or alkoxyl.The alkyl of preferred straight or branched comprises methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl, isobutyl group, and the tert-butyl group.
Term " cycloalkyl " comprises that being connected to form one or more can be to condense or isolating ring, straight or branched, saturated or undersaturated aliphatic alkyl.Ring can replace with other groups, as halogen, and hydroxyl, aryl, aryloxy group, alkoxyl, or alkyl.Preferred cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, and suberyl.
Term " Heterocyclylalkyl " refers to contain at least one hetero atom such as O, S or N, can be to condense or isolating cycloalkyl ring in ring.Ring can replace with other groups, as halogen, and hydroxyl, aryl, aryloxy group, alkoxyl, or alkyl.Preferred Heterocyclylalkyl comprises pyrrolidinyl, tetrahydrofuran base, piperazinyl, piperidyl, morpholinyl, and THP trtrahydropyranyl.
Term " thiazolinyl " comprises the alkyl of the straight or branched with at least one carbon-carbon double bond, and its chain can randomly insert one or more hetero atoms.Its chain hydrogen can replace with other groups, as halogen.The thiazolinyl of preferred straight or branched comprises pi-allyl, 1-butylene base, 1-methyl-2-acrylic and 4-pentenyl.
Term " cycloalkenyl group " comprises straight or branched, saturated or undersaturated aliphatic alkyl is connected to form one or more non-aromatic rings that contain carbon-carbon double bond, and it can be to condense or isolating.Ring can replace with other groups, as halogen, and hydroxyl, alkoxyl, or alkyl.Preferred cycloalkenyl group comprises cyclopentenyl and cyclohexenyl group.
Term " heterocycloalkenyl " refers to contain one or more hetero atoms such as O, N or S, can be to condense or isolating cyclenes basic ring in ring.Ring can replace with other groups, as halogen, and hydroxyl, aryl, aryloxy group, alkoxyl, or alkyl.Preferred heterocycloalkenyl comprises pyrrolidinyl, dihydro pyranyl and dihydrofuran base.
Term " carbonyl " representative and the double linked carbon atom of oxygen atom, wherein carbon atom has two free valence states.
The amino that on behalf of its nitrogen-atoms and the bonded freedom of carbonylic carbon atom or sense, term " aminocarbonyl " modify, carbonyl itself combines with another atom by its carbon atom.
Fluorine represented in term " halogen ", chlorine, bromine, or iodine.
Term " aryl " refers to aromatic carbocyclic ring.Ring can be isolating, as phenyl, maybe can be condensed, as naphthyl.Ring hydrogen can replace with other groups, as alkyl, and halogen, free or functionalized hydroxyl, trihalomethyl etc.The example of aryl comprises the phenyl of phenyl and replacement, as 2-, and 3-, or 4-halogenophenyl, alkyl phenyl, and 3-(trifluoromethyl) phenyl.
Term " aralkyl " refers to the alkyl that at least one hydrogen on the alkyl substituent is wherein replaced by aryl.Its example comprises the benzyl of benzyl and replacement, as 2-, and 3-, or (4-halogenophenyl) methyl and (4-alkyl phenyl) methyl.
Term " heteroaryl " refers to contain at least a hetero atom such as O in ring, S, or the aromatic hydrocarbon ring of N.Heteroaryl ring can be isolating, has 5～6 annular atomses, maybe can be condensed, has 8～10 atoms.Having open valent heteroaryl ring hydrogen or hetero atom can replace with other groups, as alkyl or halogen.The example of heteroaryl comprises imidazoles, pyridine, indole, quinoline, furan, thiophene, benzothiophene, pyrroles, pyrazoles ， oxazole ， isoxazole, thiazole, tetrahydroquinoline, benzofuran, Dihydrobenzofuranes and dihydrobenzo indole.
Term " aryloxy group ", " heteroaryloxy ", " alkoxyl ", " cycloalkyloxy ", " heterocycle alkoxyl ", " alkene oxygen base ", " cyclenes oxygen base ", " heterocycle alkene oxygen base ", the aryl of representing logical peroxide bridge to be connected respectively with " alkynyloxy group ", heteroaryl, alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, or alkynyl.
Term " alkoxy carbonyl ", " aryloxycarbonyl ", " heteroaryloxy carbonyl ", " cyclo alkoxy carbonyl ", " heterocycle alkoxy carbonyl ", " allyloxycarbonyl ", " ring allyloxycarbonyl ", " heterocycle allyloxycarbonyl " and " alkynyloxy group carbonyl " represents its oxygen atom and the bonded alkoxyl of carbonylic carbon atom respectively, aryloxy group, heteroaryloxy, cycloalkyloxy, the heterocycle alkoxyl, alkene oxygen base, cyclenes oxygen base, heterocycle alkene oxygen base, or alkynyloxy group, carbonyl itself combines with another atom by its carbon atom.
Indole Antitubulin chemical compound of the present invention is general formula (1):
Formula (1)
Wherein:
X is a hydrogen, halogen, and alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, acyl group, carboxyl (C=OOR), alkoxyl, hydroxyl, the hydroxyl (for example, acyloxy) that sense is modified, aryl, heteroaryl,
Wherein Y and Z are NR independently, O, or S, and wherein R is a hydrogen, alkyl, aryl, acyl group, cycloalkenyl group, heterocycloalkenyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aminocarbonyl,
R
3And R
3' be alkyl independently, aryl, heteroaryl,
Or X is NR
8R
9, wherein, R
8And R
9Be hydrogen independently, alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, acyl group, aryl, or heteroaryl;
A, B, C and D are nitrogen or carbon independently,
Condition is if A is a nitrogen, so R
4Do not exist, and if A be carbon, R so
4Be hydrogen, halogen or alkyl;
If B is a nitrogen, so R
5Do not exist, and if B be carbon, R so
5Be hydrogen, halogen or alkyl;
If C is a nitrogen, so R
6Do not exist, and if C be carbon, R so
6Be hydrogen, halogen or alkyl;
If D is a nitrogen, so R
7Do not exist, and if D be carbon, R so
7Be hydrogen, halogen or alkyl;
R
1Be hydrogen, alkyl, alkaryl, acyl group, or aryl; And
R
2Be hydrogen, alkyl, acyl group, aryl, alkoxy carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, cyclo alkoxy carbonyl, heterocycle alkoxy carbonyl, allyloxycarbonyl, ring allyloxycarbonyl and heterocycle allyloxycarbonyl.
Preferably, R
1Be the benzyl that replaces, more preferably halogeno-benzyl (2-, 3-, or (4-halogenophenyl) methyl), most preferably (4-chlorphenyl) methyl.
Preferably, R
4, R
5, R
6, and R
7It is hydrogen atom.
Preferably, R
3Or R
3' be hydrogen, another substituent group (R
3Or R
3') be pyridine radicals (pyridine ring).More preferably, R
3Or R
3' be hydrogen, another substituent group (R
3Or R
3') be the 4-pyridine radicals.
The preferred substance of indole Antitubulin of the present invention is those (what particularly N-replaced replaces with 3-) of record in United States Patent (USP) 2003/0195244, and it is introduced into the present invention as a reference and become a part of the present invention.
The preferred substance of indole Antitubulin of the present invention is those (2-acyl indol classes) of putting down in writing in the open 2002/0091124A1 of the U.S., and it is introduced into the present invention as a reference and become a part of the present invention.
The most preferably material of indole of the present invention is in United States Patent (USP) 6,008,231; In 6,232,327 and 6,693,119 record those (N-replace indole-3-acetaldehyde amides), it is introduced into the present invention as a reference and become a part of the present invention.
The most preferred indole of the present invention is D-24851, has the chemical constitution of formula 2:
Formula (2).
Indole of the present invention can be synthetic by method known to those skilled in the art, and these methods are disclosed in the aforementioned patent and publication that is incorporated herein by reference.
The amount of one or more Antitubulins is about 0.01%～about 20% weight/volume (w/v) in the compositions of the present invention, preferred about 0.05%～about 15%w/v, more preferably from about 0.1%～about 10%w/v.
Its distribution of sizes of particle of the present invention comprises activating agent with multiple factors vary, the surfactant of existence, dosage regimen and dosage.Usually, its distribution of sizes of granule is about 15nm～50 micron, preferably about 50nm～10 microns, more preferably from about 50nm～2 micron.When the particle that gives was injected in preparation, they had effective grain size.Preferably, this particle size will be less than about 5 microns (micron particles), and more preferably, size is less than about 2 microns (nanoparticles).
Surfactant/suspended substance
Be used in the present invention that the suitable surfactant of coated particle can be selected from ionic surface active agent, non-ionic surface active agent, zwitterionic surfactant, phospholipid, biologically-derived surfactant or aminoacid and derivant thereof.Ionic surface active agent can be an anion or cationic.The amount of surfactant in compositions is about 0.01%～10%w/v, preferred about 0.05%～about 5%w/v.
The anion surfactant that is fit to includes but not limited to: alkylsulfonate; arylsulphonate; alkylphosphonic, alkyl phosphonate, potassium laurate; sodium lauryl sulfate; sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate; phosphatidic acid and its salt; sodium carboxy methyl cellulose, cholic acid and its salt (for example, cholic acid; deoxycholic acid; glycocholic acid; the salt of taurocholic acid and glycodesoxycholic acid); with carboxy methyl cellulose calcium; stearic acid and its salt (for example, sodium stearate and calcium), phosphate; sodium lauryl sulphate; carboxy methyl cellulose calcium, sodium carboxy methyl cellulose, dioctyl sulfo-sodium succinate (DOSS); the dialkyl of sulfo-sodium succinate, sodium lauryl sulfate and phospholipid.
The cationic surfactant that is fit to includes but not limited to: quaternary ammonium compound; benzalkonium chloride, cetyl trimethylammonium bromide, chitosan; lauryl dimethyl benzyl ammonium chloride; the fatty acyl carnitine hydrochlorate, alkyl halide pyridine, cetyl pyridinium chloride; cation lipid; the polymethyl methacrylate trimethylammonium bromide, sulfonium compound, polyvinylpyrrolidone-2-dimethyl amino ethyl methacrylate Dimethylsulfate; cetyl trimethyl ammonium bromide; phosphonium compounds, quaternary ammonium compound, benzyl-two (2-chloroethyl) ethyl ammonium bromide; the Oleum Cocois trimethyl ammonium chloride; the Oleum Cocois trimethylammonium bromide, Oleum Cocois methyl dihydroxy ethyl ammonium chloride, Oleum Cocois methyl dihydroxy ethyl ammonium bromide; the decyl triethyl ammonium chloride; the decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl ethoxy chlorine ammonium bromide, C
12-15-dimethyl hydroxyethyl ammonium chloride, C
12-15-dimethyl ethoxy chlorine ammonium bromide, Oleum Cocois dimethyl hydroxyethyl ammonium chloride, Oleum Cocois dimethyl ethoxy ammonium bromide, myristyl trimethyl methylsulfuric acid ammonium, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethyleneoxy)
4Ammonium chloride, lauryl dimethyl (ethyleneoxy)
4Ammonium bromide, N-alkyl (C
12-18) dimethyl benzyl ammonium chloride, N-alkyl (C
14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide alkyl-leptodactyline, dialkyl group-dimethyl ammonium, lauryl trimethyl ammonium chloride, the alkyl amido alkyl dialkyl ammonium salt of ethoxylation, the trialkyl ammonium salts of ethoxylation, the dialkyl benzene dialkylammonium chloride, the N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C
12Trimethylammonium bromide, C
15Trimethylammonium bromide, C
17Trimethylammonium bromide, dodecylbenzyl triethyl ammonium chloride, diallyl dimethyl ammoniumchloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three cetyl ammonio methacrylates, the decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride, " POLYQUAT 10 " (mixture of polymeric quaternary ammonium compound), tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester, benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride (stearalkonium chloride), cetyl bromination pyridine, cetyl pyridinium chloride, the halide salt of quaternised polyoxy ethyl alkylamine, Fixanol, amine, amine salt, the acid imide kazoe, protonated season acrylamide, methylated quaternary polymers, cation guar gum, benzalkonium chloride, Dodecyl trimethyl ammonium chloride, triethanolamine, and poloxamine.
