CN1377282A - Fatty acid-anticancer conjugates and uses thereof - Google Patents

Abstract

The invention provides conjugates of fatty acids and anticancer agents useful in treating cancer, and compositions and formulations thereof. Methods for using the conjugates are also provided.

Description

Fatty acid-anticancer conjugates and application thereof

The field of the invention

The present invention relates to be used for the treatment of the fatty acid of cancer and the conjugate of antitumor and anticancer agent, and their compositions and prescription.The present invention also provides the method for using conjugate.

Background of the present invention

In medical domain, improving medicine is a fixed target to the selectivity of destination organization.Usually, it is desirable to drug selectivity be administered into its target, dosage can be lowered like this, and so the side effect meeting is lowered.Especially true for toxic agent such as antitumor and anticancer agent situation, the effective therapeutic dose of treatment cancer usually is subjected to antitumor and anticancer agent to normally, the restriction of the toxic side effects of health tissues because obtain.These problems relevant with lacking drug selectivity can be come example by Taxol (TAXOL).

TAXOL Taxol ^(paclitaxel) from the bark of Ramulus et folium taxi cuspidatae (Taxusbrevifilia), separated first in 1972, obtained the approval of U.S. food and medication management department in 1992, obtain the approval of treatment breast carcinoma subsequently its treatment transitivity ovarian cancer.Its mechanism of action is believed formation and the superstability that relates to improve microtubule, and required microtubule decomposes thereby cell division is finished in prevention.Also have report, TAXOL influences kinase activity and blocking-up to shifting very important process with the also expression of indefinite mechanism of action inducing cell factor.

TAXOL has attracted the attention of unusual intensive scientific domain, not only because the anti proliferative mechanism of action of its uniqueness, also because it can resist the cancer of almost all having tested effectively, and because of finding that it is a kind of analog of spontaneous numerous closely related chemical compounds.These chemical compounds, i.e. Ramulus et folium taxi cuspidatae alkanes, being identified as at present is one group of new anticancer compound.

TAXOL also is a significant disadvantages to the anticancer intensity in different tissues source.Ideal antitumor and anticancer agent has tissue specificity, thereby reduces the side effect to normal (splitted) cell.Therefore need have tissue-specific TAXOL analog.Another shortcoming of TAXOL is its extreme indissolubility.TAXOL can comprise Cremophor ^Effectively take in the solvent of EL (Oleum Ricini of polyoxyethylene alkylene), this combination can cause serious super quick immunoreation.Because these shortcomings also owing to the possibility of demonstrating as other spontaneous taxanes with active anticancer of modifying TAXOL at numerous positions, have begun having more the research of selectivity taxane.

At present, synthetic (or separation) more than 200 kinds of taxanes, and in vivo with the external test of carrying out active anticancer.Yet the result is very disappointing, so that National Cancer Institute (NCI) is no longer interesting to test TAXOL analog.Usually, for the TAXOL analog, solubility problem exists always, and/or potential obviously reduces, and/or selectivity do not improve, and/or the ratio of median toxic dose and median effective dose (" therapeutic index ") has unacceptably reduced.

TAXOL has following molecular formula:

Taxane has basic tricyclic structure (A, B, and C), and is replacement or unsubstituted.The quantity of TAXOL carbon atom is as follows as usual:

According to the taxane of having tested at present, the same with there being many problems to solve, there are many problems to produce again, in predetermined selectivity, active and dissolubility aspect, universal law is not also determined easily.At first, not generation of relevant optionally rule.Those have strong active taxane and demonstrate and have active the same active widely with TAXOL, do not show aspect the TAXOL analog and have made progress but have more optionally in development.

Some relevant active information produce.Keeping significant, but usually be under the active situation that descends, at C7, C9, C10, C19 has done multiple replacement in R and its combination.Yet at C2, the replacement on C4 and the 2 ' OH does not allow usually.These conclusions only are general, as, because the replacement on C9-C10 (cyclic derivatives) also is unallowed, but the replacement on C2 (position replaces between on the phenyl) allows.Similarly, although the minimal structure demand of side chain is not also determined for therapeutic effect, the C13 side chain, particularly 2 ' OH still needs.

Improve the deliquescent effort of TAXOL and also do not produce successful clinical prods.A kind of method is the prodrug of preparation TAXOL, and its prodrug changes into TAXOL and some other products in vivo.Also carry out the trial of esterification C7 hydroxyl and 2 ' oh group, wished key stable in solvent (to allow application method-intravenous injection fast preferably, through at least 24 hours) but cracking easily in vivo.The group of test all is hydrophilic, comprises amine, short carboxylic acid (using as succinic anhydrides and glutaric anhydride), sulfonic acid, aminoacid and phosphate.Usually, although use some derivant to obtain some successes, activity has reduced.Moreover, although advise 2 ' OH derivant, produce the concrete pattern that allows people to predict product useful on which group on the TAXOL can be substituted with the generation treatment reliably than the more easily cracking of C7OH derivant.

In which kind of TAXOL of precognition can be to have added several other factors on the effective problem again.Proposed the multiple mechanism of action in the literature, may in a kind of such mechanism, activity not influenced a locational change, but in another kind of mechanism, may eliminate activity.In addition, influence active change valuably and may be unfavorable for influencing biological effectiveness.As, TAXOL influences intracellular microtubule and forms, but the structural change at the increase intracellular reactive may influence the ability that the TAXOL acquisition enters cell unfriendly.And known TAXOL can conjugated protein, by the change of TAXOL conjugated protein aspect produce to still the unknown of active influence (at structure, cell absorbs and the dissolubility aspect).

Existing report, TAXOL does not enter brain, is foreclosed by blood brain barrier significantly.Do not know why be like this,, and can enter cell, so estimate to pass blood brain barrier because TAXOL is lipophilic.

In 200 kinds of analog of test, most promising is Taxotere (docetaxel), because it has activity and the dissolubility that increases slightly.Yet curiously, Taxotere is different from TAXOL on the general position that activity not have influence strongly, so people can not predict the improvement of Taxotere from these differences, even afterwards.

Taxotere has following molecular formula:

Fatty acid is former to be puted together with medicine, passes blood brain barrier to assist medicine with conjugate.DHA (docosahexenoic acid) is the spontaneous of 22 carbon atoms, and unbranched fatty acid passes the effectiveness that has showed abnormality in advance in the blood brain barrier puting together with medicine.DHA adheres to by acid groups and hydrophilic drugs, makes these medicines have more hydrophobicity (lipotropy).DHA is the important composition of brain, has been approved for a kind of additive in the infant formula at present.It is present in lactation women's the milk.The mechanism of action that the medicine that DHA assistance is puted together with it passes blood brain barrier is unknown.

Another example that fatty acid and medicine are puted together effect is pipotiazine and stearic acid, Palmic acid, enanthic acid, 9-undecylenic acid or 2, the adhewsive action of 2-dimethyl-Palmic acid.Pipotiazine is a kind of medicine that works in the central nervous system.The purpose that pipotiazine and fatty acid are puted together is the oily solute that produces medicine, as the liquid injectate of the release of drug slow when intramuscular shines.The release of medicine shows depends on selected concrete fatty acid, the activity of testing drug in the central nervous system.

The oils and fats molecule comprises fatty acid, also puts together so that conjugate has more lipotropy than medicine with medicine.Usually, the lipotropy of increase has also been proposed to enter in the brain thereby strengthen conjugate as strengthening the intestinal absorption medicine in lymphsystem, thus the metabolic mechanism of avoiding conjugate in liver, to pass through in advance.The type of the oils and fats molecule that uses has comprised phosphate ester, non-spontaneous have side chain and unbranched fatty acid and spontaneous have side chain and unbranched few to 4 carbon atoms to fatty acid more than 30 carbon atom scopes.In an example, observe enhanced receptor-binding activity (for adenosine receptor antagonists), suppose the side lipid molecular with the interactional interaction of molecules of immobilized artificial membrane, in the film microenvironment of receptor as the end anchors of receptors ligand.Yet not observing to render a service when using the identical lipid derivate of adenosine receptor antagonists increases, so the result that may occur of these researchs does not produce universality.

General introduction of the present invention

We find, produce the toxicity of the fatty acid and the anticancer compound effect of the puting together reduction anticancer compound of fatty acid-anticancer chemical compound conjugate, and do not compare with puting together anticancer compound, increased the effectiveness of anticancer compound aspect the inhibition cancer proliferation.

We find, fatty acid-anticancer chemical compound conjugate presents restriction to the blood plasma space of being tried body of accepting this treatment unexpectedly, make us uncannily that conjugate has (i) and compare less volume distributed median (in many cases little 100 times), (ii) compare less clearance rate (in many cases little 100 times) with the independent anticancer compound of not puting together with the independent anticancer compound of not puting together.And same unexpected is to find to compare with unconjugated anticancer compound, and fatty acid-anticancer chemical compound conjugate is present in the tumor cell with higher concentration.

According to one aspect of the present invention, provide a kind of to the compositions of being tried the fatty acid-anticancer chemical compound conjugate that body takes.Said composition is included in at least a fatty acid-anticancer chemical compound conjugate that is tried in the packing material that body takes.The amount of fatty acid-anticancer chemical compound is than the maximum tolerated dose (MTD) of unconjugated at least a anticancer compound about at least 10% (based on the ratio of weight with the weight of anticancer compound itself of anticancer compound in the conjugate, or calculate according to puting together with the mol ratio of not puting together anticancer compound) in packing material.Preferably, the amount of fatty acid-anticancer chemical compound is than the MTD about at least 20% of unconjugated at least a anticancer compound in packing material, at least about 30%, at least about 40%, about at least 50%, about at least 75%, at least about 100%, at least about 200%, about at least 300%, or about at least 400%.Preferably in the embodiment, packing material is the packing material of intravenous administration at some.In other embodiments, anticancer compound is a taxane, is paclitaxel or docetaxel preferably.In important embodiment, conjugate does not have capsule to wrap in the liposome.

According to another aspect of the present invention, provide treatment to suffer from the method for being tried body of abnormal mammalian cell propagation pathological changes.Method comprises to being tried body takes the compositions that comprises at least a fatty acid-anticancer chemical compound conjugate, with than the maximum tolerated dose (MTD) of unconjugated at least a anticancer compound greatly at least about 10% amount.Preferably, the amount of at least a fatty acid-anticancer chemical compound of taking is than the MTD about at least 20% of unconjugated at least a anticancer compound, at least about 30%, at least about 40%, about at least 50%, about at least 75%, at least about 100%, at least about 200%, about at least 300%, or about at least 400%.In other embodiments, anticancer compound is a taxane, is paclitaxel or docetaxel preferably.In important embodiment, conjugate does not have capsule to wrap in the liposome.