The ionic surfactant pack that is fit to is drawn together but is not limited to: polyoxyethylene aliphatic alcohol ether, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, sorbitol ester, glyceride, glyceryl monostearate, Polyethylene Glycol, polypropylene glycol, polypropylene glycol ester, cetyl alcohol, 18 hexadecanol, stearyl alcohol, the aralkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer, poloxamer, poloxamine, methylcellulose, hydroxylated cellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, noncrystalline cellulose, polysaccharide, starch, starch derivatives, hetastarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, the amine amide, dextran, glycerol, Radix Acaciae senegalis, cholesterol, tragacanth, glyceryl monostearate, 18 hexadecanol, cetomacrogol emulsifying is cured, sorbitol ester, polyoxyethylene alkyl ether, castor oil derivatives, the polyoxyethylene sorbitol fatty acid ester, Polyethylene Glycol, polyoxyethylene 8 stearate salt, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, Hydroxypropyl Methylcellulose Phathalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, the 4-(1 of oxirane and formaldehyde, 1,3, the 3-tetramethyl butyl) cascophen, poloxamer, alkyl aryl polyether sulfonate, the mixture of sucrose stearate salt and sucrose distearate, C
18H
37CH
2C (O) N (CH
3) CH
2(CHOH)
4(CH
2OH)
2The different Nonylphenoxy of p-gathers ((+)-2,3-Epoxy-1-propanol), capryl-N-methyl glucose amide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltose pyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl group-N-methyl glucose amide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-glucopyranoside; Pelargonyl group-N-methyl glucose amide; n-nonyl-β-D-glucopyranoside; caprylyl-N-methyl glucose amide; n-octyl group-β-D-glucopyranoside, octyl group-β-D-sulfo-glucopyranoside, PEG-cholesterol; the PEG-cholesterol derivative; the PEG-vitamin A, PEG-vitamin E, and the random copolymer of vinyl acetate and vinyl pyrrolidone.
Zwitterionic surfactant is electroneutral, but has local positive charge and negative charge at same intramolecularly.How clean electricity on the molecule can be depending on pH, and therefore when hanging down pH, some zwitterionic surfactants can be used as cationic surfactant, and when high pH, they can also be used as anion surfactant.The zwitterionic surfactant that is fit to includes but not limited to zwitterionic phospholipid.These phospholipid comprise phosphatidylcholine; PHOSPHATIDYL ETHANOLAMINE; diacyl-glyceroyl-phosphoethanolamine is (as two myristoyls-glyceroyl-phosphoethanolamine (DMPE); two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine (DPPE); distearyl-glyceroyl-phosphoethanolamine (DSPE); with two oleoyls-glyceroyl-phosphoethanolamine (DOPE); pegylated phospholipid; the PEG-phosphatidylcholine; PEG-diacyl-glyceroyl-phosphoethanolamine; the PEG-PHOSPHATIDYL ETHANOLAMINE; PEG-diacyl-glyceroyl-phosphoethanolamine; PEG-two myristoyls-glyceroyl-phosphoethanolamine; PEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine; PEG-distearyl-glyceroyl-phosphoethanolamine; PEG-two oleoyls-glyceroyl-phosphoethanolamine; methoxy poly (ethylene glycol) (mPEG)-phospholipid; the mPEG-phosphatidylcholine; mPEG-diacyl-glyceroyl-phosphoethanolamine, mPEG-PHOSPHATIDYL ETHANOLAMINE, mPEG-diacyl-glyceroyl-phosphoethanolamine; mPEG-two myristoyls-glyceroyl-phosphoethanolamine; mPEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine, mPEG-distearyl-glyceroyl-phosphoethanolamine and mPEG-two oleoyls-glyceroyl-phosphoethanolamine.
Can use the mixture of phospholipids that comprises anion and zwitterionic phospholipid in the present invention.This mixture includes but not limited to lysophosphatide, lecithin or soybean phospholipid or its any combination.
The biologically-derived surfactant that is fit to comprises but is not limited to: lipoprotein, gel, casein, lysozyme, albumin, casein, heparin, hirudin, or other albumen.
Preferred ionic surface active agent is a bile salts, and preferred bile salts is a NaTDC.Preferred nonionic is poly-alkoxyl ether, and preferably poly-alkoxyl ether is polyoxyethylene-polyoxypropylene triblock copolymer, as Poloxamer 188 and Poloxamer 407.Another kind of preferred surfactants is a lipid, and wherein poly-alkoxyl ether is covalently bound by ehter bond and lipid.Preferred this class surfactant is a pegylated phospholipid.Another kind of preferred surfactants be pegylated phospholipid methylation ether (for example, mPEG-DSPE).
In a preferred embodiment of the invention, particle suspending is in the aqueous medium that also comprises the pH regulator agent.The pH regulator agent that is fit to includes but not limited to sodium hydroxide, hydrochloric acid, tris buffer, monobasic, binary, tricarboxylic acid and its salt, citrate buffer, phosphate, glycerol-1-phosphate, glycerol-2-phosphate, acetate, lactate, three (methylol) aminomethane, amino sugar, one, two and trialkylated amine, meglumine (N-methyl glucoside amine), and aminoacid.Aqueous medium can also comprise osmotic pressure regulator, such as but not limited to glycerol, monosaccharide such as glucose, disaccharide such as sucrose, and trehalose and maltose, trisaccharide such as Raffinose, and sugar alcohol such as mannitol and sorbitol.
In embodiments of the invention, the aqueous medium of removing the particle suspension compositions forms dried granule.The method of removing aqueous medium can be any method as known in the art.An example is evaporation.Another example is lyophilizing.Dried granule can be mixed with any acceptable physical form, includes but not limited to solution, tablet, and capsule, suspended substance, cream, lotion, emulsion, aerosol, powder is added in reservoir or the matrix means with slow release (pasting as implant or skin) etc.Aqueous suspension of the present invention also can be freezing, the stability when storing to improve.Freezing aqueous suspension to be improving the common unsettled U.S. Patent application Serial No.10/270 that stability is disclosed in commonly-assigned us, and in 267, it is introduced into the present invention as a reference and become a part of the present invention.
Preferred compositions comprises the particulate aqueous suspension of the Antitubulin of 0.05%～10%w/v, with the ionic surface active agent of 0.05%～5%w/v (for example, dexycholate) or zwitterionic surfactant (for example, mPEG-DSPE), (for example gather alkoxyl ether with 0.05%～5%w/v, Poloxamer 188) and be used to regulate the glycerol coated particle of preparation osmotic pressure.
Particle suspension of the present invention can be by method known to those skilled in the art and these method preparations that the following describes.
Granule/suspended substance preparation method
The energy adding method of preparation particle suspension of the present invention is disclosed in the common unsettled U.S. Patent application Serial No.60/258 of commonly-assigned us, 160; 09/874,799; 09/874,637; 09/874,499; 09/964,273; 10,/03 5,821,60/347,548; 10/021,692; 10/183,035; 10/213,352; 10/246,802; 10/270,268; In 10/270,267 and 10/390,333; Introduce the present invention as a reference and become a part of the present invention.The general process of the suspended substance that preparation the present invention uses is as follows.
These methods can be divided into three major types.Each class methods has following steps: (1) dissolves the Antitubulin chemical compound in mixable first organic solvent of water, produce first solution; (2) second solvent of mixing first solution and water is separated out Antitubulin, produces pre-suspended substance; And (3) high shear mixing or heat form be added to energy in the pre-suspended substance, and the Antitubulin with required above-mentioned size range of stable form is provided.
Based on distinguishing three class methods by X-ray diffraction research, differential scanning calorimetry (DSC) research or other physical properties that are fit to the Antitubulin of research mensuration of adding before the step at energy and energy adds after the step.
I. first kind method
First kind method generally includes following steps: dissolve Antitubulin in mixable first solvent of water, make solution and aqueous solution then, form pre-suspended substance, wherein Antitubulin is studied according to X-ray diffraction, DSC, it is amorphous form, hemihedral crystal type or supercool liquid type that light or ultramicroscope or other analytical technologies are measured, and the average effective particle diameter is in above-mentioned effective grain size scope.Carry out energy behind the blend step and add step, and in preferred form of the present invention, be annealing steps.
II. second class methods
Second class methods comprise identical with first kind method step basically step, but following aspect difference.The X-ray diffraction of pre-suspended substance, DSC or other Antitubulins that the analysis showed that is fit to are crystal forms and have the average effective particle diameter.Antitubulin after energy adds step have with energy adding step before substantially the same average effective particle diameter, but compare with the granule of pre-suspended substance, more be difficult for being condensed into larger particle.Although be not limited to theory, think that granule stability difference may be owing to the reason in the rearrangement of solid-liquid interface place surfactant molecule.
III. the 3rd class methods
The 3rd class methods have been improved initial two steps of first and second class methods, to guarantee that the Antitubulin in the pre-suspended substance is the frangible form (for example, fine acicular and lamellar) with average effective particle diameter.By the solvent of selecting to be fit to, surfactant or combinations-of surfactants, the temperature of each solution, mixing ratio and precipitation rate etc. can form friable particle.Also can strengthen fragility by in the blend step of first solution and aqueous solution, introducing lattice defect (for example, the plane of fracture).This will be by the rapid crystallization realization that for example provides in separating out step.In energy adds step, that these frangible crystal change into dynamic stabilization and have a crystal less than the average effective particle diameter of pre-suspended substance.Dynamic stabilization is meant with the unsettled granule of kinetics and compares that the trend of particle aggregation reduces.In this case, energy adding step makes friable particle break and is coated with.Be in frangible attitude by the granule of guaranteeing pre-suspended substance, do not compare, organic compound can be formed in more easily and quickly the granule in the required size scope with there being to adopt the organic compound processing that makes its step that becomes frangible form.
Energy adds step can carry out by any way, and the cavitation erosion of wherein pre-suspended substance experience is sheared or impulsive force.In preferred form of the present invention, it is annealing steps that energy adds step.In the present invention, annealing is defined as by once or repeatedly applying energy (direct heating or mechanical stress), and thermal relaxation makes the unsettled material of thermokinetics change into the more process of stable form then.By making solid form change into more orderly lattice structure, can realize that energy reduces from more unordered.Selectively, by make the surfactant molecule rearrangement carry out this stabilisation at the solid-liquid interface place.
These three class methods are discussed respectively below.Yet, should be appreciated that, can the system of selection condition, as option table surface-active agent or combinations-of surfactants, dosage of surfactant, reaction temperature, the solution mixing ratio, precipitation rates etc. are so that pending any medicine is at following arbitrary apoplexy due to endogenous wind.
First kind method and the second and the 3rd class methods can be divided into two groups again, are respectively method A and the method B that is schematically shown among Fig. 4 and Fig. 5.
First solvent according to the present invention is solvent or the solvent mixture that wherein the relative dissolving of relating to organic compounds also can be miscible with second solvent.This solvent includes but not limited to the mixable proton compound of water, wherein hydrogen atom in the molecule and electronegative atom bonding, and as oxygen, nitrogen, or other families VA, VIA and VIIA in the periodic table of elements.The example of this solvent includes but not limited to alcohol, amine (uncle or secondary), oxime, Hydroxylamine HCL, carboxylic acid, sulfonic acid, phosphonic acids, phosphoric acid, amide and urea.
Other examples of first solvent also comprise aprotic organic solvent.In these aprotic solvent some can form hydrogen bond with water, but only as proton acceptor, effectively give the proton group because they lack.One class aprotic solvent is the dipolar aprotic solvent according to IUPAC (IUPAC Compendium of Chemical Terminology, second edition, 1997) definition:
A kind of have greater than about 15 the high relative dielectric constant and the solvent of sizable permanent dipole moment, and it can not be fit to labile hydrogen atom and form strong hydrogen bonding, for example dimethyl sulfoxide.
Dipolar aprotic solvent can be selected from: amide (replace fully, do not connect the nitrogen of hydrogen atom), urea (replace fully, do not connect the hydrogen atom of nitrogen), ether, cyclic ethers, nitrile, ketone, sulfone, sulfoxide, the phosphate ester of Qu Daiing fully, phosphonate ester, phosphamide, nitro compound etc.Dimethyl sulfoxide (DMSO), N-N-methyl-2-2-pyrrolidone N-(NMP), 2-Pyrrolidone, 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl acetylamide (DMA), dimethyl formamide (DMF) ， diox, acetone, oxolane (THF), tetramethylene sulfone (sulfolane), acetonitrile, and hexamethyl phosphoramide (HMPA), Nitrocarbol., 1,2-propylene glycol carbonic ester, they are members of this class.
Can also select common water immiscible, but under small size (less than 10%), have enough water solubilities, and under these volumes that reduce as the solvent of mixable first solvent of water.Example comprises aromatic hydrocarbon, alkene, alkane and halogenated aromatic thing, alkenyl halide and halogenated alkane.Aromatic substance includes but not limited to benzene (replacement or unsubstituted), monocycle or polycyclic aromatic hydrocarbon.The example of substituted benzene includes but not limited to dimethylbenzene (adjacent, or to) and toluene.The example of alkane includes but not limited to hexane, neopentane, heptane, isobutyltrimethylmethane., and cyclohexane extraction.The example of halogenated aromatic thing includes but not limited to chlorobenzene, bromobenzene, and chlorotoluene.The example of halogenated alkane and alkene includes but not limited to trichloroethane, dichloromethane, dichloroethanes (EDC) etc.
Other example of above-mentioned solvent based includes but not limited to: N-N-methyl-2-2-pyrrolidone N-(N-N-methyl-2-2-pyrrolidone N-), 2-Pyrrolidone (2-Pyrrolidone), 1; 3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide, dimethyl acetylamide; carboxylic acid (as acetic acid and lactic acid), and aliphatic alcohol (as methanol, ethanol; isopropyl alcohol, 3-amylalcohol and n-propanol); benzyl alcohol, glycerol, butanediol (1; the 2-butanediol, 1,3 butylene glycol; 1,4-butanediol and 2; the 3-butanediol), ethylene glycol, propylene glycol; the glyceride of list and diacylization, dimethyl Soquad, acetone; dimethyl sulfone, dimethyl formamide, 1; the 4-diox, tetramethylene sulfone (sulfolane), acetonitrile; Nitrocarbol., tetramethylurea, hexamethyl phosphoramide (HMPA); oxolane (THF), diethyl ether, t-butyl methyl ether (TBME); aromatic hydrocarbon, alkene, alkane; the halogenated aromatic thing, alkenyl halide, halogenated alkane; dimethylbenzene, toluene, benzene; the benzene that replaces, ethyl acetate, methyl acetate; butyl acetate, chlorobenzene, bromobenzene; chlorotoluene, trichloroethane, dichloromethane; dichloroethanes (EDC), hexane, neopentane; heptane, isobutyltrimethylmethane., cyclohexane extraction; Polyethylene Glycol (PEG), PEG ester, PEG-4; PEG-8; PEG-9, PEG-12, PEG-14; PEG-16; PEG-120, PEG-75, PEG-150; macrogol ester; the PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate; PEG-8 stearic acid cetylate; PEG-150 stearic acid cetylate, Polyethylene Glycol Sorbitol, PEG-20 Sorbitol isostearate; polyalkylene glycol monoalkyl ether; the PEG-3 dimethyl ether, PEG-4 dimethyl ether, polypropylene glycol (PPG); the polypropylene alginate esters; the PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether; the PPG-15 stearyl ether; propylene glycol dicaprylate/dicaprate, propylene glycol laurate, and Tetrahydrofurfuryl polyethylene glycol ether (tetrahydrofurfuryl alcohol polyglycol ether).
Preferred first solvent is N-N-methyl-2-2-pyrrolidone N-(NMP).Another kind of preferred first solvent is a lactic acid.
Second solvent is an aqueous solvent.This aqueous solvent can be a water itself.This solvent can also contain buffer, salt, surfactant, water-soluble polymer, and the combination of these excipient.
Method A
In method A, Antitubulin at first is dissolved in first solvent, produces first solution.Depend on the dissolubility of Antitubulin in first solvent, Antitubulin can add about 0.01%～about 20% weight/volume (w/v).May need concentrate is heated to about 100 ℃ from about 30 ℃, to guarantee in first solvent, dissolving Antitubulin fully.
Second aqueous solution contains one or more and is added to wherein surfactant.Surfactant can be selected from above-mentioned ionic surface active agent, non-ionic surface active agent, cationic surfactant, zwitterionic surfactant, phospholipid, or biologically-derived surfactant.
Also preferably the pH regulator agent is added in second solution, as sodium hydroxide, hydrochloric acid, aminoacid such as glycine, tris buffer or citrate, acetate, lactate, meglumine etc.Its pH of second solution is about 2～about 12.
Mix first and second solution then.Preferably, with may command speed first solution is added in second solution.Adding speed depends on the kinetics of separating out of material size and Antitubulin.Usually, for small scale experiments method (preparing 1 liter), added speed about 0.05cc/ minute～about 50cc/ minute.In adition process, constant agitation solution.Use the light microscope method to observe amorphous granular, the hypocrystalline solid, or supercool but liquid form pre-suspended substance.Described method is further comprising the steps of: make pre-suspended substance carry out annealing steps, make amorphous granular, supercool but liquid or hypocrystalline solid changes into the more crystallization of stable, solid.According to the dynamic light scattering method (for example, light is proofreaied and correct spectrum, laser diffraction, low angle laser light scattering (LALLS), middle angle laser light scattering (MALLS)), light transmission method method (Coulter method, for example), rheology, or microscopic method (light or electronics) measurement, the granule that obtains has the effective average particle size in the above-mentioned scope.
Energy adds step and comprises by following method adding energy: sonicated, homogenize, and counter-current flow (for example homogenizes, Mini DeBEE 2000 homogenizers, from BEE Incorporated, NC obtains, and wherein fluid jet leads along first path, and structure is inserted in first path, fluid is led with controlled stream once more along new path, makes fluid emulsifying or mixing), Micro Fluid, or ballistic additive method is provided, shear or cavitation erosion power.In this stage, sample can be cooled or heat.In a preferred form of the present invention, carry out annealing steps by homogenizing.In another preferred form of the present invention, anneal by ultrasonic Treatment.In another preferred form of the present invention, by using United States Patent (USP) 5,720, the emulsifying device described in 551 is annealed, and it is introduced into the present invention as a reference and become a part of the present invention.
Depend on annealing rate, the temperature that preferably will handle sample is adjusted to 30 ℃ from about 0 ℃.Selectively, in handling solid, carrying out required phase transformation, in annealing steps, also may need the thermoregulation of pre-suspended substance is arrived-30 ℃～about 100 ℃ temperature range approximately.
Method B
Method B is different with method A in the following areas.First difference is that surfactant or combinations-of surfactants are added in first solution.Surfactant can be selected from above-mentioned ionic surface active agent, non-ionic surface active agent, cationic surfactant, zwitterionic surfactant, phospholipid, or biologically-derived thing.The pharmaceutical suspension body that obtains from the method for the invention can be used as injection solution and directly gives, as long as use the solution disinfection device that is fit to.
Sterilization
By before mixing the pre-suspended substance of formation, make medicine concentrate (medicine, solvent and optional surfactant) and diluent media (water and optional buffer and surfactant) sterilization separately, can realize sterilizing.Sterilization method includes but not limited at first to filter by 0.45-micron particle filter then by 3.0 micron filter pre-filterings, steam or heating disinfection then, or by two unnecessary 0.2-micron membranes filter sterilised filtrations.
Prepare solvent-free suspended substance
Randomly, can make solvent-free suspended substance by after separating out, removing to desolvate.This can be by centrifugal, dialysis, and diafiltration, separate in the field of force, and high-pressure filteration or other isolation technics well known in the art realize.Usually remove lactic acid or N-N-methyl-2-2-pyrrolidone N-fully by 1～3 continuous centrifugal step; After each centrifugal, decant goes out supernatant and discards.Do not have the new volume suspended substance carrier of organic solvent to be added in the residual solid, mixture is disperseed.It should be appreciated by those skilled in the art that and in this reconstruction step, can use other high shear mixing technology.
The displacement excipient
In addition, use the described separation method of epimere, the excipient displacement that any unwanted excipient such as surfactant can more be needed.After centrifugal or filtration, solvent and initial excipient can discard with supernatant.Can add the suspended substance carrier that does not have solvent and do not have the new volume of first excipient then.Selectively, can add new surfactant.For example, centrifugal and remove supernatant after, by medicine, N-N-methyl-2-2-pyrrolidone N-(solvent), Poloxamer 188 (initial excipient), NaTDC, the suspended substance that G ﹠ W constitutes can be by phospholipid (new surfactant), the G ﹠ W displacement.
Lyophilizing
Forming freeze dried suspended substance by lyophilizing can dry suspended substance, reconstitutes the suspended substance that is suitable for giving.For preparing stable, dried solid, before lyophilizing, can add filler, as mannitol, sorbitol, sucrose, starch, lactose, trehalose or Raffinose.Can use any suitable freeze-drying process, make the suspended substance lyophilizing, for example:
Load down at+25 ℃
Arrive-45 ℃ at 1 hour internal cooling
3.5 hours-45 ℃ of retention times
Elevated temperature is to+15 ℃ continuously under pressure 0.4mbar, and on average drying is 33 hours
Following final dry 10 hours at+20 ℃ under pressure 0.03mbar
Cryoprotective agent: mannitol
Except above-mentioned little separation method, any other the known separation method that is used to prepare active agent particle (more preferably, nano-particle) in this area all can be used among the present invention.The example of other separation methods below is described.These examples only are used for explanation, are not intended to limit the scope of the invention.
The emulsion separation method
A kind of suitable emulsion is separated out technology and is disclosed in common U.S.Ser.No.09/964 unsettled, commonly-assigned us, and in 273, it is introduced into the present invention as a reference and become a part of the present invention.In this technology, this method may further comprise the steps: (1) provides the heterogeneous system with organic facies and water, has the medicine active compound in the organic facies; And (2) sonicated system, with evaporation organic facies part, separate out at aqueous phase and average effective particle diameter chemical compound less than about 2 μ m.Provide the step of heterogeneous system may further comprise the steps: (1) makes the immiscible solvent of water mix with the medicine active compound and forms organic solution, (2) preparing aqueous base solution and (3) of containing one or more surface active cpds makes organic solution and aqueous solution form heterogeneous system.The step of mixing organic facies and water can comprise use piston-clearance-type homogenizer, colloid mill, and high-speed mixing equipment, extrusion equipment manually stirs or shakes equipment, microfluidization device, or other provide the equipment or the technology of shear conditions.Coarse emulsion has diameter dimension in water approximately less than the oil droplet of 1 μ m.Coarse emulsion is formed microemulsion by sonicated, finally forms the nanometer size particles suspended substance.
The another kind of technology of preparation nanometer size particles is disclosed in common U.S.Ser.No.10/183 unsettled, commonly-assigned us, and in 035, it is introduced into the present invention as a reference and become a part of the present invention.This method may further comprise the steps: (1) provides the coarse dispersion of the heterogeneous system with organic facies and water, has medical compounds in the organic facies; (2) provide energy to form a differential prose style free from parallelism to coarse dispersion; (3) a freezing differential prose style free from parallelism; And (4) lyophilizing differential prose style free from parallelism obtains the medical compounds granule of submicron-scale.Provide the step of heterogeneous system may further comprise the steps: (1) makes the immiscible solvent of water mix with the medicine active compound and forms organic solution; (2) preparation contains the aqueous base solution of one or more surface active cpds; And (3) make organic solution and aqueous solution form heterogeneous system.The step of mixing organic facies and water comprises use piston-clearance-type homogenizer, colloid mill, and high-speed mixing equipment, extrusion equipment manually stirs or shakes equipment, microfluidization device, or other provide the equipment or the technology of shear conditions.
The anti-solvent of solvent is separated out
The anti-solvent of solvent that is fit to is separated out technology and is disclosed in United States Patent (USP) 5,118, and in 528 and 5,100,591, it is introduced into the present invention as a reference and become a part of the present invention.This method may further comprise the steps: (1) prepares the liquid phase of bioactive substance in solvent that can be added with one or more surfactants or solvent mixture; (2) second liquid phase of preparation non-solvent or non-solvent mixture, non-solvent can be miscible with the solvent or the solvent mixture of material; (3) stirring is added to the solution of (1) and (2) together down; And (4) remove undesired solvent, makes the colloidal suspension of nano-particle.' 528 patent disclosures at the material grains that does not have can make under the supplying energy less than 500nm.
Phase reversal is separated out
A kind of suitable phase reversal is separated out and is disclosed in United States Patent (USP) 6,235,224,6,143,211 and U.S. Patent application 2001/0042932 in, it is introduced into the present invention as a reference and become a part of the present invention.Phase reversal is to be used for describing the term that the dissolved polymers of continuous phase dicyandiamide solution changes into the physical phenomenon of solid macromolecule network, and wherein polymer is a continuous phase.Inducing a kind of method of phase reversal is that non-solvent is added in the continuous phase.The transformation of two-phase mixture from single-phase to unsettled takes place in polymer: the poor part of polymer rich part and polymer.The non-solvent micelle of polymer rich in mutually drips as nucleation site, and with polymer-coated.' 224 patent disclosures under certain conditions the phase reversal of polymer solution can spontaneous formation comprise the discrete micron particle of nano-particle.' 224 patent disclosures in solvent the dissolving or dispersed polymeres.Medicament also dissolves or is dispersed in the solvent.For making crystal become kind of step effective in the method, need medicament to be dissolved in the solvent.Polymer, medicament and solvent form the mixture with continuous phase together, and wherein solvent is a continuous phase.Then mixture is added in 10 times of excessive mixable non-solvents at least, make the medicament micron particle of mean diameter 10nm～10 μ m of spontaneous formation micro encapsulation.Particle diameter is subjected to solvent non-solvent volume ratio, polymer concentration, the viscosity of polymer-solvent solution, the influence of the characteristic that the molecular weight of polymer and solvent-nonsolvent are right.This method has for example avoided producing the step of microdroplet by the emulsion that forms solvent.This method has also been avoided stirring and/or shearing force.