In another aspect of the present invention, provide to being tried body and taken the test kit of fatty acid-anticancer chemical compound conjugate composition.What test kit comprised the packing material that contains the compositions that comprises at least a fatty acid-anticancer chemical compound conjugate and gave this treatment of needs is tried body with than the big indication of taking at least a fatty acid-anticancer chemical compound conjugate at least about 10% amount of the maximum tolerated dose (MTD) of unconjugated at least a anticancer compound.Preferably, tried body and suffered from the abnormal mammalian cell pathological changes.Preferably, the amount of at least a fatty acid-anticancer chemical compound conjugate of taking is than the MTD about at least 20% of unconjugated at least a anticancer compound, at least about 30%, at least about 40%, about at least 50%, about at least 75%, at least about 100%, at least about 200%, about at least 300%, or about at least 400%.In other embodiments, anticancer compound is a taxane, is paclitaxel or docetaxel preferably.In important embodiment, conjugate does not have capsule to wrap in the liposome.

According to another aspect of the present invention, provide a kind of method that in being tried body, increases the therapeutic index of anticancer compound.This method comprises puts together fatty acid and anticancer compound, forms fatty acid-anticancer chemical compound conjugate, and is taken fatty acid-anticancer chemical compound conjugate to trying body.Therefore, with respect to the prescription of not puting together of anticancer compound, the therapeutic index of the anticancer compound of taking is improved.Preferably, tried body and suffer from abnormal mammalian cell propagation pathological changes, being tried body is human preferably.In other embodiments, anticancer compound is a taxane, is paclitaxel or docetaxel preferably.In important embodiment, conjugate does not have capsule to wrap in the liposome.

According to another aspect of the present invention, provide the method that body is taken fatty acid-anticancer chemical compound conjugate of being tried to this treatment of needs.This method is included in to be less than in 3 hours injects conjugate.Preferably, at 2 hours or be less than 2 hours and inject conjugate.Preferably, tried body and suffer from abnormal mammalian cell propagation pathological changes, being tried body is human preferably.In other embodiments, anticancer compound is a taxane, is paclitaxel or docetaxel preferably.In important embodiment, conjugate does not have capsule to wrap in the liposome.In preceding method, preferably, the dosage of the anticancer compound of the fatty acid of taking-put together surpasses the maximum tolerated dose of unconjugated anticancer compound.

According to another aspect of the present invention, provide the injectable preparation of a kind of at least a fatty acid-taxane conjugate composition.Preparation comprises at least a fatty acid-taxane conjugate composition greater than about 6 mg/ml.Preferably, preparation comprises greater than about 7 mg/ml, 8 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml, 80 mg/ml, or at least a fatty acid-taxane conjugate composition of 100 mg/ml.Preferably, taxane comprises paclitaxel and docetaxel.

The present invention also provides a kind of Injectable composition that comprises at least a fatty acid-taxane conjugate of at least a fatty acid-taxane conjugate that is less than about 0.3 mg/ml.Preferably, compositions comprise be less than about 0.275,0.25,0.225,0.2,0.15, or at least a fatty acid-taxane conjugate of 0.1 mg/ml.Taxane comprises paclitaxel and docetaxel.

According to another aspect of the present invention, provide fatty acid-taxane conjugate composition.Said composition comprises that the amount of at least a fatty acid-taxane conjugate is greater than about 6 mg/ml.Compositions also comprises surfactant.Compositions comprises greater than about 7 mg/ml, 8 mg/ml, 10 mg/ml preferably, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml, 80 mg/ml, or at least a fatty acid-taxane conjugate composition of 100 mg/ml.Preferably, taxane comprises paclitaxel and docetaxel.

In certain embodiments, the surfactant in fatty acid-taxane conjugate composition is Cremophor EL or EL-P.Preferably, the concentration of Cremophor is between about 9.6% to about 49.7% (volume ratio).

In another aspect of the present invention, provide other fatty acids-taxane conjugate composition.Compositions comprises at least at least a fatty acid-taxane conjugate greater than about 37 mg/ml.Preferably, compositions comprises at least about 40 mg/ml, 50 mg/ml, 60 mg/ml, 80 mg/ml, or at least a fatty acid-taxane conjugate of 100 mg/ml.Preferably, taxane comprises paclitaxel and docetaxel.

According to another aspect of the present invention, provide to have fatty acid-amount of taxane conjugate and the volume of surfactant between the fatty acid-taxane conjugate composition of some ratio.Compositions comprises at least a fatty acid-taxane conjugate and a kind of surfactant; The ratio of at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 50 mg/ml.Preferably, the ratio of at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, or 100 mg/ml.Preferably, surfactant comprises CremophorEL and EL-P.Preferably, taxane comprises paclitaxel and docetaxel.In other embodiments, compositions comprises solvent, is ethanol preferably; The ratio of surfactant and solvent is about 1: 1 preferably.

In another aspect of the present invention, provide have fatty acid-amount of taxane conjugate and the volume of solvent between the fatty acid-taxane conjugate composition of some ratio.Said composition comprises at least a fatty acid-taxane conjugate and a kind of solvent; The ratio of at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 42 mg/ml.Preferably, the ratio of at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, or 100 mg/ml.Preferably, solvent comprises ethanol, and preferably, taxane comprises paclitaxel and docetaxel.In other embodiments, compositions comprises surfactant, and preferably, surfactant is Cremophor EL and EL-P; The ratio of surfactant and solvent is about 1: 1 preferably.

According to another aspect of the present invention, provide the compositions of the fatty acid-taxane conjugate that comprises solvent and surfactant.Compositions comprises the fatty acid-taxane conjugate between about 7 to about 120 milligrams, the solvent between about 40% to about 100%, and the surfactant between about 1% to about 60%.In embodiment preferably, compositions comprises the fatty acid-taxane conjugate between about 20 milligrams to about 120 milligrams, the solvent between about 40% to about 100%, and the surfactant between about 1% to about 60%.Better, compositions comprises the fatty acid-taxane conjugate between about 35 milligrams to about 45 milligrams, the solvent between about 45% to about 55%, and the surfactant between about 45% to about 55%.In the embodiment of especially recommending, compositions comprises the fatty acid-taxane conjugate between about 6 milligrams to about 20 milligrams, solvent between about 5% to about 15%, and the surfactant between about 5% to about 15%, or the fatty acid-taxane conjugate between about 6 milligrams to about 12 milligrams, solvent between about 8% to about 12%, and the surfactant between about 8% to about 12%, or the fatty acid-taxane conjugate between about 1 milligram to about 5 milligrams, solvent between about 1% to about 10%, and the surfactant between about 0.5% to about 4%.Preferably, solvent is an ethanol, and surfactant is Cremophor EL or EL-P.

Noted earlier for all, fatty acid is the C8-C26 fatty acid preferably.Better, fatty acid is spontaneous unbranched C8-C26 fatty acid.Better, fatty acid is chosen from following group, comprises C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 (Palmic acid), C16:1 (gaidic acid), C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 (arachic acid 11), C18:2-6 (linoleic acid), C18:3-3 (α-linoleic acid), C18:3-5 (octadecylene three acid), C18:3-6 (β-linoleic acid), C18:4-3, C20:1 (20 carbon, 11 olefin(e) acids), C20:2-6, C20:3-6 (dihomo-y-linoleic acid), C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (20 carbon diene acid), C22:1 (docosenoic acid), C22:4-6 (docosatetratenoic acid), C22:5-6 (clupanodonic acid), C22:5-3 (clupanodonic acid), C22:6-3 (docosahexenoic acid), and C24:1-9 (nervonic acid).Be docosahexenoic acid preferably.

At foregoing, in product and the method, provided dosage, the scope of ratio and amount.Scope comprises the data between the data that specifically provide and each and each data.Therefore, as, when when the amount of fatty acid-taxane conjugate is specific being " greater than about 6 mg/ml, 7 mg/ml, 8 mg/ml; 10 mg/ml, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml; 80 mg/ml, 100 mg/ml ", scope comprises 6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 or the like comprise the conjugate of amount of each data of gamut.

According to another aspect of the present invention, provide a kind of treatment to suffer from the method for being tried body of unusual mammal propagation pathological changes.Method comprises to being tried body takes fatty acid-taxane conjugate, and the amount of conjugate is at least 250,275, and 300,350,400,450,500,550,600,650,700,750,800,850,900,950,1000,1050,1150,1200,1250,1300,1350 or 1400 milligrams of/square metre body surface areas (BSA).In one embodiment, consumption was through 24 hours or be less than 24 hours, and 6 hours or be less than 6 hours, 3 hours or be less than 3 hours, or 2 hours or be less than hour to give and tried body and take.In some embodiments, fatty acid is the fatty acid of C8-C26, and in important embodiment, fatty acid is that C16-C22 is unbranched, spontaneous fatty acid.In the embodiment of some special recommendation, fatty acid can be a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.In best embodiment, fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.In embodiment preferably, taxane is paclitaxel.In important embodiment, when taxane was paclitaxel, fatty acid was puted together on 2 ' the OH position of paclitaxel.In best embodiment, fatty acid is a docosahexenoic acid.

In any aforesaid embodiment, maximum tolerated dose can be determined according to the known method of those skilled in the art in this field.The maximum tolerated dose of chemical compound lot is known.Some maximum tolerated doses of known antitumor and anticancer agent are listed below.

According to another aspect of the present invention, provide composition substance.Said composition comprises the crystal of the conjugate of unsaturated C16-26 fatty acid of polymerization and medicine.In embodiment preferably, fatty acid is the fatty acid of C16-C22.In some embodiments, fatty acid is spontaneous, unbranched fatty acid.In certain embodiments, fatty acid can be a linoleic acid, Palmic acid, arachidonic acid, 20 carbon diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.In the embodiment of special recommendation, fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 carbon diene acid, or docosahexenoic acid.The crystalline polymorph of docosahexenoic acid-paclitaxel is described in an embodiment.

In any aforesaid embodiment, in the medicine that medicine can be listed below.Medicine must contain the position (active group) that an energy and fatty acid are puted together.Generalization scholar in this field can make such decision.The medicine catalogue is an antitumor and anticancer agent preferably, Anti-virus agent and tranquilizer.Anticancer compound can be a taxane.In certain embodiments, taxane is paclitaxel.In important embodiment, when taxane was paclitaxel, fatty acid was puted together on 2 ' the OH position of paclitaxel.In best embodiment, fatty acid is a docosahexenoic acid.