The pH displacement is separated out
The step that technology is usually included in dissolved substance in the certain pH solution of medicine dissolution is separated out in pH displacement, changes pH then to the no longer dissolved step of medicine.Depend on specific medical compounds, pH can be tart or alkaline.Neutralization solution then forms the pre-suspended substance of the nanometer size particles of pharmaceutical active compounds.A kind of suitable pH displacement separation method is disclosed in United States Patent (USP) 5,665, and in 331, it is introduced into the present invention as a reference and become a part of the present invention.This method may further comprise the steps: in alkaline solution, make medicament with crystal growth modifier (CGM) dissolving, then in the surface modification that is fit to in the presence of the surfactant, with the microparticle dispersion of sour neutralization solution formation medicament.Can carry out the step that dispersion is cleaned in diafiltration after separating out step, then dispersion concentration is adjusted to desired level.It is reported that the Z-average diameter that the microcrystal grain that this method forms is measured according to photon correlation spectroscopy is less than 400nm.
Other examples of pH displacement separation method are disclosed in United States Patent (USP) 5,716,642; 5,662,883; 5,560,932; And in 4,608,278, it is introduced into the present invention as a reference and become a part of the present invention.
Inject separation method
The injection that is fit to is separated out technology and is disclosed in United States Patent (USP) 4,997, and in 454 and 4,826,689, it is introduced into the present invention as a reference and become a part of the present invention.At first, the solid chemical compound that dissolving is fit in the organic solvent that is fit to forms solvent mixture.Then, under-10 ℃ approximately～about 100 ℃ temperature, can inject solvent mixture with the non-solvent of separating out of immiscible organic solvent, the about 0.01ml/ of charge velocity minute～about 1000ml/ minute/the 50ml volume, make the particulate suspended substance of the non-condensed solids of the chemical compound of separating out, uniform basically average diameter is less than 10 μ m.It is preferred that the solution of separating out non-solvent is injected in stirring (for example, by stirring).Non-solvent can contain surfactant, with stable particle, prevents cohesion.Granule and separated from solvent then.Depend on solid chemical compound and required particle diameter, can change the parameters such as ratio, charge velocity, stir speed (S.S.) and volume of temperature, non-solvent and solvent according to the present invention.Particle diameter and non-solvent: the ratio and the implantation temperature of solvent volume are directly proportional, and are inversely proportional to charge velocity and stir speed (S.S.).It can be aqueous or nonaqueous separating out non-solvent, and this depends on the relative solubility of chemical compound and required suspending carrier.
The temperature displacement is separated out
Technology is separated out in temperature displacement, is also referred to as hot-melt technology, is disclosed in the United States Patent (USP) 5,188,837 of Domb, and it is introduced into the present invention as a reference and become a part of the present invention.In an embodiment of this invention, prepare the fat ball as follows: (1) is fusion or dissolving material such as medicine to be carried in melting carrier, forms the liquid of material to be carried; (2) under the temperature of the melt temperature that is higher than material or carrier, phospholipid and aqueous medium are added in fused material or the carrier together; (3) mix suspending body under the temperature of the melt temperature that is higher than carrier is up to obtaining uniform little preparation; (4) cool off preparation fast to room temperature or following then.
Solvent evaporation is separated out
Solvent evaporation is separated out technology and is disclosed in United States Patent (USP) 4,973, and in 465, it is introduced into the present invention as a reference and become a part of the present invention.' 465 patent disclosures prepare the method for crystallite, may further comprise the steps: (1) provides the pharmaceutical composition that is dissolved in the combination of shared organic solvent or solvent and the solution of phospholipid, (2) a kind of solvent of evaporation or multiple solvent and (3) make the membrane suspension that obtains by a kind of solvent in the vigorous stirring evaporation water solution or multiple solvent.Come to separate out chemical compound by add energy evaporation sufficient amount of solvent to solution except that desolvating.Also can remove and desolvate by other known technologies, as applying vacuum to solution, or above solution nitrogen blowing.
Reaction is separated out
The step that is included in dissolved substance chemical compound in the suitable solvent and forms solution is separated out in reaction.The addition of chemical compound should be in chemical compound saturation point or its time in solvent.By with chemical reagent reaction modified compound, or modify by adding energy such as heat or UV light etc., make the chemical compound of modifying in solvent, have more low solubility and separate out from solution.
Compressed fluid is separated out
The suitable technology of separating out by compressed fluid is disclosed in United States Patent (USP) 6,576, and in 264, it is introduced into the present invention as a reference and become a part of the present invention.This method is included in the step of dissolving water-insoluble drug in the solvent and forming solution.Then solution is sprayed in the entrance pressure contracted flow body, fluid can be gas, liquid or supercritical fluid.In the solution of solute, add compressed fluid, solute is reached or, and separate out microparticle near the over-saturation attitude at solvent.In this case, compressed fluid is as anti-solvent, and anti-solvent is used to reduce the cohesive energy metric density of the solvent of dissolved substance.
Selectively, medicine can be dissolved in the compressed fluid, sprays aqueous phase then.The fluidic solvent ability that the rapid expanding of compressed fluid reduces, this makes solute separate out as the microparticle of aqueous phase conversely.In this case, compressed fluid is as solvent.
Prepare particulate additive method
Also can prepare granule of the present invention by the mechanical lapping activating agent.Mechanical lapping comprises such as jet grinding, the pearl mill, and ball milling, sledge mill, technology such as fluid energy mill, or wet milling techniques, as be disclosed in United States Patent (USP) 5,145, those in 684, it is introduced into the present invention as a reference and become a part of the present invention.
The particulate another kind of method of preparation the present invention is the suspension activating agent.In this method, by directly being added to, granule forms pre-suspended substance in the aqueous medium, and the Dispersion of Particles that makes activating agent is in aqueous medium.Granule is coated with to suppress particle aggregation with surface modifier usually.One or more other excipient can be added in the activating agent or be added in the aqueous medium.
Embodiment 1: the suspended substance (compositions 1) for preparing (300g) D-24851 on a small scale
To contain 0.1% NaTDC, the aqueous tenside solution of 2.2% glycerol (stress drugs) and 0.142% sodium hydrogen phosphate (buffer) is cooled to low temperature (＜10 ℃).The lactic acid solution of D-24851 and Poloxamer 188 is added in the above-mentioned surfactant solution.Form suspended substance through mixing these two kinds of solution.Total suspended substance weight is 300g, about 1% (w/w) of drug level.Carry out high pressure homogenizing after separating out immediately, pressure is about 10,000psi, temperature＜70 ℃.The centrifugal lactic acid of removing, suspended substance homogenizes once more, and is about 10,000psi, temperature＜70 ℃.After homogenizing, use light scattering to detect the suspended substance particle diameter.The about 190nm of mean diameter.
Embodiment 2: preparation 2, the suspended substance of 000g D-24851 (compositions 2)
To contain 0.1% NaTDC, the aqueous tenside solution of 2.2% glycerol (stress drugs) and 0.142% sodium hydrogen phosphate (buffer) is cooled to low temperature (＜10 ℃).The lactic acid solution of D-24851 and Poloxamer 188 is added in the above-mentioned surfactant solution.Form suspended substance through mixing these two kinds of solution.Total suspended substance weight is 2,000g, about 1% (w/w) of drug level.Carry out high pressure homogenizing after separating out immediately, pressure is about 10,000psi, temperature＜70 ℃.The centrifugal lactic acid of removing, suspended substance homogenizes once more, and is about 10,000psi, temperature＜70 ℃.After homogenizing, use light scattering to detect the suspended substance particle diameter.The about 325nm of mean diameter.
Embodiment 3: and mass preparation (6, the 000g) suspended substance of D-24851 (compositions 3)
To contain 0.1% NaTDC, the aqueous tenside solution of 2.2% glycerol (stress drugs) and 0.142% sodium hydrogen phosphate (buffer) is cooled to low temperature (＜10 ℃).The lactic acid solution of D-24851 and Poloxamer 188 is added in the above-mentioned surfactant solution.Form suspended substance through mixing these two kinds of solution.Total suspended substance weight is 6,000g, about 1% (w/w) of drug level.Carry out high pressure homogenizing after separating out immediately, pressure is about 10,000psi, temperature＜70 ℃.The centrifugal lactic acid of removing, suspended substance homogenizes once more, and is about 10,000psi, temperature＜70 ℃.After homogenizing, use light scattering to detect the suspended substance particle diameter.The about 370nm of mean diameter.
Embodiment 4: the stability of nanoparticle suspension body of the present invention
Use and quicken stress (freeze-thaw and centrifugal is stirred in thermal cycle) and store the stability that reaches 6 months test suspension bodies down at 5 ℃.Mean diameter does not have significant change, 99% and 100% value (for compositions 3).In addition, in any stress test, all do not observe cohesion.Measured particle diameter and estimate cohesion and use following equation calculating percent aggregation in 1 minute by before sonicated and afterwards:
Cohesion %=(P
99-P
99S) * 100/P
99S
P wherein
99Representative before sonicated particle size distribution 99%, P
99SRepresentative after the sonicated particle size distribution 99%.
Embodiment 5:D-24851 (" compositions 4)
Preferred composition of the present invention:
Constituent concentration
D-24851 10mg/g
Poloxamer 188 1mg/g
Deoxycholic acid, sodium salt 1mg/g
Glycerol 22mg/g
Sodium hydrogen phosphate 1.42mg/g
NaOH solution, HCl solution is used for pH regulator
Water for injection is adjusted to gross weight 100g
pH 8.5
Embodiment 6:Solutol/ propylene glycol preparation (compositions 5)
Prepare following compositions and compositions of the present invention is made comparisons.
Every 500g solution composition:
D-24851 1.0g(0.2％，w/w)
Solutol HS15 375.0g
1,2-propylene glycol 125.0g
Embodiment 7: lactic acid formulation (compositions 6)
Prepare following compositions and compositions of the present invention is made comparisons.Lactic acid formulation is the supersaturated solution that is used for the D-24851 of orally give.Because oversaturated drug level and physical instability, therefore, importantly solution must be before giving new system.Medicine provides with the preparation group.These groups comprise following 3 bottles or 3 containers:
The content of drug vial (bottle 1)
1 bottle/container (100mL container), contain:
Indibulin(D-24851) 60.0mg
The content of solvent bottle A (bottle 2)
1 bottle/container (10mL container), contain:
Lactic acid 90% 9041.3mg
The content of solvent bottle B (bottle 3)
1 bottle/container (75mL container), contain:
Glucose 5705.5mg
Herba Passiflorae Caeruleae essence 10.0mg
Pure water 51347.0mg
The composition of preparation back D-24851-lactic acid drinkable solutions
1 bottle/container, contain:
Become component
D-24851 60.0mg
Lactic acid 7269.2mg
Glucose 5601.8mg
Herba Passiflorae Caeruleae essence 9.8mg
Pure water 50413.4mg
Embodiment 8: preferred compositions
| Composition | Concentration |
| The chemical compound of formula 1 | Scope 0.1%-10%w/w |
| First preferred surfactants (or class) non-ionic surface active agent, for example poloxamer | Scope 0.01%-5%w/w |
| Second preferred surfactants (or class) anion or zwitterionic surfactant, cholate for example, phospholipid, or mixture | Scope 0.01%-5%w/w |
| Excipient 1 buffer agent, for example sodium phosphate | Scope 1- |
| Excipient | |
| 2 stress drugs, for example glycerol or trehalose | Scope 1%-5%w/w |
Embodiment 9: preferred compositions
The D-24851 suspended substance preparation batch of material of table 1-by directly homogenizing and forming
| Lot number | Surfactant 1 | |
Stress drugs | Buffer |
| 1 | Phospholipid E80,1.2% | - | Trehalose, 4% | Na 2HPO 4，0.142％ |
| 2 | Phospholipid E80,1.2% | - | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 3 | Phospholipid E80,1.2% | DMPG，0.1％ | Trehalose, 4% | Na 2HPO 4，0.142％ |
| 4 | DMPC，1.2％ | DMPG，0.1％ | Trehalose, 4% | Na 2HPO 4，0.142％ |
| 5 | Soybean phospholipid 100H, 1.2% | DMPG，0.1％ | Trehalose, 4% | Na 2HPO 4，0.142％ |
| 6 | Phospholipid E80,1.2% | NaTDC, 0.1% | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 7 | Phospholipid E80,0.6% | NaTDC, 0.05% | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 8 | Phospholipid E80,2.4% | - | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 9 | Phospholipid E80,2.4% | NaTDC, 0.1% | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
Table 2-is by the D-24851 suspended substance preparation batch of material of the little separating out/formation that directly homogenizes
| Lot number | Surfactant 1 | |
Stress drugs | Buffer |
| 10 | Phospholipid E80,1.2% | - | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 11 | Phospholipid E80,1.2% | NaTDC, 0.1% | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 12 | Poloxamer 188(0.1％) | NaTDC, 0.1% | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 13 | Solutol HS-15(1.5％) | - | Glycerol, 2.2% | Na 2HPO 4，0.142％ |
| 14 | E80，1.2％ | Hetastarch, 1% | Glycerol, 2.2% | TRIS，0.06％ |
Embodiment 10:
In cross-over design, 6 macaques (3 male and 3 female) are studied.Oral and vein gives the testing drug compositions.