According to another aspect of the present invention, provide the method for the conjugate of unsaturated C16-C22 fatty acid of a kind of separation of polymeric and medicine.Method comprises that covalency puts together fatty acid and medicine, forms conjugate, forms the conjugate crystal, and isolation of crystalline.In some embodiments, fatty acid is buttery in room temperature.Fatty acid preferably, medicine, anticancer compound and conjugate are all as described above.

According to another aspect of the present invention, provide test kit.Test kit comprises and contains first packing material, a packing of the indication of second packing material and binding soln and mixture, first packing material contains the solution of the conjugate of the fatty acid that is dissolved in first solvent and taxane, second packing material produces second solvent and surfactant mixtures, easy and first solvent of second solvent.In one embodiment, first solvent is an ethanol, and in certain embodiments, surfactant is Cremophor.In other embodiments, second solvent is an ethanol, and in important embodiment, the ratio of the Cremophor and second solvent was at least 1: 1,2: 1, and 3: 1, or 4: 1.Fatty acid preferably, anticancer compound and conjugate are as described above.In the embodiment of special recommendation, the concentration of the conjugate in solvent is about 100 mg/ml.

According to another aspect of the present invention, the medication preparation product are provided.The medication preparation product comprise the intravenous administration solution of the conjugate of C8-C26 fatty acid and taxane, and wherein solution is substantially free of liposome.Fatty acid preferably, anticancer compound, conjugate is as described above.

According to another aspect of the present invention, provide a kind of preparation to the method for being tried the intravenous administration solution that body takes of suffering from the mammalian cell proliferation pathological changes.Method comprises (a) is dissolved in the fatty acid in first solvent and the conjugate solution of taxane, combine with (b) second solvent and surfactant mixtures, easy and first solvent of second solvent, described in conjunction with producing pre--compound, premix is joined in the intravenous administration solution.In one embodiment, first solvent is an alcohol, is preferably ethanol.In certain embodiments, surfactant is Cremophor.In other embodiments, second solvent is an alcohol, is preferably ethanol, and in important embodiment, the ratio of the Cremophor and second solvent was at least 1: 1,2: 1, and 3: 1, or 4: 1.Fatty acid preferably, anticancer compound and conjugate are as described above.In the embodiment of special recommendation, the conjugate concentration in the solvent is about 100 mg/ml.

These and other aspects of the present invention, and multiple advantage and application are with reference to the detailed description of embodiment can be more obvious preferably.

The summary of accompanying drawing of the present invention

Fig. 1 has demonstrated test kit 11, comprises packing 15, and first reagent 17 of the present invention (as contains TAXOPREXIN ^CONCENTRATE[" concentrates "] packing material), second reagent 19 of the present invention (as contains TAXOPREXIN ^The packing material of CONCENTRATE dilution [" dilution "]), in using, treatment uses the indication 21 of this reagent.

Detailed description of the present invention

Cis-DHA (DHA) is spontaneous aliphatic acid. It is the unbranched aliphatic acid that contains six two keys, is all cis. Its structure is as follows:

DHA can separate from fish oil, or can chemical synthesis. Yet these methods can produce transisomer, and the separating isomerism body is very difficult and expensive, and the mankind, may have safety problem. The preparation method is all cis-isomers of biosynthesis preferably. It is Maryland State taxi driver brother Lun Biya Martek Biological Science Co., Ltd that DHA originates preferably. Martek has a patent system of using microalgae to prepare DHS, and it is the synthetic single isomers of DHA only, is all cis-isomer. The patent of Martek comprises U.S. Patent No. 5,374,657,5,492,938,5,407,957 and 5,397,591.

DHA also is present in lactescent women's milk, and Martek obtains the license of DHA as the nutritional supplement of infant formula in Europe.

Know, DHA is in the situation that aerobic exists unstable. In order to stablize DHA and its conjugate, it is very important adding antioxidant after it is synthetic in material. A kind of antihunt means are novel synthetic materials of preparation in following solution: 100 gram alcohol DHA-paclitaxel add 100 gram carriers (100 milliliters of propane diols, 70 milligrams of alpha-tocopherols, 5 milligrams of dilauryl thio-2 acids, 50 milligrams of ascorbic acid) prepare and be kept in the amber bottle argon gas, sealed vial also is kept at 4 ℃. Following antioxidant can use: ascorbic acid, ascorbyl palmitate, dilauryl acid ascorbyl ester, hydroquinones, butylated hydroxyarisol, Sodium Metabisulfite, t-B carrotene and alpha-tocopherol. Heavy metal chelant such as ethylenediamine tetraacetic-acetic acid (EDTA) also can use.

At first Paclitaxel is (people such as Wani, american chemical Scientific Periodicals, 93,2325,1971) of separating from the bark of Chinese yew (Taxus brevifolia). Its separation and synthetic report widely arranged in the literature. Applicant is the paclitaxel that obtains from commercial sources, as the Hauser laboratory from Colorado state Boulder.

The present invention is compound " Taxoprexin preferably^TM" be a kind of covalent conjugates of DHA and paclitaxel. Its chemical constitution, synthetic, purify and in vitro act on United States Patent (USP) 5,795, be described in 909, its whole disclosures are all by being incorporated in this piece of writing in this citation. Its structure is illustrated as " conjugate 1 " in the embodiment 1 of that patent.

The maximum tolerated dose of any treatment compound (MTD) is defined as the part clinical assessment of compound. As, the I phase tests and can comprise the maximum tolerated dose of determining test compounds, maximum toxicity (DLT) and the pharmacokinetics of allowing of dosage. " maximum tolerated dose ", as used herein, refer to the maximum dose of the pharmaceutical agent of using for treatment disease specific or patient's condition adult patients energy safety clothes. Therefore, according to the open record that obtains, the MTD of the treatment compound of any food and the drug control committee (FDA) approval is well-known to the those of ordinary skill in this field. The MTD of any concrete treatment compound can fill a prescription (as injectable formula according to it, implantable biology loses the composition formula that depolymerizes, formula of oral), route of administration (as, intravenous route, oral, approach in tumour), administering mode is (as injecting, the pill injection), the variation of dosage (hour, day, week) etc. and changing. The tested body that MTD usually is defined as 50% drug administration demonstrates the maximum maximum dose that allows toxicity of dosage. The dosage of the antineoplastic reagent of determining in doctor's desktop reference (PDR) can be defined as the MTD of these reagent. MTD also determines only to comprise the dosage (comprising anti-tumor agent comprising salmosin) of the medicine that is used as single agents, does not comprise and adds other cells that change MTD, gene, medicine or other reagent. Other clinical relevant and generally accepted restrictions are well-known to the those of ordinary skill in this field.

Measurement to maximum tolerated dose can be expressed as drug weight/tested body weight, drug weight/body surface area etc. The MTD of anticancer compound usually is expressed as weight/square metre body surface area (milligram/square metre). As the MTD that injects the paclitaxel of human body is 225 milligrams/square metre. The clinical tolerance dosage that the most often uses is 175 milligrams/square metre. MTD also can be expressed as the dosage relevant with the time composition, as drug weight/body surface area/sky.

For the treatment reagent that does not also carry out the human clinical trial, or also at human body, do not carry out the treatment reagent (as tentative or high toxicity compound) that any MTD determines, those of skill in the art can estimate MTD by using zootype. The MTD that calculates in animal can be according to one group of physiologic parameters, as death, and special toxicity, drug-induced Body weight loss. Use death as terminal, MTD takes every dosage of surviving in wherein test group to test animal. Use toxicity as terminal, MTD can be observe appropriateness but be not the dosage of serious toxicity. Use Body weight loss as terminal, MTD surpasses the dosage of inducing the body weight certain percentage to change. Using the additive method of definite MTD of zootype and different terminals is known to the those of ordinary skill in this field. The mankind MTD for the treatment of compound and the correlation of animal MTD are accepted enforcement in pharmaceutical field.

As, the conjugate (Taxoprexin of definite DHA and paclitaxel^TM) maximum tolerated dose in animal (mouse, vole and dog), it is than the about 4-5 of independent paclitaxel doubly (weight ratio), or than the about 3-4 of independent paclitaxel doubly (molar concentration rate).

Another aspect of the present invention provides to tested body and has taken minute composition and formula, is human subject preferably, and the amount that contains the fatty acid-anticancer compound composition has surpassed does not put together the anticancer compound maximum tolerated dose. Fatty acid-anticancer compound conjugate is preferably in taking the packing material of use to tested body. Preferably, packing material is the packing material of intravenous administration, as the IV bag.

In packing material the amount of fatty acid-anticancer compound than the MTD of unconjugated compound greatly at least about l0%. Preferably, in packing material the amount of fatty acid-anticancer compound than unconjugated at least a anticancer compound greatly at least about 20%, 30%, 40 %, 50%, 75%, 100%, 200%, 300%, or 400%. Anticancer compound is taxane preferably, specifically paclitaxel or docetaxel.

The method of taking these compositions to the tested body of suffering from the abnormal mammalian cell Proliferation Lesion also is provided.

The kit that comprises a certain amount of fatty acid-anticancer compound also is provided. Kit comprises one or more have conjugate anticancer compound and mixing, dilutes and/or take the packing material of indication, and the amount of anticancer compound is greater than the MTD that does not put together anticancer compound. Kit also can comprise that other have one or more solvents, surfactant, the packing material of anticorrisive agent and/or diluent (as salt solution (0.9% sodium chloride) commonly used or 5% glucose (D5W)), and mix, dilution, and/or take the packing material of conjugate for the tested body that needs this treatment. Kit concrete property of the present invention, generally designate as numeral 11, demonstrates in Fig. 1. Kit 11 comprises following main element: packing 15, the first reagent 17 of the present invention (as contain TAXOPREXIN CONCENTRATE[" concentrate "] packing material), the the second reagent 19 of the present invention packing material of TAXOPREXIN CONCENTRATE dilution [" dilution "] (as contain), use the indication 21 of this reagent in the treatment application. Technical staff in this field can modify packing 15 easily to adapt to concrete needs.

Anticancer compound in kit can liquid solution, or with the powder of drying, provide. When the anti-compound that provides was dried powder, powder can add suitable solvent again to prepare, and it also can provide. The conjugate of liquid form can be (dilution before taking) that concentrates or make to tested body and take. Solvent depends on medicine and takes mode. For the medicine of knowing, suitable solvent is well-known, and publishes in the literature.