Dosage is as follows:
A: compositions 6, p.o., 5mg/kg/ dosage
B: compositions 4, p.o., 5mg/kg/ dosage
C: compositions 4, i.v., 5mg/kg/ dosage
D: compositions 5, i.v., 0.2mg/kg/ dosage
Gather the blood sample of all animals in the following time:
Oral: before and after giving 0.5,1,2,4,6,8,10,12,16,20,24,30,36,42,48 and 54h.Giving back 60h collection extra blood sample (compositions 4).
Vein: before and after giving 0.033,0.083,0.17,0.25,0.5,0.75,1,2,3,4,5 and 6h.Giving back 10,16,24,36,48 and 60h collection extra blood sample (compositions 4).
Sample collection: in the pipe that contains the Li-heparin, collect blood sample, and the centrifugal blood plasma that obtains.Give the animal of compositions 4 for vein, sample is divided into two similar sample aliquot.The centrifugal blood plasma that obtains of sample, another sample of whole blood is preserved under about-20 ° with the test plasma sample.Measure blood plasma and the haemoconcentration of Indibulin by effective HPLC method.Quantitative limit (LOQ) is 2ng/ml.The about 100-300 μ of the specimen volume l that obtains.Blood plasma that obtains and haemoconcentration are used for the evaluation of non-differentiation pharmacokinetics.
After oral and vein gave, the intermediate value blood plasma of D-24851 and haemoconcentration-time were distributed in table 1 and the table 2 and provide:
Table 3
| The pharmacokinetic parameter plasma concentration of D-24851 after vein or the orally give | ||||||||||
| On average geo (95％CI in) | Intermediate value (Min-Max) | |||||||||
| Form | Approach | C max [ng/ml] | AUC O-t continues [ng·h/ml] | AUC [ng·h/ml] | CL [ml/min/kg] | V ss [l/kg] | V z [l/kg] | MRT [h] | t max [h] | t 1/2 [h] |
| The solu/ propylene glycol 1) 0.2mg/kg | i.v. | 401 (279-576) | 287 (228-360) | 319 (249-409) | 10.5 (8.16-13.4) | 1.14 (0.82-1.59) | 1.73 (1.06-2.80) | 1.82 0.18-2.80) | 0.06 (0.03-0.08) | 1.85 (1.01-3.47) |
| Compositions 4-D-24851 nanoparticle suspension body 2) 5mg/kg | i.v. | 586 (349-985) | 5501 (3947-7666) | 6374 (4357-9325) | - | - | 27.4 * (15.5-48,2) | 25.8 (17.8-37.6) | 0.06 (0.03-0.08) | 26.7 (23.7-50.0) |
| Lactic acid 3) 5mg/kg | p.o. | 59.1 (22.2-157) | 676 (356-1284) | 803 (405-1592) | - | - | 10.3 (4.05-26.3) | 15.2 (8.73-26.6) | 4.00 (2.00-16.0) | 12.8 (6.18-15.3) |
| Compositions 4-D-24851 nanoparticle suspension body 2) 5mg/kg | p.o. | 27.8 (15.3-50.4) | 182 (119-281) | - | - | - | - | - | 6.00 (4.00-6.00) | - |
The pharmacokinetic parameter of D-24851 (plasma concentration) behind table 3 vein or the orally give
1)n＝6，
2)n＝5，
3)n＝4
*Plasma concentration shows has the atypical curve progress that absorbs phase.Therefore by using the available dosage fractional computation apparent volume of distribution that gives of general.
Table 4
| The pharmacokinetic parameter haemoconcentration of D-24851 after vein or the orally give | ||||||||||
| On average geo (95％CI in) | Intermediate value (Min-Max) | |||||||||
| Prescription | Approach | C max [ng/ml] | AUC O-t continues [ng·h/ml] | AUC [ng·h/ml] | CL [ml/min/kg] | V ss [l/kg] | V z [l/kg] | MRT [h] | t max [h] | t 1/2 [h] |
| Compositions 4-D-24851 nanoparticle suspension body 2) 5mg/kg | i.v. | 47516 (35571-63472) | 13375 (9233-19374) | 14023 (9736-20198) | 5.94 (4.13-8.56) | 2.60 (1.02-6.65) | 11.6 (5.93-22.7) | 7.30 (3.27-16.3) | 0.03 (0.03-0.03) | 20.0 (11.2-41.8) |
| Compositions 4-D-24851 nanoparticle suspension body 1) 5mg/kg | p.o. | 17.2 (12.0-24.6) | 131.5 (81.5-212) | - | - | - | - | - | 6.00 (4.00-12.0) | - |
1)n＝5；
2)n＝6
The pharmacokinetic parameter of D-24851 (haemoconcentration) behind table 4 vein or the orally give
In embodiment 10 described schemes, the nanoparticle suspension body preparation of D-24851, preferred composition 4 is characterized in that I.V. injection slow release pharmacokinetics afterwards.As table 1 and table 2 and shown in Figure 1, to compare with compositions 5, the intravenous injection of compositions 4 does not produce typical i.v. curve of blood plasma.The high c that replaces the D-24851 plasma concentration
MaxValue is to obtain sustained release profile with quick index decreased.When the expection of the valid density of D-24851 surpassed 100mg/ml, the effectiveness of nanoparticle suspension body (compositions 4) will be above 15 hours, and the effectiveness of solutol solution (compositions 5) will be only less than 2 hours.
Suppose the dosage linearity of 0.2-5mg/kg,, different components is calculated absolute bioavailability based on the plasma A UC value of the Solutol/ propylene glycol solution of the 0.2mg/kg dosage that gives compositions 5 with respect to vein.
Single oral gives after the 10% aqueous lactic acid solution of 5mg/kg, and the absolute bioavailability of compositions 4 is calculated as 11.5%.
Since the lactic acid content height, so lactic acid solution (compositions 6) is extremely bitter, causes vomiting, and tolerance is poor.On the other hand, nanoparticle suspension body (compositions 4) provides attractive selection, because all lactic acid all are removed, so nanoparticle suspension body tolerance is better.
Because after the i.v. injectable composition 4, shown pharmacokinetics performance and therefore the plasma half-life of D-24851 increase, after injection because lower C
MaxValue obtains to know clearly better toleration.Total toleration of compositions 4 also improves, and descends in whole treatment circulation to the accumulated dose of mammiferous D-24851 because give.In addition, because the effective plasma level level of compositions 4 is than several times of compositions 5 length, so obtained longer dosing interval; Give to descend in whole treatment cycle to mammiferous frequency, and still realized the same effect of tumor suppression, but compare with the more frequent solution that gives, side effect obviously reduces.
Embodiment 11: the toxicity profile of comparative composition 4
Be to estimate the subchronic toxicity of compositions 4, the time in 4 weeks scheme internal therapy Canis familiaris L. (3 male and 3 female).Compositions 4 is with the horizontal intravenous injection of various dose: 2.61mg/kg, 5.62mg/kg and 12.1mg/kg.
Gather the blood sample of all animals in the following time:
Use back 1h, 2h, 4h, 8h, 16h, 24h, 36h and 48 hours.Use HPLC to measure the concentration level of D-24851.
Shown in table 3 and table 4, the D-24851 plasma concentration is relevant with dosage.Blood plasma distributes similar with the magnitude that gave in the 27th day to the 1st day.
Table 5
| The pharmacokinetic parameter of D-24851 is average ar(n=3 is for every kind of sex) (min-max) the 1st day | |||||||
| Dosage [mg/kg] | Sex | C max，sd[ng/ml] | t max，sd[h] | AUC sd[ng·h/ml] | AUC τ，sd[ng·h/ml] | t 1/2[h] | CL/f [ml/(min·kg)] |
| 2.61 | Male | 147 (130-166) | 1.67 (1.00-2.00) | nc | nc | nc | nc |
| Female | 210 (183-258) | 1.67 (1.00-2.00) | nc | 3403 (2945-3705) | 41.0 *(19.7-81.7) | nc | |
| 5.62 | Male | 241 (190-267) | 2.00 (2.00-2.00) | 2468 (2347-2654) | 2593 (2488-2784) | 6.63 (6.04-7.28) | 38.1 (35.3-39.9) |
| Female | 279 (271-289) | 2.00 (2.00-2.00) | nc | 3543 (2855-4633) | 20.00 *(4.49-45.4) | nc | |
| 12.1 | Male | 592 (552-618) | 2.67 (2.00-4.00) | 6981 (5994-8338) | 6874 (5914-7937) | 8.74 (5.26-12.0) | 29.5 (24.2-33.6) |
| Female | 860 (414-1483) | 2.33 (1.00-4.00) | 8254 (3873-13082) | 7666 (4054-11217) | 11.6 (4.70-22.3) | 31.1 (15.4-52.1) | |
*Because inadequate curve fitting, these values only are used for orientation
The pharmacokinetic parameter of table 5 D-24851 (the 1st day)
Table 6
| The pharmacokinetic parameter of D-24851 is average ar(n=3 is for every kind of sex) (min-max) the 27th day | |||||||
| Dosage [mg/kg] | Sex | C max，md [ng/ml] | t max，md [h] | AUC O-t continues, md [ng·h/ml] | AUC τ，md [ng·h/ml] | t 1/2 [h] | CL/f [ml/(min·kg) ] |
| 2.61 | Male | 224 (147-290) | 1.33 (1.00-2.00 ) | 1447 (1240-1586) | 1736 (1574-1865 ) | 40.7 (35.0-46.7 ) | nc |
| Female | 148 (138-164) | 2.33 (1.00-4.00 ) | 1104 (1049-1178) | 1413 (1356-1485 ) | 28.3 * (22.3-31.7 ) | nc | |
| 5.62 | Male | 186 (176-200) | 2.33 (1.00-4.00 ) | 1323 (1065-1460) | 1852 ** (1840-1864 ) | 5.10 ′* (4.99-5.22 ) | 38.1 (35.3-39.9) |
| Female | 315 (271-376) | 2.33 (1.00-4.00 ) | 2737 (2265-3085) | 2963 (2616-3189 ) | 14.8 (7.02-30.3 ) | nc | |
| 12.1 | Male | 435 (396-460) | 2.67 (2.00-4.00 ) | 5558 (4935-6738) | 5621 (4935-6738 ) | 11.9 (10.1-12.9 ) | 29.5 (24.2-33.6) |
| Female | 329 (286-390) | 2.67 (2.00-4.00 ) | 4853 (4059-5564) | 4853 (4059-5564 ) | 24.2 (22.4-27.6 ) | 31.1 (15.4-52.1) | |
*Because inadequate curve fitting, these values only are used for orientation
The PK parameter of table 5 D-24851 (the 27th day)
The sustained release profile that obtains is because its binding mode is useful especially for D-24851 and other Antitubulins of the present invention.For Antitubulin, importantly in the special circulation of proliferative cell, provide effective drug level.Because not all cell all is in the same cell cycle at one time, therefore need in long-time, provide enough plasma concentration, as far as possible multiple cancer cell is had therapeutic effect.Therefore the present invention is used in particular for high toxicity antitumor agent such as D-24851, because can reduce accumulated dose, and can provide the therapeutic scheme of variation.Therefore, the parenteral pharmacokinetic profiles advantage that gives compositions 4 should have higher efficacy of drugs than conventional compositions.
The invention still further relates to treatment mammal, preferred human method, comprise the compositions of the present invention that gives mammal treatment effective dose.Usually, this amount gives or gives by controlled rate with bolus for the Antitubulin of about 0.01mg/kg～about 100mg/kg.Preferably, dosage is about 0.1mg/kg～about 10mg/kg.
This area clinician can determine approach that gives (for example, local, parenteral or oral) and dosage based on such as the precise nature of disease to be treated, the factors such as the order of severity, patient's age and general physical qualification of disease.The concrete preparation type of selecting depends on various factors, as chemical compound, give frequency and disease to be treated.
As mentioned above, compositions of the present invention is used for the treatment of the aspect that the purposes of cancer is a particular importance of the present invention.Cancer types to be treated includes but not limited to metastatic carcinoma, comprises the diffusion of metastatic carcinoma, the tumor of anti-anticarcinogen, and to the tumor of Antitubulin sensitivity, or its combination.Treatable other medical conditions include but not limited to autoimmune disease, and asthma and anaphylactic reaction and inflammatory diseases include but not limited to pancreatitis, septic shock, allergic rhinitis, and rheumatic arthritis.Also can give compositions of the present invention as immunosuppressant be used for other immunoregulatory activities.
Embodiment 12: compositions 4﹠amp in rat; 5 IV pharmacokinetics comparative study
Research D-24851 nanoparticle suspension body (compositions 4) vein pharmacokinetics in rat.By changing Yoshida
Dosage and the frequency of SC in rat model that the AH13 sarcoma is transplanted monitors tumor growth subsequently, optimizes dosage.IV treatment in the tail vein begins at the 0.1g tumor weight.Measure the pharmacokinetics in the rat in 1 month research, dosage IV q2d2,5 and 10mg/kg is by HPLC analysed for plasma and whole blood sample.10mg/kg IV gives in male rat (n=3)
14After the C-D-24851, measure tissue distribution, make comparisons, also be used for PK relatively with D-24851 (n=4) in the 0.25mg/kg IV organic solution.
The mean diameter of nanoparticle suspension body is 260nm, wherein 99%＜0.540 μ m.Administration frequency can be reduced to weekly twice, improves dosage level simultaneously, and the result produces 98% tumor suppression, table 7.In the scheme of optimizing, the importance of levels of drugs is shown in Fig. 6.
Table 7
| Scheme | Dosage | Accumulated dose | Tumor suppression |
| Give/14d | (mg/kg) | (mg/kg) | (％) |
| 14 | 5 | 70 | 66 |
| 7 | 10 | 70 | 100 |
| 6 | 10 | 60 | 88 |
| 4 | 15 | 60 | 98 |
Table 7. tumor suppression and the dependency that gives frequency and dosage.
Vein pharmacokinetics after single gives discloses, and plasma concentration rises, the t at 2 hours
MaxObtain C
Max, slow release level in a few hours begins to drain phase, Fig. 7 then then.When AUC is increased to largely, observe and C
MaxDose ratio, may reflect the saturated of metabolic enzyme, table 8.Such small concentrations in the organic solution has reduced AUC, t widely
Max, and t
1/2
Table 8
| Dosage form | Dosage | C max | t max | AUC | t 1/2 | ||||
| (mg/kg) | (ng/ml) | (h) | (ng·h/ml) | (h) | |||||
| M | F | M | F | M | F | M | F | ||
| D-24851 nanoparticle suspension body (compositions 4) | 2 | 80.4 | 90.8 | 2 | 2 | 517 | 663 | 12 | 6.4 |
| D-24851 nanoparticle suspension body (compositions 4) | 5 | 155 | 172 | 2 | 2 | 921 | 1775 | 3.6 | 7.2 |
| D-24851 nanoparticle suspension body (compositions 4) | 10 | 297 | 373 | 2 | 2 | 2729 | 5016 | 5.7 | 9.5 |
| Solutol/ propylene glycol solution (compositions 5) | 0.25 | 83.5 | 92.8 | 0.2 | 0.1 | 80.6 | 73 | 1.1 | 0.7 |
Table 8. single-dose IV gives D-24851 nanoparticle suspension body (compositions 4) and Solutol/ propylene glycol solution (compositions 5) the PK parameter to rat
In rat, repeat IV and give 10mg/kg q2d, show after the 15th day can with the 1st day after the AUC and the C that compare
Max, Fig. 8.Therefore, do not observe measurable drug accumulation.With respect to male rat, AUC and t that the female rats epiphase goes out to increase
1/2Usually, the high prolongation pharmacokinetics that loads has been supported the scheme dependency of observing, and comprises frequently giving high medication amount.Comparatively speaking, Solutol/ propylene glycol solution preparation (compositions 5) provides limited dosage, has the levels of drugs of utmost point short time.
The PK that prolongs with
14C ADME studies observed tissue distribution unanimity as a result.After initial IV gives, in the organ liver of MPS and spleen, observe high level, descend subsequently.Comparatively speaking, use the Solutol/ propylene glycol solution (compositions 5) of medicine, the flat variation slowly in time increases edema caused by disorder of the liver.Along with the slow release that the medicine (compositions 4) of D-24851 nanoparticle suspension body preparation is organized from MPS, other organs increase as the level in fat and the intestinal.For compositions 5, Comparatively speaking, originally levels of drugs arrives peaking in these its hetero-organizations, descend table 9 subsequently.In Solutol/ propylene glycol solution carrier,, only there is the 0.25mg/kg medicine can be transported to rat owing to the toxicity reason.Comparatively speaking, the 10mg/kg medicine in the D-24851 nanoparticle suspension body is given.
Table 9
| 14C-D-24851 ADME tissue distribution (%) | ||||||||
| |
Compositions 5 | |||||||
| Tissue | 6h | 18h | 30h | 48h | 4h | 8h | 24h | 48h |
| Liver | 33 | 18 | 24 | 17 | 11 | 11 | 13 | 20 |
| Spleen | 6.7 | 3.2 | 2.7 | 2.6 | 1.2 | 1.2 | 1.3 | 1.6 |
| Small intestinal | 4.8 | 4.4 | 6.7 | 4.7 | 9.9 | 4.4 | 3.8 | 3.1 |
| Fat | 5.9 | 18 | 11 | 24 | 19 | 22 | 15 | 11 |
Tissue distribution after table 9.IV gives: D-24851vs.Solutol/ propylene glycol solution
Observe the dosage correlation anticancer effect for D-24851, the enough loading preparations that need IV to carry.Use crystal nanoparticle suspension body can finish this point satisfactorily.Tissue distribution shows that originally the nanoparticle suspension body is target with organ liver and the spleen of MPS.Subsequently, medicine obviously discharges, medicine organize level for example hydrophobic drug to be had in other organs of affinity in expection fat rises.Pharmacokinetics shows that after IV gave, level rises in the blood plasma, and was consistent from the release that begins to store with the solubilized medicine, the levels of drugs that obtains prolonging, and this is that effect is needed.
Compare with the Solutol/ propylene glycol solution preparation of compositions 5, the D-24851 nanoparticle suspension body of compositions 4 allows quite high dosage (15vs.0.25mg/kg), and the plasma concentration level that obtains prolonging.Based on the mechanism of action of the molten cancer of cell cycle sensitivity, shown in preliminary efficacy study, the active expection of this slow release has high effect.Tissue distribution research is consistent with the IV storage effect that pharmacokinetics shows.
By utilizing compositions of the present invention, be considered to before finding exist the medicine of bioavailability problem in dosage form, to have excellent bioavailability.
Claims (78)
1. nanoparticle pharmaceutical compositions comprises the granule of Antitubulin of at least a following formula of the about 15nm of effective average-size～about 50 microns
The chemical compound of formula (1)
Wherein:
X is a hydrogen, halogen, and alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, acyl group, carboxyl, alkoxyl, hydroxyl, the hydroxyl that sense is modified, aryl, heteroaryl,
Wherein Y and Z are NR independently, O, or S, and wherein R is a hydrogen, alkyl, aryl, acyl group, cycloalkenyl group, heterocycloalkenyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aminocarbonyl,
R
3And R
3' be alkyl independently, aryl, heteroaryl,
Or X is NR
8R
9, wherein, R
8And R
9Be hydrogen independently, alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, acyl group, aryl, or heteroaryl;
A, B, C and D are nitrogen or carbon independently,
Condition is if A is a nitrogen, R
4Do not exist, and if A be carbon, R so
4Be hydrogen, halogen or alkyl;
If B is a nitrogen, so R
5Do not exist, and if B be carbon, R so
5Be hydrogen, halogen or alkyl;
If C is a nitrogen, so R
6Do not exist, and if C be carbon, R so
6Be hydrogen, halogen or alkyl;
If D is a nitrogen, so R
7Do not exist, and if D be carbon, R so
7Be hydrogen, halogen or alkyl;
R
1Be hydrogen, alkyl, alkaryl, acyl group, or aryl;
R
2Be hydrogen, alkyl, acyl group, aryl, alkoxy carbonyl, aryloxycarbonyl, heteroaryloxy carbonyl, cyclo alkoxy carbonyl, heterocycle alkoxy carbonyl, allyloxycarbonyl, ring allyloxycarbonyl and heterocycle allyloxycarbonyl.
2. compositions as claimed in claim 1, wherein X is:
3. compositions as claimed in claim 2, wherein Y and Z are oxygen, R
3Be aryl or heteroaryl, R
3' be hydrogen, R
1It is alkaryl.
4. compositions as claimed in claim 1, wherein X is an acyl group, acyl group aryl or acyl group heteroaryl.
5. compositions as claimed in claim 3, wherein R
1Be halogeno-benzyl, A, B, C and D are carbon, R
2, R
4, R
5, R
6And R
7Be hydrogen, R
3It is pyridine.
6. compositions as claimed in claim 1, wherein said Antitubulin chemical compound is
7. compositions as claimed in claim 1, wherein said Antitubulin chemical compound is selected from:
N-(pyridin-4-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(4-methylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(4-luorobenzyl)-indol-3-yl] acetaldehyde amide;
N-(pyridin-3-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(4-nitrobenzophenone)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(2-chloropyridine-3-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-6-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(the acetaldehyde amide of pyridine-4-)-[1-(4-luorobenzyl)-6-cyclopentyloxy carbonylamino indol-3-yl];
N-(3,4,5-trimethoxy benzyl)-N-(pi-allyl aminocarbonyl-2-methyl-prop-1-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-methoxyl group indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-oxyindole-3-yl] acetaldehyde amide; And
N-(pyridin-4-yl-[1-(4-luorobenzyl)-5-ethoxy carbonyl aminomethylindole-3-yl] acetaldehyde amide.
8. compositions as claimed in claim 1, also comprise at least a surfactant, it is selected from: non-ionic surface active agent, anion surfactant, cationic surfactant, biologically-derived surfactant, zwitterionic surfactant and aminoacid and derivant thereof.
9. compositions as claimed in claim 8, wherein said non-ionic surface active agent is selected from: polyoxyethylene aliphatic alcohol ether, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, sorbitol ester, glyceride, glyceryl monostearate, Polyethylene Glycol, polypropylene glycol, the polypropylene glycol ester, cetyl alcohol, 18 hexadecanol, stearyl alcohol, aralkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer, poloxamer, poloxamine, methylcellulose, hydroxylated cellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, noncrystalline cellulose, polysaccharide, starch, starch derivatives, hetastarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine amide, dextran, glycerol, Radix Acaciae senegalis, cholesterol, tragacanth, glyceryl monostearate, 18 hexadecanol, cetomacrogol emulsifying is cured, sorbitol ester, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene sorbitol fatty acid ester, Polyethylene Glycol, polyoxyethylene 8 stearate salt, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, Hydroxypropyl Methylcellulose Phathalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, the 4-(1,1 of oxirane and formaldehyde, 3, the 3-tetramethyl butyl) cascophen, poloxamer, alkyl aryl polyether sulfonate, the mixture of sucrose stearate salt and sucrose distearate, C
18H
37CH
2C (O) N (CH
3) CH
2(CHOH)
4(CH
2OH)
2The different Nonylphenoxy of p-gathers ((+)-2,3-Epoxy-1-propanol), capryl-N-methyl glucose amide, n-decyl-β-D-glucopyranoside, n-β-decyl-D-maltose pyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl group-N-methyl glucose amide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-glucopyranoside; Pelargonyl group-N-methyl glucose amide; n-nonyl-β-D-glucopyranoside; caprylyl-N-methyl glucose amide; n-octyl group-β-D-glucopyranoside, octyl group-β-D-sulfo-glucopyranoside, PEG-cholesterol; the PEG-cholesterol derivative; the PEG-vitamin A, PEG-vitamin E, and the random copolymer of vinyl acetate and vinyl pyrrolidone.
10. compositions as claimed in claim 8, wherein said anion surfactant is selected from: alkylsulfonate, arylsulphonate; alkylphosphonic, alkyl phosphonate, potassium laurate; sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate; sodium alginate, dioctyl sulfo-sodium succinate, phosphatidic acid and its salt; sodium carboxy methyl cellulose, cholic acid and its salt, cholic acid; deoxycholic acid, glycocholic acid, taurocholic acid; glycodesoxycholic acid; carboxy methyl cellulose calcium, stearic acid and its salt, calcium stearate; phosphate; sodium lauryl sulphate, carboxy methyl cellulose calcium, sodium carboxy methyl cellulose; the dioctyl thio succinate; the dialkyl of sulfo-sodium succinate, sodium lauryl sulfate, and phospholipid.