As mentioned above, therapeutic index is the ratio of median toxic dose and effective dose 50. Compare with unconjugated anticancer compound, aliphatic acid and anticancer compound are puted together formation fatty acid-anticancer compound conjugate and have been reduced the toxicity of anticancer compound, and have increased validity. Therefore, the present invention also provides the method that increases the anticancer compound therapeutic index in tested body. Method comprises puts together formation fatty acid-anticancer compound conjugate with aliphatic acid and anticancer compound, takes fatty acid-anticancer conjugates for tested body. With respect to unconjugated anticancer compound formula, the therapeutic index of anticancer compound conjugate has improved. Preferably, anticancer compound is taxane, specifically paxlitaxel or docetaxel.

Although conjugate can wrap in liposome by capsule, preferably, conjugate is not by liposome. This method tested body preferably is the mankind.

It is described herein that to put together anticancer compound less and more effective than not puting together accordingly anticancer compound toxicity. Therefore, fatty acid-anticancer compound conjugate can be with the toxicity identical with corresponding unconjugated anticancer compound but more effective amount take, or with identical validity but the less dosage of toxicity take. Generally, with respect to unconjugated anticancer compound, the effect of puting together of aliphatic acid and anticancer compound increases maximum tolerated dose.

The invention provides the injectable preparation of at least a aliphatic acid-taxane conjugate composition. The preparation of injectable preparation is used for to taking with the tested body of taxane treatment, as suffers from the tested body of cancer. The injectable preparation contains the taxane derivatives concentration higher than the possible concentration of expecting in the past. As, the present injection formula of paclitaxel contains 0.3 mg/ml-1.2 mg/ml concentration, is diluted in hydrotropic solution. Made us finding uncannily, as disclosed herein, contained the taxane derivative of puting together aliphatic acid, concentration that can be very high takes for tested body, and the maximum toxicity that allows of the dosage of not observing in other taxane formulas. The injectable preparation contains greater than the about aliphatic acid described herein of 6 mg/ml-taxane conjugate. Preferably, preparation contains greater than about 6 mg/ml, greater than about 7 mg/ml, greater than about 8 mg/ml, greater than about 9 mg/ml, greater than about 10 mg/ml, greater than the about aliphatic acid described herein of 12 mg/ml etc.-taxane conjugate.

In addition, also provide and contained the low dosage taxane injectable preparation lower than the taxane amount in the formula of present clinical use. With respect to unconjugated taxane, the amazing active growth of aliphatic acid-taxane conjugate makes at the identical active anticancer of acquisition can take less dosage simultaneously. Therefore, the injectable preparation that provides content to be less than 0.3 mg/ml, its formula has active anticancer when taking for the tested body of suffering from cancer. Preferably, low dosage injectable preparation content is less than approximately 0.25 mg/ml, is less than 0.2 about mg/ml, is less than approximately 0.15 mg/ml, is less than 0.1 about mg/ml, etc.

Other compositions that contain abundant fatty acid-taxane conjugate also are provided. In some embodiments, composition contains greater than about 6 at least a aliphatic acid of mg/ml-taxane conjugate and surfactants. Preferably, composition levels is greater than about 7 mg/ml, greater than about 8 mg/ml, and greater than about 9 mg/ml, greater than about 10 mg/ml, greater than about 12 mg/ml, etc. In other embodiments, composition comprises at least a aliphatic acid at least about 37 mg/ml-taxane conjugate. Preferably, this composition contains at least about 40 mg/ml, at least about 50 mg/ml, at least about 60 mg/ml, at least about 80 mg/ml, at least about at least a aliphatic acid of 100 mg/ml-taxane conjugate.

According to the standard method for preparing liposome, aforementioned preparation, but formula and composition capsule wrap in liposome, do not wrap in wherein but be preferably.

The all compositions of this paper that contain taxane or other anticancer compounds also can at random contain other anticancer compounds. Composition also can contain prepares other compositions of applying in the anticancer compound of taking to the mankind, comprises surfactant, solvent, and anticorrisive agent, diluent etc., all these are standards at pharmaceutical field.

Can be used on suitable surfactant of the present invention and comprise non-ion reagent, as LCFA and their derivative that is not dissolved in water. These comprise fatty alcohol, as lauryl cetyl and hard ester acyl-glycero, and glyceryl ester such as spontaneous list, two and glyceryl ester, and the fatty acid ester of fatty alcohol, as propane diols, polyethylene glycol, sorbitan, sucrose, cholesterol. Also spendable is those compounds that contain the polyoxyethylene group that is added together by ehter bond and alcohol groups. Comprise polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycerine and steroid ester at the useful especially compound of the present invention. The surfactant of special recommendation is Cremophor^EL and Cremophor^EL-P, it is the polyoxyethylenated castor oil surfactant.

Other surfactants also consider to can be used to dissolve composition described herein. As, consider polysorbate80, polysorbate20, sodium laurate, enuatrol, and sorbitan monooleate also can use in the context of the present invention. Anion surfactant also can be used to implement the present invention. These include, but not limited to sodium taurocholate, sodium lauryl sulfate, NaTDC, sodium laurate, enuatrol and potassium laurate.

In certain embodiments, dewatered ethanol can be used as the solvent of composition described herein. In other embodiments, ethylene glycol such as propane diols or polyethylene glycol are also within the scope of the invention. Simple compound polyol also can be used as suitable solvent. And, use the alcohol of not dehydration also to be suitable within the scope of the invention. Can recognize, for complete dissolved fat acid-anti-cancer composition is determined solvent and its suitable concentration in technical staff's technical scope, and not need unsuitable test.

As, the conjugate (Taxoprexin of DHA and paclitaxel ^TM) can in EtOH, provide with 100 mg/ml.Spissated conjugate can be with 4: 1 CremophorEL: EtOH surfactant/solvent diluted chemical compound to 2: 3, produce the DHA-paclitaxel intermediate solution of 40 mg/ml of Cremophor/EtOH carrier.This intermediate solution can be diluted in the injection carrier at 1: 5, as saline 5% glucose commonly used, obtains the whole compositions of DHA-paclitaxel of 8 mg/ml of Cremophor/EtOH.

DHA and other are spontaneous, unbranched fatty acid can with any anticancer compound conjugate basically, and use according to method of the present invention.Those skilled in the art also can recognize and are listed in the catalogue and are useful many other chemical compounds according to the present invention.

Anticancer compound includes, but are not limited to following compounds and classes of compounds: anti-tumor agent comprising salmosin is as Acivicin; Aclacnomycin A (Aclarubicin): Acodazole Hydrochloride; 42339 (Acronine): Adozelesin; Adriamycin (Adriamycin); Aldesleukin; Altretamine; Ambomycin (Ambomycin); Ametantrone Acetate; Aminoglutethimidium (Aminoglutethimide); Amsacrine; Nastrozole; Anthramycin (Anthramycin); Winter amidase (Asparaginase): Asperlin; Azacitidine:Azetepa; Azotomycin (Azotomycin); Batimastat:Benzodepa:Bicalutamide:Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulphate (Bleomycin Sulfate); Brequinar Sodium; Bropirimine; Busulfan (Busulfan); Cactinomycin; Clausterone (Calusterone); Caracemide; Carbetimer; Carboplatin; Carmustine (Carmustine); Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil (Chlorambucil); Four sieve ryemycins (Cirolemycin); Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide (Cyclophosphamide); Arabic cytosine glucosides (Cytarabine); Dacarbazine (Dacarbazine); DACA (N-[2-(dimethyl-amino) ethyl acridine-4-carboxylic acid amine); Dactinomycin (Dactinomycin); Daunomycin hydrochloride (DaunorubicinHydrochloride); Lead promise mycin (Daunomycin); Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Two nitrogen compounds (Diaziquone); Docetaxel; The inferior ryemycin (Doxorubicin) in Ya De; The inferior ryemycin hydrochloride (Doxorubicin Hydrochloride) in Ya De; Droloxifene; Droloxifene Citrate; First androstanolone propionic ester (DromostanolonePropionate); Diazamycine (Duazomycin); Edatrexate; EflornithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; 5-fluorouracil deoxynucleoside (Floxuridine); Fludarabine Phosphate; Fluorouracil (Fluorouracil); 5-FdUMP; Flurocitabine; Fosquidone; FostriecinSodium; Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea (Hydroxyurea); The plain hydrochloride (IdarubicinHydrochloride) of jaundice; Ifosfamide (Ifosfamide); Ilmofosine; Interferon A lfa-2a; Interferon A lfa-2b; Interferon A lfa-nl; Interferon A lfan3; Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Mexician scammony hydrochloride (Irinotecan Hydrochloride); Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine (Lomustine); Losoxantrone Hydrochloride; Masoprocol; Maytansine (Maytansine); Dichloromethyldiethylamine hydrochloride (Mechlorethamine Hydrochloride); Megestrol acetate (MegestrolAcetate); 16 methine megestrols (Melengestrol Acetate); Alkeran (Melphalan); Menogaril; Purinethol (Mercaptopurine); First ammonia folic acid (Methotrexate); First ammonia sodium folate Sodium pteroylgutamate (Methotrexate Sodium); Metoprine; Meturedepa (Meturedepa); Mitindomide; Mitocarcin; Silk splits erythroderma (Mitocromin); Silk splits lucky mycin (Mitogillin); Silk splits horse mycin (Mitomalcin); Mitomycin (Mitomycin); Mitosper; Adjacent phenalgin is to phenalgin dichloroethanes (Mitotane); Mitoxantrone Hydrochloride; Mycophenolic acid (Mycophenolic Acid); No constant boiling mixture (Nocodazole); Nogalamycin (Nogalamycin); Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin (Peliomycin); Pentamustine; Pentoside sulfate (PeplomycinSulfate); Perfosfamide; Pipobroman (Pipobroman); A-20968 (Piposulfan); Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Methylmitomycin (Porfiromycin); Prednimustine; Procarbazine hydrochloride (Procarbazine Hydrochloride); Puromycin (Puromycin); Puromycin hydrochloride (PuromycinHydrochloride); Pyridine furan rhzomorph (Pyrazofurin); Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Me-CCNU (Semustine); Simtrazene (Simtrazene); Sparfosate Sodium; Rare thiomycin (Sparsomycin); Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Rufocromomycin (Streptonigrin); Streptozotocin (Streptozocin); Strontium chloride (Strontium Chloride Sr 89); Sulofenur; Talisomycin; Taxane (Taxane); Taxoid; Tecogalan Sodium; Dermatitis bacterium (Tegafur); Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testis lactone (Testolactone); Thiamiprine; Thioguanine (Thioguanine): tespamin (Thiotepa); Thymitaq; Tiazofurin Tirapazamine; Tomudex; TOP-53; TopotecanHydrochloride:Toremifene Citrate; Trestolone Acetate; TriciribinePhosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride: uracil mustard gas (Uracil Mustard); Uredepa (Uredepa); Vapreotide; Verteporfin; Vinblastine (Vinblastine); Vinblastine sulfate (Vinblastine Sulfate); Vincristine (Vincristine); Vincristine sulfate (Vincristine Sulfate); Desacetyl vinblastine amide (Vindesine); Sulphuric acid desacetyl vinblastine amide (Vindesine Sulfate); Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine sulfate (Vinleurosine Sulfate); Vinorelbine Tartrate; Vinrosidine sulfate (Vinrosidine Sulfate); Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; ZorubicinHydrochloride; 2-chlorodeoxyadenosine (2-Chlorodeoxy adenosine); 2 '-deoxyformycin (2 '-Deoxyformycin); 9-aminocamptothecin (9-aminocamptothecin); Raltitrexed; N-propargyl-5,8-dideazafolic acid; 2-chloro-2 '-arabino-fluoro-2 '-deoxyadenosine; 2-chloro-2 '-deoxyadenosine; Anisomycin (anisomycin); Trichostatin A; HPRL-G129R; CEP751; Linomide; Sulfur mustard gas (sulfur mustard); Nitrogen mustard (nitrogen mustard) (mechlor ethamine); Cyclophosphamide (cyclophosphamide); Alkeran (melphalan); Chlorambucil (chlorambucil); Ifosfamide (ifosfamide); Busulfan (busulfan); N-methyl-N-nitrosourea (MNU); N, N '-two (2 chloroethyl)-N-nitroso ureas (BCNU); N-(2-chloroethyl)-N '-cyclohexyl-N-nitroso ureas (CCNU); N-(2-chloroethyl)-N '-(trans-4-methylcyclohexyl-N-nitroso ureas (MeCCNU); N-(2-chloroethyl)-N ' (diethyl) etherophosphoric acid-N-nitroso ureas (fotemustine); Streptozotocin (streptozotocin); Diacarbazine (DTIC); Mitozolomide; Temozolomide; Tespamin (thiotepa); Mitomycin (mitomycin C); AZQ; Adozelesin; Cisplatin (Cisplatin); Carboplatin; Ormaplatin; Oxaliplatin; C1-973; DWA 2114R; JM216; JM335; Two (platinum); Tomudex; Azacitidine; Arabic cytosine glucosides (cytarabine); Gemcitabine; Ismipur (6-Mercaptopurine); 6-thioguanine (6-Thioguanine); Hypoxanthine (Hypoxanthine); The teniposide 9-aminocamptothecin; Topotecan; CPT-11; Adriamycin (Doxorubicin); Daunomycin (Daunomycin); Epirubicin; Darubicin; Mitoxantrone; Losoxantrone; Dactinomycin (Dactinomycin) (radiation mycin D); Amsacrine; Pyrazoloacridine; Alltrans retinol; The 14-hydroxyl-backward-retinol; All-trans retinoic acid; N-(4-hydroxyphenyl) looks yellow amide; The 13-cis-retinoic acid; 3-methyl TTNEB; The 9-cis-retinoic acid; Fludarabine (2-F-ara-AMP); 2 chlorine deoxyadenosines (2-Cda).

Other anti-tumor compounds include :20-pi-1, 25 dihydroxyvitamin D3; 5 - ethynyluracil; abiraterone; Arak neomycin (aclarubicin); acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid (aminolevulinic acid); amrubicin; amsacrine; anagrelide; anastrozole; Peg even within the fat (Andrographolide); inhibitors of angiogenesis (angiogenesis inhibitors); Antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein - 1; antiandrogen substance (antiandrogen), phosphorus prostate cancer (prostatic carcinoma); antiestrogen (antiestrogen); anti-cancer substances (Antineoplaston); antisense oligonucleotide (antisense oligonucleotides); aphidicolin glycinate; programmed cell death gene regulatory factors (apoptosis gene modulators); regulator of programmed cell death (apoptosis regulators); no Purine nucleic acid (apurinic acid); ara-CDP-DL-PTBA; arginine deaminase (Arginine deaminase); asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL Antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate: bleomycin (bleomycin A2); Bo Bleomycin (bleomycin B2); bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives (Camptothecin derivatives) (eg, 10 - hydroxy camptothecin); canarypox IL-2; capecitabine; carboxamide - amino - triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor (cartilage derived inhibitor); carzelesin; casein kinase inhibitors (casein kinase inhibitors) (ICOS); castanospermine; cecropin (cecropin B); cetrorelix; chlorine (chlorins); chloro-quinoline sulfonamides (chloroquinoxaline sulfonamide); cicaprost; cis-porphyrin (cis-porphyrin); cladribine; ammonia Bottom Diaminodiphenol analogs (clomifene analogues); clotrimazole (clotrimazole); collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytosine arabinoside (cytarabine ocfosfate); dissolved Cytokines (cytolytic factor); cytostatin; dacliximab; decitabine; dehydrodidemnin B; 2 'deoxy Kefu neomycin (2'deoxycoformycin) (DCF); deslorelin; dexifosfamide; dexrazoxane; dexverapamil; two nitrogen compounds (Diaziquone); didemnin B; didox; diethylnorspermine; dihydro-5 - Azacytidine (dihydro-5-azacytidine); dihydro taxol (dihydrotaxol), 9 -; dioxamycin; biphenyl spiromustine; discodermolide; Docosanol (Docosanol); dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; Lam ene (elemene); emitefur; epirubicin; epothilones (A, R = H; B, R = Me); epithilones; epristeride; estramustine analogue; Estrogen agonist (estrogen agonists); estrogen antagonist (estrogen antagonists); etanidazole; etoposide; etoposide 4'-phosphate (Etopofos); exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate (Gallium nitrate); galocitabine; ganirelix; gelatinase inhibitor (Gelatinase inhibitors); gemcitabine; glutathione inhibitors (Glutathione inhibitors); hepsulfam; heregulin; cyclohexyl pair acetamide (Hexamethylene bisacetamide); Homoharringtonine alkali (Homoharringtonine) (HHT); hypericin (hypericin); ibandronic acid; yellow bile pigment (idarubicin); idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immune stimulant peptide (Immunostimulant peptides); insulin-like growth factor-1 - receptor inhibition Preparation (insulin-like growth factor-1 receptor inhibitor); interferon inflammatory Agents (interferon agonists); interferons (interferons); leukocyte interlayer Su (interleukins); iobenguane; iododoxorubicin; drug potato (ipomeanol), 4 -; drug potato (irinotecan); iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; sulfuric incense Mushroom sugar (lentinan sulfate); leptolstatin; letrozole; leukemia inhibitory factor (Leukemia inhibiting factor); leukocyte interferon (leukocyte alpha mterferon); leuprolide + female hormone (estrogen) + progesterone (Progesterone); leuprorelin; L four imidazole (levamisole); liarozole; Linear polyamine analogues (linear polyamine analogue); lipophilic disaccharide reduction of ammonia Acid (lipophilic disaccharide peptide); lipophilic platinum compounds (lipophilic platmum compounds); lissoclinamide 7; lobaplatin; guanidine ethyl phosphate Serine (lombricine); lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; Lytic peptide (lytic peptides); maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinases White enzyme inhibition (matrix metalloproteinase inhibitors); menogaril; merbarone; meterelin; methioninase; metoclopramide (metoclopramide); MIF inhibitors; mifepristone; miltefosine; mirimostim; mismatch duplexes RNA (mismatched double stranded RNA); mithramycin (mithracin); Imipramine hydrazone (mitoguazone); mitolactol; mitomycin analogues (mitomycin analogues); mitonafide; silk toxins fibroblast growth factor - saponin (Mitotoxin fibroblast growth factor-saporin); mitoxantrone; mofarotene; molgramostim; monoclonal antibody (monoclonal antibody). Human test Rio If Ning (human chorionic gonadotrophin); monophosphoryl lipid Quality + fungal cell wall SK (monophosphoryllipid A + mycobacterium cell wall sk); mopidamol; multiple drug resistance gene inhibitor (multiple drug resistance gene inhibitor); multiple tumor suppressor 1 - group therapy (multiple tumor suppressor 1-based therapy); mustard anticancer agents (mustard anticancer agent); mycaperoxide B; fungal cell wall extract (Mycobacterial cell wall extract); myriaporone; N-acetyldinaline; N-substituted benzamides (N-substituted benzamides); nafarelin; nagrestip; Allyl oxymorphone + pentazocine (naloxone + pentazocine); napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; Enzyme neutral endopeptidase (neutral endopeptidase); nilutamide; nisamycin; Nitric oxide modifier (nitric oxide modulators); nitroxide antioxidant (Nitroxide antioxidant); nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides (oligonucleotides); onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer (oral cytokine inducer); ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; much sodium pentosan (Pentosan polysulfate sodium); amyl glucoside (pentostatin); pentrozole; perflubron; perfosfamide; perilla alcohol (perillyl alcohol); phenazinomycin; phenylacetate (phenylacetate); phosphatase inhibitor (Phosphatase inhibitors); quinone (picibanil); pilocarpine hydrochloride Matter (pilocarpine hydrochloride); pirarubicin; piritrexim; placetin A; placetin B; blood stimulant plasminogen inhibitor (plasminogen activator inhibitor); platinu tetrachlorodecaoxide; tetrazomine; thalibiastine; thalidomide; thiocoraline; thrombosis prime (Thrombopoietin); thrombosis hormone analogues (thrombopoietin mimetic); thymalfasin; thymus erythropoietin receptor agonists (thymopoietin receptor agonist); thymotrinan; thyroid-stimulating hormone (thyroid stimulating hormone); tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene; totipotent fine Cytokines (totipotent stem cell factor); translation inhibitors (translation inhibitors); retinoic acid (tretinoin); triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor Preparations (tyrosine kinase inhibitors); tyrphostins; UBC inhibitors; ubenimex; genitourinary Dou Yansheng growth inhibitory factor (urogenital sinus- derived growth inhibitory factor); urokinase receptor antagonist (urokinase receptor antagonists); vapreotide; variolin B; vector system (vector system), red blood cell gene therapy (erythrocyte gene therapy); velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer. ...

Antiproliferative reagent: Piritrexim Isothionate.

Anti-prostate hyperplasia: Sitogluside.