11. compositions as claimed in claim 10, wherein said phospholipid are natural or synthetic.
12. compositions as claimed in claim 11, wherein said phospholipid is selected from: phospholipid, anionic phospholipid, Phosphatidylserine, phosphatidyl inositol, phosphatidyl glycerol, the phosphatidyl inosine, phosphatidic acid, lysophosphatide, Polyethylene Glycol-phospholipid conjugate, lecithin, soybean phospholipid phospholipid, anion PEG-phospholipid, and anion methoxyl group PEG-phospholipid.
13. compositions as claimed in claim 11, wherein said phospholipid also comprises the functional group covalently bound with part.
14. compositions as claimed in claim 13, wherein said part is selected from: albumen, peptide, carbohydrate, glucoprotein, antibody and pharmaceutically active agents.
15. compositions as claimed in claim 8, wherein said cationic surfactant is selected from quaternary ammonium compound, benzalkonium chloride; the cetyl trimethylammonium bromide; chitosan, lauryl dimethyl benzyl ammonium chloride, fatty acyl carnitine hydrochlorate; the alkyl halide pyridine; the cetyl pyridinium chloride, cation lipid, polymethyl methacrylate trimethylammonium bromide; sulfonium compound; polyvinylpyrrolidone-2-dimethyl amino ethyl methacrylate Dimethylsulfate, cetyl trimethyl ammonium bromide ， phosphonium compounds; quaternary ammonium compound; benzyl-two (2-chloroethyl) ethyl ammonium bromide, Oleum Cocois trimethyl ammonium chloride, Oleum Cocois trimethylammonium bromide; Oleum Cocois methyl dihydroxy ethyl ammonium chloride; Oleum Cocois methyl dihydroxy ethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride; decyl dimethyl ethoxy chlorine ammonium bromide, C
12-15-dimethyl hydroxyethyl ammonium chloride, C
12-15-dimethyl ethoxy chlorine ammonium bromide, Oleum Cocois dimethyl hydroxyethyl ammonium chloride, Oleum Cocois dimethyl ethoxy ammonium bromide, myristyl trimethyl methylsulfuric acid ammonium, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethyleneoxy)
4Ammonium chloride, lauryl dimethyl (ethyleneoxy)
4Ammonium bromide, N-alkyl (C
12-18) dimethyl benzyl ammonium chloride, N-alkyl (C
14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide alkyl-leptodactyline, dialkyl group-dimethyl ammonium, lauryl trimethyl ammonium chloride, the alkyl amido alkyl dialkyl ammonium salt of ethoxylation, the trialkyl ammonium salts of ethoxylation, the dialkyl benzene dialkylammonium chloride, the N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C
12Trimethylammonium bromide, C
15Trimethylammonium bromide, C
17Trimethylammonium bromide, dodecylbenzyl triethyl ammonium chloride, diallyl dimethyl ammoniumchloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three cetyl ammonio methacrylates, the decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride, POLYQUAT, tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester, benzalkonium chloride, the stearyl dimethyl benzyl ammonium chloride, cetyl bromination pyridine, cetyl pyridinium chloride, the halide salt of quaternised polyoxy ethyl alkylamine, MIRAPOL, ALKAQUAT, Fixanol, amine, amine salt, the acid imide kazoe, protonated season acrylamide, methylated quaternary polymers, cation guar gum, benzalkonium chloride, Dodecyl trimethyl ammonium chloride, triethanolamine, and poloxamine.
16. compositions as claimed in claim 8; wherein said zwitterionic surfactant is selected from: zwitterionic phospholipid; phosphatidylcholine; diacyl-glyceroyl-phosphoethanolamine; PHOSPHATIDYL ETHANOLAMINE; diacyl-glyceroyl-phosphoethanolamine; two myristoyls-glyceroyl-phosphoethanolamine (DMPE); two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine (DPPE); distearyl-glyceroyl-phosphoethanolamine (DSPE); two oleoyls-glyceroyl-phosphoethanolamine (DOPE); pegylated phospholipid; the PEG-phosphatidylcholine; PEG-diacyl-glyceroyl-phosphoethanolamine; the PEG-PHOSPHATIDYL ETHANOLAMINE; PEG-diacyl-glyceroyl-phosphoethanolamine; PEG-two myristoyls-glyceroyl-phosphoethanolamine; PEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine; PEG-distearyl-glyceroyl-phosphoethanolamine; PEG-two oleoyls-glyceroyl-phosphoethanolamine; methoxy poly (ethylene glycol) (mPEG)-phospholipid; the mPEG-phosphatidylcholine; mPEG-diacyl-glyceroyl-phosphoethanolamine, mPEG-PHOSPHATIDYL ETHANOLAMINE, mPEG-diacyl-glyceroyl-phosphoethanolamine; mPEG-two myristoyls-glyceroyl-phosphoethanolamine; mPEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine, mPEG-distearyl-glyceroyl-phosphoethanolamine and mPEG-two oleoyls-glyceroyl-phosphoethanolamine.
17. compositions as claimed in claim 8, wherein said biologically-derived surfactant is selected from lipoprotein, gel, casein, lysozyme, albumin, casein, heparin, hirudin or other albumen.
18. compositions as claimed in claim 8, wherein said aminoacid and derivant thereof are selected from: leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, and phenylalanine.
19. compositions as claimed in claim 1 also comprises the pH regulator agent.
20. compositions as claimed in claim 19, wherein said pH regulator agent is selected from sodium hydroxide, hydrochloric acid, the tris buffer, monobasic, binary, tricarboxylic acid and its salt, citrate buffer, phosphate, acetate, lactate, three (methylol) aminomethane, amino sugar, one, two and trialkylated amine, meglumine (N-methyl glucoside amine), and aminoacid.
21. compositions as claimed in claim 1 also comprises osmotic pressure regulator.
22. compositions as claimed in claim 21, wherein said osmotic pressure regulator is selected from: glycerol, monosaccharide, inorganic salt and sugar alcohol.
23. compositions as claimed in claim 1, wherein said Antitubulin chemical compound amount is 0.1mg/g～200mg/g.
24. compositions as claimed in claim 1, wherein said Antitubulin chemical compound amount is 0.5mg/g～50mg/g.
25. compositions as claimed in claim 1, wherein said Antitubulin chemical compound amount is about 1mg/g～50mg/g.
26. compositions as claimed in claim 1, about 10 microns or littler of its effective mean diameter of wherein said granule.
27. compositions as claimed in claim 1, about 2 microns or littler of its effective mean diameter of wherein said nano-particle.
28. compositions as claimed in claim 1, wherein said compositions gives by being selected from following approach: parenteral, and oral, the oral cavity, periodontal, rectum, nose, pulmonary, the part, percutaneous, vein, muscle, subcutaneous, Intradermal, ophthalmic is in the brain, in the lymph, pulmonary, intraarcticular, the interior and intraperitoneal of sheath.
29. being mixed with, compositions as claimed in claim 1, wherein said compositions be selected from following liquid dispersion: ejection preparation, and solution, delayed release preparation, the sustained release preparation prolongs delivery formulations, beat delivery formulations and immediate release formulation.
30. compositions as claimed in claim 1, wherein said compositions is mixed with and is selected from following solid dosage forms: tablet, the tablet of coating, capsule, ampoule, suppository, lyophilized formulations, delayed release preparation, the sustained release preparation, prolong delivery formulations, the delivery formulations of beating, immediate release formulation and sustained release preparation.
31. being mixed with, compositions as claimed in claim 28, wherein said compositions be selected from following dosage form: patch, the powder formulation that can suck, suspended substance, cream and ointment.
32. a manufacturing contains the method for the pharmaceutical composition of at least a Antitubulin chemical compound, be included under the condition of the suspended substance that is enough to form the Antitubulin compound particle, make at least a Antitubulin chemical compound and at least a surfactant mixing certain hour of claim 1.
In suspended substance, add energy 33. method as claimed in claim 32, wherein said method comprise, form the Antitubulin granule.
34. method as claimed in claim 33, wherein said energy step comprises sonicated, homogenizes, and grinds, and high shear is extruded, or Micro Fluid.
35. method as claimed in claim 34 wherein forms pre-suspended substance and may further comprise the steps:
(i) at least a Antitubulin of dissolving effective dose in mixable first solvent of water forms solution; And
(ii) make the described solution and second solvent, form the pre-suspended substance of granule of frangible form.
36. method as claimed in claim 35, wherein said first solvent is selected from: N-N-methyl-2-2-pyrrolidone N-, lactic acid, 2-Pyrrolidone; dimethyl sulfoxide, dimethyl acetylamide, lactic acid, methanol; ethanol, isopropyl alcohol, 3-amylalcohol; the n-propanol, glycerol, butanediol; ethylene glycol, propylene glycol, the monoglyceride of list and diacylization; the dimethyl Soquad, acetone, dimethyl formamide; 1,4-diox, Polyethylene Glycol; macrogol ester, Polyethylene Glycol Sorbitol, polyalkylene glycol monoalkyl ether; polypropylene glycol, polypropylene alginate esters, PPG-10 butanediol; the PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether; the propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol laurate; the propylene glycol carbonic ester, lactic acid, and acetic acid.
37. method as claimed in claim 35, wherein said second solvent is selected from water, buffer, salt, surfactant, water-soluble polymer, and the combination of excipient.
38. method as claimed in claim 36 also comprises surfactant or combinations-of surfactants are added to step in first solvent.
39. method as claimed in claim 38, wherein said surfactant is selected from: non-ionic surface active agent, anion surfactant, cationic surfactant, biologically-derived surfactant, zwitterionic surfactant and aminoacid and derivant thereof.
40. method as claimed in claim 39, wherein said non-ionic surface active agent is selected from: polyoxyethylene aliphatic alcohol ether, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene fatty acid ester, sorbitol ester, glyceride, glyceryl monostearate, Polyethylene Glycol, polypropylene glycol, the polypropylene glycol ester, cetyl alcohol, 18 hexadecanol, stearyl alcohol, aralkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer, poloxamer, poloxamine, methylcellulose, hydroxylated cellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, noncrystalline cellulose, polysaccharide, starch, starch derivatives, hetastarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine amide, dextran, glycerol, Radix Acaciae senegalis, cholesterol, tragacanth, glyceryl monostearate, 18 hexadecanol, cetomacrogol emulsifying is cured, sorbitol ester, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene sorbitol fatty acid ester, Polyethylene Glycol, polyoxyethylene 8 stearate salt, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, hydroxyethyl-cellulose, Hydroxypropyl Methylcellulose Phathalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, the 4-(1,1 of oxirane and formaldehyde, 3, the 3-tetramethyl butyl) cascophen, poloxamer, alkyl aryl polyether sulfonate, the mixture of sucrose stearate salt and sucrose distearate, C
18H
37CH
2C (O) N (CH
3) CH
2(CHOH)
4(CH
2OH)
2The different Nonylphenoxy of p-gathers ((+)-2,3-Epoxy-1-propanol), capryl-N-methyl glucose amide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltose pyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl group-N-methyl glucose amide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-glucopyranoside; Pelargonyl group-N-methyl glucose amide; n-nonyl-β-D-glucopyranoside; caprylyl-N-methyl glucose amide; n-octyl group-β-D-glucopyranoside, octyl group-β-D-sulfo-glucopyranoside, PEG-cholesterol; the PEG-cholesterol derivative; the PEG-vitamin A, PEG-vitamin E, and the random copolymer of vinyl acetate and vinyl pyrrolidone.
41. method as claimed in claim 39, wherein said anion surfactant is selected from: alkylsulfonate, arylsulphonate; alkylphosphonic, alkyl phosphonate, potassium laurate; sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate; sodium alginate, dioctyl sulfo-sodium succinate, phosphatidic acid and its salt; sodium carboxy methyl cellulose, cholic acid and its salt, cholic acid; deoxycholic acid, glycocholic acid, taurocholic acid; glycodesoxycholic acid; carboxy methyl cellulose calcium, stearic acid and its salt, calcium stearate; phosphate; sodium lauryl sulphate, carboxy methyl cellulose calcium, sodium carboxy methyl cellulose; the dioctyl thio succinate; the dialkyl of sulfo-sodium succinate, sodium lauryl sulfate, and phospholipid.
42. method as claimed in claim 39, wherein said phospholipid are natural or synthetic.