Treatment of benign prostate hyperplasia reagent: tamarind seed gum (TamsulosinHydrochloride).

Prostate growth inhibitor: Pentomone.

Radioreagent: Fibrinogen (Fibrinogen 1125); FludeoxyglucoseF18; Fluorodopa F18; Insulin (Insulin I125); Insulin (Insulin I131); Lobenguane I 123; Adipiodone sodium (Iodipamide Sodium I 131); Iodantipyrine (Iodoantipyrine I 131); Iodocholesterol (Iodocholesterol I131); Iodohippurate Sodium I 123; Iodohippurate Sodium I 125; Iodohippurate Sodium I 131; Iodopyracet (Iodopyracet I 125); Iodopyracet (Iodopyracet I 131); Lofetamine Hydrochloride I 123; Iomethin I 125; Iomethin I 131; Brain shadow acid sodium (Iothalamate Sodium I125); Brain shadow acid sodium (Iothalamate Sodium I 131); Tyrosine (tyrosine1 131); Liothyronine I 125; Liothyronine I 131; Hydroxyl isopropyl alcohol acetas Mercury-197 (Merisoprol Acetate Hg 197); Hydroxyl isopropyl alcohol acetas Mercury-203 (Merisoprol Acetate Hg 203); Hydroxyl isopropyl alcohol Mercury-197 (Merisoprol Hg197); Selenomethionine selenium 75 (Selenomethionine Se 75); Technetium Tc 99m antimony trisulfide colloid (Technetium Tc 99m Antimony Trisulfide Colloid); Technetium Tc 99m Bicisate; Technetium Tc 99m Disofenin; Technetium Tc 99m Etidronate; Technetium Tc 99m Exametazime; Technetium Tc 99m Furifosmin; Technetium Tc 99mGluceptate; Technetium Tc 99m Lidofenin; Technetium Tc 99m Mebrofenin; Technetium Tc99m Medronate; Technetium Tc 99m Medronate Disodium; Technetium Tc 99mMertiatide; Technetium Tc 99m Oxidronate; Technetium Tc 99m Pentetate; Technetium Tc 99mPentetate calcium trisodium; Technetium Tc 99m Sestamibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m Succimer; Technetium Tc 99m sulfur colloid; Technetium Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin; Technetium Tc 99m Tiatide; Thyroxine (Thyroxine 1125); Thyroxine (Thyroxine 1 131); Polyvinylpyrrolidone under the iodine (Tolpovidone 1 131); Triolein (Triolein 1 125); Triolein (Triolein 1 131).

Anticancer assisted and strengthened reagent: three rings resist-downern (as imipramine, desmethylimipramine, amitryptyline, clomipramine, trimeprimine, doxepin, desitriptilina, protriptyline, chlorine piperazine oxygen, maprotiline); Non-three ring anti-downerns (as sertraline, trazodone and citalopram); Ca antagonist (as verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitor (as prectolact, fluoroform croak promazine and clomipramine); Amphotericin B; Triparanol analog (as tamoxifen); Antiarrhythmic drug (as quinidine); Antihypertensive drug (as reserpine); Thiol depletion agent (as buthionine and sulfo group oxime) and multi-drug resistance slow down reagent such as Cremophor EL.Chemical compound of the present invention also can be taken as the excitatory factor of granulocyte colony with cytokine.

Good anticancer reagent (MTD of some and they is presented in the bracket) comprising: gemcitabine (1000 milligrams/square metre); Methotrexate (15 milligrams of/square metre i.v.+leuco＜500 milligram/square metre i.v.w/o leuco); 5-FU (500 milligrams/square metre/days * 5 days); FUDR (100 milligrams/kilogram * 5-Mus; 0.6 milligram/kg/day-human i.a.); FdUMP; Hydroxyurca (35 milligrams/kg/day, the man); Docetaxel (the 60-100 milligram/square metre); Discodermolide; Epothilones; Vincristine (1.4 milligrams/square metre); Vinblastine (raise gradually: the 3.3-11.1 milligram/square metre, or near 18.5 milligrams/square metre); Vinorelbine (30 milligrams/square metre/week); Between position-pac; Mexician scammony (the 50-150 milligram/square metre, 1 */week depend on reaction); SN-38 (than effective about 100 times of Mexician scammony); 10-OH campto; Topotecan (1.5 milligrams/square metre/days-mankind, 1 * ivLDl0 Mus=75 milligram/square metre); Etoposide (100 milligrams/square metre, the man); Amycin; Flavopiridol; Cis-Pt (100 milligrams/square metre, the man); Carbo-Pt (360 milligrams/square metre, the man); Bleomycin (20 milligrams/square metre); Ametycin (20 milligrams/square metre); Mithramycin (30ug/ kilogram); Capecitabine (2.5 grams/square metre, oral); Arabic cytosine glucosides (100 milligrams/square metre/days); 2-CL-2 ' deoxyadenosine; Fludarabine-PO ₄(25 milligrams/square metre/days, * 5 days); Mitoxantrone (the 12-14 milligram/square metre); Mitozolomide (＞400 milligrams/square metre); Pentoside; Tomudex.

As used herein, taxane is to have the molecule that three ring carbon atoms are communicated with net, and it mixes the carbon-to-carbon multikey, and it can comprise substituent group, functional group and other rings by comprising carbon atom-non-carbon atom key.As used herein, the structure of taxane is at United States Patent (USP) 5,795, shows in 909.

Taxoid is a molecule relevant with taxane on the structure, wherein top taxane carbon atom is communicated with net and has changed, as by one or more isocyclic cracking, by removing or adding the carbon substituent group, by connecting the common each other not carbon atom of bonding, by disconnecting usually the carbon atom of bonding each other, or by the taxane carbon atom being communicated with some other reorganization or adjustment of net, but wherein taxane carbon atom one or more construction featuress of being communicated with net still keep.

Make the chemical compound used in this invention can be with anticancer cocktail form administration.Anticancer cocktail is to use any chemical compound and another kind of antitumor and anticancer agent such as cancer therapy drug in the present invention, cytokine, and/or the mixture of assisted and strengthened reagent.It is common using cocktail in the treatment cancer.In this embodiment, drug administration carrier commonly used (as, pill, tablet, implant, Injectable solution etc.) can comprise and make conjugate used in this invention and antitumor and anticancer agent and/or assisted and strengthened reagent.

Usually, except cancer, anticancer conjugates of the present invention also can be used in the treatment mammalian cell proliferation pathological changes, comprises psoriasis, photochemical cutin disease etc.They further can be used to treat diabetes and diabetic complication, the excess acid secretion, and with the cholesterol-associated cardiovascular patient's condition (as hyperlipidemia and high-cholesterol disease), dysentery, ovarian disease (as endometriosis, ovarian cyst) and conduct contraception reagent.

Other composition substances are provided in another aspect of the present invention.According to this aspect of the present invention, compositions comprises the pure basically crystal of the conjugate of fatty acid and medicine.In the present invention was aspect this, fatty acid was the polymerization unsaturated fatty acid.In some embodiments, fatty acid is that C16-26 is spontaneous preferably, unbranched fatty acid.Fatty acid can be chosen from following group, comprise C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 (Palmic acid), C16:1 (gaidic acid), C16:2, C18:0 (stearic acid), C18:1 (oleic acid), C18:1-7 (arachic acid 11), Cl8:2-6 (linoleic acid), C18:3-3 (α-linoleic acid), C18:3-5 (octadecylene three acid), C18:3-6 (β-linoleic acid), C18:4-3, C20:1 (20 carbon, 11 olefin(e) acids), C20:2-6, C20:3-6 (dihomo-y-linoleic acid), C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (20 carbon diene acid), C22:1 (docosenoic acid), C22:4-6 (docosatetratenoic acid), C22:5-6 (clupanodonic acid), C22:5-3 (clupanodonic acid), C22:6-3 (docosahexenoic acid), and C24:1-9 (nervonic acid).Special recommendation be docosahexenoic acid.In certain embodiments, fatty acid can be a linoleic acid, Palmic acid, arachidonic acid, 20 carbon diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.In the embodiment of special recommendation, fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 carbon diene acid, or docosahexenoic acid.

According to this aspect of the present invention, medicine can be any medicine that can form conjugate with fatty acid.Preferably, medicine contains the free group with the reaction of the free acid of fatty acid.Better, medicine contains free-OH or NH ₂Group.Medicine includes, but are not limited to, following reagent: epinephrine reagent; Adrenocortical steroid; The adrenal cortex inhibitor; The ethanol scavenger; Aldosterone antagonist; Aminoacid; Ammonia anesthetis; Anabolism reagent; Analeptic; Analgesic; Androgen; Anesthesia, attached; Anesthetis; Anorexia reagent; Antagonist; Preceding pituitary inhibitors; Anthelmintic; Anti-acne reagent, antiadrenergic drug reagent; Antiallergic reagent; Anti-ameba worm reagent; Antiandrogen reagent; Anti-anemia reagent; Antianginal reagent; Anxiety reagent; Arthritis reagent, asthma reagent; Atherosclerosis reagent; Antibacterial agent; Anti-cholelithiasis reagent; Anti-cholelithiasis generates reagent; Anti-parasympathetic nervous physiological action nerve; Anticoagulant; Anticoccidal; Convulsion reagent; Antidepressant reagent; Anti-diabetic reagent; Stopping leak reagent; Antidiuretic; Detoxifcation reagent; Anti-emetic; Epilepsy reagent; Anti-estrogen reagent; Antilysis fibrin reagent; Antifungal agents; Glaucoma reagent; Hemophilia reagent; Hemorrhage reagent; Hydryllin; Lipidemia reagent; Antihyperlipoproteinemic; Resisting hypertension reagent; Hypotension reagent; Infection reagent, anti-local infection reagent; Anti-inflammatory agent; Anti-keratinization reagent; Malaria reagent; Antibacterial agent; Migraine reagent; Resisting mitosis reagent; Antifungal agents ends the reagent of feeling sick; Anti-tumor agent comprising salmosin, antineutropenic, antiobessional agent; Anti-parasitic reagent; Anti-Parkinson disease reagent; Anti-wriggling reagent; Antipneumocystic; Antiproliferative reagent; Anti-prostate hyperplasia reagent; Protozoacide reagent; Antipruritic reagent; Stable reagent; Anti-rheumatism reagent; Schistosomicide reagent; Seborrhea reagent; Secretion inhibitor reagent; Spasmolytic reagent; Antithrombotic forms reagent; Cough-relieving reagent; Antiulcer reagent; Anti-urinary calculi reagent; Anti-virus reagent; Appetite suppressant; Treatment of benign prostate hyperplasia reagent; Blood glucose regulation reagent; Bone resorption inhibitor; Bronchiectasis reagent; The carbon dehydratase inhibitor; The heart tranquilizer; Protect heart reagent; Cardiac tonic; Hot blood vessel reagent; Short bile secretion reagent; Quasi acetylcholine reagent; The quasi acetylcholine agonist; Acetylcholine esterase brings back to life the examination deactivator; The coccidiosis inhibitor; The thinking auxiliary reagent; The thinking reinforcing agent; Inhibitor; The diagnosis adjuvant; Diuretic; Dopaminergic reagent; Kill ectoparasite reagent; Emetic; Enzyme inhibitor; Estrogen; Dissolving fibrin reagent; Fluorometric reagent; Oxygen radical removing reagent; The gastrointestinal movement reinforcing agent; Sugar (cortical hormone agent; Gonad stimulates principle; Hair growth stimulant; Hemorrhage; Histamine H 2 receptor's antagonist; Hormone; Reduce blood cholesterol reagent; Hypoglycemia reagent, blood fat reducing reagent; Hypotension reagent; Imaging agents; Immunoreagent; Reagent is adjusted in immunity; Immunomodulating reagent; Immunostimulant; Immunosuppressant; Sexual impotence tumor auxiliary reagent; Inhibitor; Keratolysis reagent; The LNRH agonist; Liver pathological changes treatment reagent; Luteolysin reagent; The memory auxiliary reagent; Intelligence performance reinforcing agent; The mood regulation agent; Mucolysis reagent; Mucus protection reagent; Hole reagent looses; Nose is separated congested reagent; Neuromuscular is prevented reagent; Neuroprotective reagent; Nmda antagonist; Non-hormone steroid derivatives; Oxytocic reagent; Plasminogen activator; Controlling of platelet factor antagonist; Platelet gathering inhibitor; After the apoplexy and head back injury in treating reagent; Reinforcing agent; Progesterone; Prostaglandin; The prostate growth inhibitor; Prothyrotropin; Act on psychosis reagent; Lung surface reagent; Radiation reagent; Regulator; Slow reagent; Heavily distribute reagent; Anti-acaricide reagent; Cause sclerosis reagent; Tranquilizer; Tranquilizing soporific reagent; Selective adenosine A1 antagonist; Be contained in the varies antagonist in the blood; Be contained in the varies inhibitor in the blood; Be contained in the varies receptor antagonist in the blood; Steroid; Stimulant; Inhibitor; The multiple sclerosis reagent of disease; Compounding ingredient; Thyroxin; Thyroid imhibitor; The thyroid analog; Tranquilizer; Treatment amyotrophic lateral sclerosis reagent; Treatment cerebral ischemia reagent; Treatment Paget disease reagent; Treat unstable pharyngalgia reagent; Uricosuric urine reagent vasoconstriction reagent; Vasodilation reagent; Cure wound reagent; Treatment wound reagent; Xanthine oxidase inhibitor.

Chemical compound inventory in these catalogues each can be at United States Patent (USP) 5,795, finds in 909, and its disclosure is all by being incorporated in this paper in this citation.The medicine group is an antitumor and anticancer agent preferably, and infection reagent comprises antibiotic and Anti-virus agent and neurological reagent comprise tranquilizer.Antitumor and anticancer agent and good anticancer reagent are as described above.

Infection reagent comprises: the Difloxacin hydrochloride; Lauryl IsoquinoliniumBromide; Moxalactam disodium (Moxalactam Disodium); Ornidazole; Pentisomicin; The Sarafloxacin hydrochloride; HIV and other retroviral protease inhibitor; HIV and other retroviral integrase inhibitors; Cephalosporin under the hydrogen ammonia (Cefaclor) (Ceclor); Nothingization guanosine (Acyclovir) (Zovirax); Norfloxacin (Norfloxacin) (Noroxin); First ammonia thiophene cephalosporin (Cefoxitin) (Mefoxin); Cefuroxime (Cefuroxime) axetil (Ceftin); Cirramycin (Ciprofloxacin) (Cipro); Amino bifurcation pyridine hydrochloride (Aminacrine Hydrochloride); Second ammonia ammonium (BenzethoniumChloride) under the chlorination: Bithionolate sodium; Bromine phenalgin oxazolone (Bromchlorenone); Urea peroxide (Carbamide Peroxide); Cetalkonium Chloride; Cetylpyridinium Chloride: chlorhexidine hydrochloride (Chlorhexidine Hydrochloride); Clioquinol; Domiphen bromide (DomiphenBromide); D25 (Fenticlor); Fludazonium Chloride; Pinkish red (Fuchsin), alkalescence (Basic); Furazolidone (Furazolidone); Gentian Violet Gentian Violet; Three close chlorine ammonia quinoline (Halquinols); Hexachlorophene (Hexachlorophene): hydrogen peroxide (Hydrogen Peroxide); Ichthyol (Ichthammol); Imidecyl iodine; Iodine; Isopropyl alcohol; Mafenide acetate (MafenideAcetate); Meralein Sodium; Mercufenol Chloride; Hydrargyrum, bonded with ammonia; The methyl chloride benzyl first and second ammonia amine (Methylbenzethonium Chloride); Nitrofural (Nitrofurazone); Nitromersol (Nitromersol); The Octenidine hydrochloride; Hydroxyl chlorine is given birth to (Oxychlorosene); Oxychlorosene sodium (OxychloroseneSodium); Parachlorophenol (Parachlorophenol), bonded with Camphora, potassium permanganate (Potassium Permanganate); Polyvinyl pyrrolidone-iodine (Povidone-Iodine); Sepazonium Chloride; Silver nitrate (Silver Nitrate); Sulfadiazine (Sulfadiazine), silver; Symclosene; Thimerfonate sodium; Thimerosal:Troclosene potassium.