43. method as claimed in claim 42, wherein said phospholipid is selected from: phospholipid, anionic phospholipid, Phosphatidylserine, phosphatidyl inositol, phosphatidyl glycerol, the phosphatidyl inosine, phosphatidic acid, lysophosphatide, Polyethylene Glycol-phospholipid conjugate, lecithin, soybean phospholipid phospholipid, anion PEG-phospholipid, and anion methoxyl group PEG-phospholipid.
44. method as claimed in claim 42, wherein said phospholipid also comprises the functional group covalently bound with part.
45. method as claimed in claim 44, wherein said part is selected from: albumen, peptide, carbohydrate, glucoprotein, antibody and pharmaceutically active agents.
46. method as claimed in claim 39, wherein said cationic surfactant is selected from: quaternary ammonium compound, benzalkonium chloride; the cetyl trimethylammonium bromide; chitosan, lauryl dimethyl benzyl ammonium chloride, fatty acyl carnitine hydrochlorate; the alkyl halide pyridine; the cetyl pyridinium chloride, cation lipid, polymethyl methacrylate trimethylammonium bromide; sulfonium compound; polyvinylpyrrolidone-2-dimethyl amino ethyl methacrylate Dimethylsulfate, cetyl trimethyl ammonium bromide ， phosphonium compounds; quaternary ammonium compound; benzyl-two (2-chloroethyl) ethyl ammonium bromide, Oleum Cocois trimethyl ammonium chloride, Oleum Cocois trimethylammonium bromide; Oleum Cocois methyl dihydroxy ethyl ammonium chloride; Oleum Cocois methyl dihydroxy ethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride; decyl dimethyl ethoxy chlorine ammonium bromide, C
12-15-dimethyl hydroxyethyl ammonium chloride, C
12-15-dimethyl ethoxy chlorine ammonium bromide, Oleum Cocois dimethyl hydroxyethyl ammonium chloride, Oleum Cocois dimethyl ethoxy ammonium bromide, myristyl trimethyl methylsulfuric acid ammonium, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethyleneoxy)
4Ammonium chloride, lauryl dimethyl (ethyleneoxy)
4Ammonium bromide, N-alkyl (C
12-18) dimethyl benzyl ammonium chloride, N-alkyl (C
14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide alkyl-leptodactyline, dialkyl group-dimethyl ammonium, lauryl trimethyl ammonium chloride, the alkyl amido alkyl dialkyl ammonium salt of ethoxylation, the trialkyl ammonium salts of ethoxylation, the dialkyl benzene dialkylammonium chloride, the N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C
12-14) dimethyl 1-naphthyl methyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C
12Trimethylammonium bromide, C
15Trimethylammonium bromide, C
17Trimethylammonium bromide, dodecylbenzyl triethyl ammonium chloride, diallyl dimethyl ammoniumchloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three cetyl ammonio methacrylates, the decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride, POLYQUAT10, tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester, benzalkonium chloride, the stearyl dimethyl benzyl ammonium chloride, cetyl bromination pyridine, cetyl pyridinium chloride, the halide salt of quaternised polyoxy ethyl alkylamine, MIRAPOL, ALKAQUAT, Fixanol, amine, amine salt, the acid imide kazoe, protonated season acrylamide, methylated quaternary polymers, and cation guar gum, benzalkonium chloride, Dodecyl trimethyl ammonium chloride, triethanolamine, and poloxamine.
47. method as claimed in claim 39; wherein said zwitterionic surfactant is selected from: zwitterionic phospholipid; phosphatidylcholine; diacyl-glyceroyl-phosphoethanolamine; PHOSPHATIDYL ETHANOLAMINE; diacyl-glyceroyl-phosphoethanolamine; two myristoyls-glyceroyl-phosphoethanolamine (DMPE); two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine (DPPE); distearyl-glyceroyl-phosphoethanolamine (DSPE); two oleoyls-glyceroyl-phosphoethanolamine (DOPE); pegylated phospholipid; the PEG-phosphatidylcholine; PEG-diacyl-glyceroyl-phosphoethanolamine; the PEG-PHOSPHATIDYL ETHANOLAMINE; PEG-diacyl-glyceroyl-phosphoethanolamine; PEG-two myristoyls-glyceroyl-phosphoethanolamine; PEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine; PEG-distearyl-glyceroyl-phosphoethanolamine; PEG-two oleoyls-glyceroyl-phosphoethanolamine; methoxy poly (ethylene glycol) (mPEG)-phospholipid; the mPEG-phosphatidylcholine; mPEG-diacyl-glyceroyl-phosphoethanolamine, mPEG-PHOSPHATIDYL ETHANOLAMINE, mPEG-diacyl-glyceroyl-phosphoethanolamine; mPEG-two myristoyls-glyceroyl-phosphoethanolamine; mPEG-two palmitic acids palm fibre acyl-glyceroyl-phosphoethanolamine, mPEG-distearyl-glyceroyl-phosphoethanolamine and mPEG-two oleoyls-glyceroyl-phosphoethanolamine.
48. method as claimed in claim 39, wherein said biologically-derived surfactant is selected from lipoprotein, gel, casein, lysozyme, albumin, casein, heparin, hirudin or other albumen.
49. method as claimed in claim 39, wherein said aminoacid and derivant thereof are selected from: leucine, alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid, methionine, and phenylalanine.
50. method as claimed in claim 32, wherein X is:
51. method as claimed in claim 50, wherein Y and Z are oxygen, R
3Be aryl or heteroaryl, R
3' be hydrogen, R
1It is alkaryl.
52. method as claimed in claim 32, wherein X is an acyl group, acyl group aryl or acyl group heteroaryl.
53. method as claimed in claim 51, wherein R
1Be halogeno-benzyl, A, B, C and D are carbon, R
2, R
4, R
5, R
6And R
7Be hydrogen, R
3It is pyridine.
54. method as claimed in claim 32, wherein said Antitubulin chemical compound is
55. method as claimed in claim 32, wherein said Antitubulin chemical compound is selected from:
N-(pyridin-4-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(4-methylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(4-luorobenzyl)-indol-3-yl] acetaldehyde amide;
N-(pyridin-3-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(4-nitrobenzophenone)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(2-chloropyridine-3-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-6-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(the acetaldehyde amide of pyridine-4-)-[1-(4-luorobenzyl)-6-cyclopentyloxy carbonylamino indol-3-yl];
N-(3,4,5-trimethoxy benzyl)-N-(pi-allyl aminocarbonyl-2-methyl-prop-1-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-methoxyl group indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-oxyindole-3-yl] acetaldehyde amide; And
N-(pyridin-4-yl-[1-(4-luorobenzyl)-5-ethoxy carbonyl aminomethylindole-3-yl] acetaldehyde amide.
56. method as claimed in claim 32, about 10 microns or littler of its mean diameter of wherein said nano-particle.
57. method as claimed in claim 32, about 2 microns or littler of its mean diameter of wherein said nano-particle.
58. the compositions of the claim 1 by giving the mammal effective dose is treated described mammiferous method.
59. method as claimed in claim 58, wherein said compositions has anticancer, asthma, antiallergic, immunosuppressant or immunoregulatory activity.
60. method as claimed in claim 58, wherein said mammal are human.
61. method as claimed in claim 58, wherein said method are used for the treatment of the medical conditions that feature is immune local disorders.
62. method as claimed in claim 58, wherein said method is used for the treatment of the tumor of anti-anticarcinogen, the metastatic carcinoma that comprises metastatic carcinoma development and diffusion, to the tumor of Antitubulin sensitivity, perhaps anti-anticarcinogen and to the tumor of Antitubulin sensitivity.
63. method as claimed in claim 58, wherein said method are used for the treatment of the medical conditions that feature is an inflammatory diseases.
64. as the described method of claim 63, wherein said medical conditions also comprises and is selected from following those: pancreatitis, septic shock, allergic rhinitis, rheumatic arthritis, and autoimmune disease.
65. the granule of at least a Antitubulin chemical compound of about 15nm of claim 1～about 50 microns is used for the treatment of purposes in the mammiferous medicine in manufacturing.
66. as the described purposes of claim 65, wherein treat the described mammiferous following medical conditions that is selected from: immunologic derangement, inflammatory diseases, the tumor of anti-anticarcinogen, the metastatic carcinoma that comprises metastatic carcinoma development and diffusion, to the tumor of Antitubulin sensitivity, perhaps anti-anticarcinogen and to the tumor of Antitubulin sensitivity, pancreatitis, septic shock, allergic rhinitis, rheumatic arthritis, and autoimmune disease.
67. as the described purposes of claim 66, wherein X is:
68. as the described purposes of claim 67, wherein Y and Z are oxygen, R
3Be aryl or heteroaryl, R
3' be hydrogen, R
1It is alkaryl.
69. as the described purposes of claim 66, wherein X is an acyl group, acyl group aryl or acyl group heteroaryl.
70. as the described purposes of claim 68, wherein R
1Be halogeno-benzyl, A, B, C and D are carbon, R
2, R
4, R
5, R
6And R
7Be hydrogen, R
3It is pyridine.
71. as the described purposes of claim 66, wherein said Antitubulin chemical compound is
72. as the described purposes of claim 66, wherein said Antitubulin chemical compound is selected from:
N-(pyridin-4-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(4-methylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(4-luorobenzyl)-indol-3-yl] acetaldehyde amide;
N-(pyridin-3-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(4-nitrobenzophenone)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(2-chloropyridine-3-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-6-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(the acetaldehyde amide of pyridine-4-)-[1-(4-luorobenzyl)-6-cyclopentyloxy carbonylamino indol-3-yl];
N-(3,4,5-trimethoxy benzyl)-N-(pi-allyl aminocarbonyl-2-methyl-prop-1-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-methoxyl group indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-oxyindole-3-yl] acetaldehyde amide; And
N-(pyridin-4-yl-[1-(4-luorobenzyl)-5-ethoxy carbonyl aminomethylindole-3-yl] acetaldehyde amide.
73. method as claimed in claim 58, wherein said Antitubulin chemical compound is
74. method as claimed in claim 58, wherein said Antitubulin chemical compound is selected from:
N-(pyridin-4-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(4-methylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(4-luorobenzyl)-indol-3-yl] acetaldehyde amide;
N-(pyridin-3-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-3-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(4-nitrobenzophenone)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(2-chloropyridine-3-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(4-fluorophenyl)-[1-(3-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-benzyl chloride base) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(2-pyridylmethyl) indol-3-yl] acetaldehyde amide;
N-(pyridine-2-yl)-(1-benzylindole-3-yl) acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-6-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-ethoxy carbonyl amino indole-3-yl] acetaldehyde amide;
N-(the acetaldehyde amide of pyridine-4-)-[1-(4-luorobenzyl)-6-cyclopentyloxy carbonylamino indol-3-yl];
N-(3,4,5-trimethoxy benzyl)-N-(pi-allyl aminocarbonyl-2-methyl-prop-1-yl)-[1-(4-luorobenzyl) indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-methoxyl group indol-3-yl] acetaldehyde amide;
N-(pyridin-4-yl)-[1-(4-luorobenzyl)-5-oxyindole-3-yl] acetaldehyde amide; And
N-(pyridin-4-yl-[1-(4-luorobenzyl)-5-ethoxy carbonyl aminomethylindole-3-yl] acetaldehyde amide.
75. method as claimed in claim 58, wherein said Nanoparticulate compositions shows improved bioavailability in mammal.
76. method as claimed in claim 58, wherein said Nanoparticulate compositions shows the slow release activity in mammal.
77. method as claimed in claim 58, wherein said mammal is improved the toleration of compositions.
78. as the described method of claim 77, wherein said improved toleration is to give the result that the interval between the Nanoparticulate compositions increases with respect to the interval of the compositions of the Antitubulin that comprises the non-nano particle form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62603604P | 2004-11-08 | 2004-11-08 | |
| US60/626,036 | 2004-11-08 | ||
| US60/642,878 | 2005-01-11 |
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| Publication Number | Publication Date |
|---|---|
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|---|---|---|---|---|
| CN112915106A (en) * | 2021-02-05 | 2021-06-08 | 张虎山 | Preparation and application of tumor immune microenvironment regulator |
| CN113603694A (en) * | 2021-07-16 | 2021-11-05 | 浙江工业大学 | 1, 2-diketone compound and preparation method and application thereof |
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2005
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112915106A (en) * | 2021-02-05 | 2021-06-08 | 张虎山 | Preparation and application of tumor immune microenvironment regulator |
| CN113603694A (en) * | 2021-07-16 | 2021-11-05 | 浙江工业大学 | 1, 2-diketone compound and preparation method and application thereof |
| CN113603694B (en) * | 2021-07-16 | 2022-07-22 | 浙江工业大学 | 1, 2-diketone compound and preparation method and application thereof |
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