Antimicrobial agents include: two acetyl dapsone pair (Acedapsone); acetyl sulfone sodium (Acetosulfone Sodium); A bleomycin (Alamecin); alexidine (Alexidine); Amdinocillin; Amdinocillin Pivoxil; Amit tetracycline (Amicycline); cerebellar nuclear envelope (Amifloxacin); cerebellar nuclei enveloped methanesulfonyl Salt (Amifloxacin Mesylate); chlorine amikacin (Amikacin); sulfuric acid Chlorine amikacin (Amikacin Sulfate); aminosalicylate (Aminosalicylic acid); Aminosalicylate sodium; oxygen ammonia under penicillin (Amoxicillin); androgyny ADM (Amphomycin); ampicillin (Ampicillin); ampicillin Sodium (Ampicillin Sodium); nalidixic sodium penicillin (Apalcillin Sodium); Apramycin; aspartame streptozotocin (Aspartocin); sulfate A Division m star (Astromicin Sulfate); Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; ammonia under penicillin amyl methyl hydrogen chloride (Bacampicillin Hydrochloride); bacitracin (Bacitracin); bacitracin methylene Disalicylate; Zinc Bacitracin (Bacitracin Zinc); spots Tony neomycin (Bambermycins); Benzoylpas calcium; deoxy erythromycin (Berythromycin); neomycin sulfate, betamethasone (Betamicin Sulfate); Biapenem; dinitramide neomycin (Biniramycin); Biphenamine hydrochloride; Bispyrithione Magsulfex; Butikacin; sulfuric acid Butyrylcholinesterase glycosides streptozotocin (Butirosin Sulfate); sulfate ciprofloxacin (Capreomycin Sulfate); Kabbah ammonia (Carbadox); carbenicillin disodium (Carbenicillin Disodium); Indanyl carbenicillin sodium (Carbenicillin Indanyl Sodium); Carbenicillin phenyl sodium (Carbenicillin Phenyl Sodium); carbenicillin Potassium (Carbenicillin Potassium); Carumonam sodium; chloramines under cephalosporins (Cefaclor); cefadroxil under (Cefadroxil); cephalosporin hydroxy azole (Cefamandole); cephalosporin hydroxy azole Nafate; cephalosporin sodium hydroxy azole (Cefamandole Sodium); ammonia under thiadiazole hydroxyl cephalosporins (Cefaparole); Hydroxy triazine under ammonia sulfur A cephalosporin (Cefatrizine); Cefazaflur sodium; cephalosporin Factor V (Cefazolin); cephalosporins V sodium (Cefazolin Sodium); Cefbuperazone; Cefdinir; Cefepime: Cefepime hydrochloride: Cefetecol; Cefixime; cefotaxime azole hydrochloride (Cefmenoxime Hydrochloride); Cyanide-yl methoxy cephalosporins (Cefmetazole); yl methoxy cephalosporins sodium cyanide (Cefmetazole Sodium); Cefonicid a sodium; Cefonicid sodium; oxygen piperazine hydroxyphenyl Azole head sodium (Cefoperazone Sodium): Water-soluble oil (Ceforanide); ammonia The cephalosporin cefotaxime sodium (Cefotaxime Sodium): yl methoxy cephalosporins disulfiram (Cefotetan); yl methoxy cephalosporins disulfide disodium (Cefotetan Disodium); thiophene Ammonia yl acetate hydrochloride cephalosporins (Cefotiam Hydrochloride); methoxy-thiophene Cephalosporins (Cefoxitin); methoxy-thiophene cephalosporin sodium (Cefoxitin Sodium); Cefpimizole; Cefpimizole sodium; cefepime tetrazole (Cefpiramide); cephalosporins Pyrazole tetrazole sodium (Cefpiramide Sodium); sulfuric acid cephalosporin genus (Cefpirome Sulfate); Cefpodoxime Proxetil; Cefprozil; methoxy cycloalkenyl cephalosporins (Cefroxadine); sulfinpyrazone under cefotaxime sodium (Cefsulodin Sodium); head Spore thiophene carboxymethyl oxime (Ceftazidime); Ceftibuten; cephalosporin cefotaxime sodium (Ceftizoxime Sodium); Ceftriaxone sodium; cefuroxime (Ceffuroxime); deoxycholate (Cefuroxime Axetil); cefuroxime Pivoxetil; cefuroxime sodium (Cefuroxime Sodium); ammonia A cephalosporin Sodium (Cephacetrile Sodium); Cephalexin (Cephalexin); cephalexin Hydrogen chloride (Cephalexin Hydrochloride); cephalosporin adenosine (Cephaloglycin); Vanguard ADM (Cephaloridine); cefotaxime sodium (Cephalothin Sodium); cephalosporin sodium pyrithione (Cephapirin Sodium); ring Hexene amine cephalosporins (Cephradine); Cetocycline hydrochloride; Cetophenicol; chloramphenicol (Chloramphenicol); chloramphenicol palmitate (Chloramphenicol Palmitate); chloramphenicol pantothenic acid ester compound (Chloramphenicol Pantothenate Complex); chloramphenicol sodium succinate (Chloramphenicol Sodium Succinate); chlorhexidine Phosphanilate (Chlorhexidine Phosphanilate); chloroxylenol (Chloroxylenol); chlortetracycline bisulfate (Chlortetracycline Bisulfate); chlortetracycline hydrochloride (Chlortetracycline Hydrochloride); Cinoxacin; ciprofloxacin (Ciprofloxacin); ciprofloxacin hydrochloride (Ciprofloxacin Hydrochloride); Ciro in adriamycin (Cirolemycin); Clarithromycin; Clinafloxacin hydrochloride; clindamycin (Clindamycin); clindamycin hydrochloride (Clindamycin Hydrochloride); clindamycin palmitate hydrochloride (Clindamycin Palmitate Hydrochloride); clindamycin phosphate (Clindamycin Phosphate); clofazimine (Clofazimine); Cloxacillin Benzathine under (Cloxacillin Benzathine); cloxacillin sodium (Cloxacillin Sodium); Cloxyquin; colistin methanesulfonate sodium (Colistimethate Sodium); sulfuric stick Streptozotocin (Colistin Sulfate); coumermycin (Coumermycin); coumermycin Sodium (Coumermycin Sodium); ammonia cyclohexanone penicillin (Cyclacillin); ring Serine (Cycloserine); Dalfopristin; diamine diphenyl sulfone (Dapsone); Daptomycin; Demeclocycline (Demeclocycline); Demeclocycline hydrochlorothiazide Compound (Demeclocycline Hydrochloride); norepinephrine tetracycline (Demecycline); Denofungin; Diaveridine; dichlorobenil isoxazole Penicillium Su (Dicloxacillin); dichlorobenil isoxazole penicillin sodium (Dicloxacillin Sodium); dihydrostreptomycin sulfate (Dihydrostreptomycin Sulfate); Dipyrithione; Dirithromycin; Doxycycline (Doxycycline); doxycycline Calcium (Doxycycline Calcium); doxycycline Fosfatex; doxycycline Hyclate; Droxacin sodium; Enoxacin; Epicillin; Epitetracycline hydrogen chloride Things; Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythromycin ethyl succinate; Erythromycin Gluceptate; Erythromycin Lactobionate; Erythromycin propionate; Erythromycin Stearate; ethambutol hydrochloride (Ethambutol Hydrochloride); B Ethionamide (Ethionamide); Fleroxacin; flucloxacillin (Floxacillin); Fludalanine; flumequine (Flumequine); fosfomycin (Fosfomycin); phosphorus ADM tromethamine (Fosfomycin Tromethamine); Fumoxicillin; Furazolium chloride; Furazolium tartrate; brown mycophenolate sodium (Fusidate Sodium); fusidic acid (Fusidic Acid); Gentamicin Sulfate (Gentamicin Sulfate); Gloximonam; gramicidin (Gramicidin); iodine chlorobenzene alkynyl ethers (Haloprogin); ketal ammonia under penicillin (Hetacillin); ketal under ammonia Penicillium Su potassium (Hetacillin Potassium); pair has imidazole (Hexedine); Ibafloxacin; Imipenem; Isoconazole; Isepamicin; INH (Isoniazid); cross the sand mold Su (Josamycin); kanamycin sulfate (Kanamycin Sulfate); North mildew Su (Kitasamycin); Levofuraltadone; Levopropylcillin potassium; Lexithromycin; lincomycin (Lincomycin); lincomycin hydrochloride (Lincomycin Hydrochloride); Lomefloxacin; Lomefloxacin hydrochloride Compounds; Lomefloxacin methanesulfonate; Loracarbef; ammonia under sulfonamides (Mafenide); Meclocycline; Meclocycline Sulfosalicylate; Megalomicin potassium phosphate; Mequidox; Meropenem; Methacycline (Methacycline); methylene oxytetracycline Su hydrochloride (Methacycline Hydrochloride); hexamethylene tetramine (Methenamine); hexamethylene tetramine hippurate (Methenamine Hippurate); hexamethylene tetramine mandelate (Methenamine Mandelate); Methicillin sodium; Metioprim; metronidazole hydrochloride (Metronidazole Hydrochloride); phosphate metronidazole (Metronidazole Phosphate); plum Jezero amoxicillin (Mezlocillin); Mezlocillin sodium (Mezlocillin Sodium): Minocycline (Minocycline); minocycline hydrochloride (Minocycline Hydrochloride); Mirincamycin hydrochloride; monensin Streptozotocin (Monensin); monensin sodium (Monensin Sodium); ethoxy naphthalene Amine penicillin sodium (Nafcillin Sodium); Nalidixate sodium; nalidixic acid (Nalidixic Acid); Tennessee streptozotocin (Natamycin); dark neomycin (Nebramycin); New Neomycin palmitate (Neomycin Palmitate); neomycin sulfate (Neomycin Sulfate); neomycin undecyl formate (Neomycin Undecylenate); sulfur Amphotericin B acid shuttle Kissi (Netilmicin Sulfate); neutral neomycin (Neutramycin); Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone; Nifurdazil: Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline; furan Tsui pyridine (Nitrofurantoin); Nitromide; norfloxacin (Norfloxacin); novobiocin sodium (Novobiocin Sodium); pyridine carboxylase (Ofloxacin); Ormetoprim; benzoyl isoxazole penicillin sodium (Oxacillin Sodium); Oximonam; Oximonam sodium; oxolinic acid (Oxolinic Acid); Terramycin (Oxytetracycline); oxytetracycline calcium (Oxytetracycline Calcium); Oxytetracycline hydrochloride (Oxytetracycline Hydrochloride); Paldimycin; Chlorophenol (Parachlorophenol); Paulomycin; peel oil (Pefloxacin); Peel oil mesylate (Pefloxacin Mesylate); penicillin G diester (Penamecillin); Penicillin G Benzathine under (Penicillin G Benzathine); penicillin G potassium (Penicillin G Potassium); penicillin G Procaine (Penicillin G Procaine); penicillin G sodium (Penicillin G Sodium); penicillin V (Penicillin V); Benzathine penicillin V for (Penicillin V Benzathine); penicillin V Hydrabamine; penicillin V potassium (Penicillin V Potassium); Pentizidone sodium; phenylamino salicylate (Phenyl Aminosalicylate); Piperacillin Sodium (Piperacillin Sodium); Pirbenicillin sodium; Piridicillin sodium; Pirlimycin hydrochloride; ammonia Benzylpenicillin hydrochloride (Pivampicillin Hydrochloride); ampicillin Pamoate (Pivampicillin Pamoate); ampicillin Probenate; multi- Polymyxin B sulfate (Polymyxin B Sulfate); methyl mitomycin (Porfiromycin); Propikacin; pair of two amide nitrogen benzene (Pyrazinamide); Pyrithione zinc; Quindecamine acetate; Quinupristin; racemic thiamphenicol (Racephenicol); Ramoplanin; Rainey neomycin (Ranimycin); raloxifene ADM (Relomycin); Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamycin B diethylamide (Rifamide); Rifampin; Rifapentine; Rifaximin; topiramate A tetracycline (Rolitetracycline); topiramate A tetracycline nitrate (Rolitetracycline Nitrate); rose neomycin (Rosaramicin); rose ADM Butyrate (Rosaramicin Butyrate); rose neomycin propionate (Rosaramicin Propionate); rose neomycin phosphate (Rosaramicin Sodium Phosphate); Rose neomycin stearate (Rosaramicin Stearate); Rosoxacin; Roxarsone; Polyamide fibers (Roxithromycin); demethyl deoxytetracyclines (Sancycline); Sanfetrinem sodium; Sarmoxicillin; Sarpicillin; absorbent nystatin (Scopafungin); basil neomycin (Sisomicin); basil neomycin sulfate (Sisomicin Sulfate); Sparfloxacin; odd actinomycin hydrochloride (Spectinomycin Hydrochloride); spiramycin (Spiramycin); Stallimycin hydrochloride; Myers neomycin (Steffimycin); streptomycin (Streptomycin Sulfate); chain ADM isoniazid (Streptonicozid); Sulfabenz; benzoyl sulfanilamide (Sulfabenzamide); sulfa acetate (Sulfacetamide); sulfonamide sodium acetate (Sulfacetamide Sodium); Sulfacytine; sulfadiazine (Sulfadiazine); Sulfadiazine sodium (Sulfadiazine Sodium); sulfadoxine-pyrimethamine (Sulfadoxine); sulfonamide Amine methoxy pyrazine (Sulfalene); Sulfamerazine; sulfonamides 5 - methoxy-pyrimidine (Sulfameter); sulfamethazine (Sulfamethazine); sulfamethoxazole thiadiazole (Sulfamethizole); sulfamethoxazole (Sulfamethoxazole); sulfonamide Amine-6-methoxy-pyrimidine (Sulfamonomethoxine); sulfonamides azole (Sulfamoxole); Sulfonamides zinc (Sulfanilate Zinc); Sulfanitran; sulfasalazine (Sulfasalazine); sulfamethoxazole thiazole (Sulfasomizole); Sulfathiazole (Sulfathiazole); Sulfazamet; sulfonamides isoxazole (Sulfisoxazole); Isoxazole sulfonamides Acetyl (Sulfisoxazole Acetyl); sulfonamides evil Azole Diolamine; sulfonamide A polymyxin B (Sulfomyxin); Sulopenem; Sultamicillin; sulfur ampicillin sodium (Suncillin Sodium); ammonia under Penicillium Su hydrochloride (Talampicillin Hydrochloride); Teicoplanin; Temafloxacin hydrochloride; Temocillin; Tetracycline (Tetracycline); four Doxycycline hydrochloride (Tetracycline Hydrochloride); tetracycline phosphate complex Compound (Tetracycline Phosphate Complex); tetrathionate (Tetroxoprim); methylsulfonylbenzoic chloramphenicol (Thiamphenicol); Thiphencillin Potassium; tolyl ticarcillin sodium (Ticarcillin Cresyl Sodium); carboxylic Thiophene penicillin disodium (Ticarcillin Disodium); ticarcillin monosodium (Ticarcillin Monosodium); Ticlatone; Tiodonium chloride; Taub Clarithromycin (Tobramycin); Tuobu La neomycin sulfate (Tobramycin Sulfate); Tosufloxacin; Trimethoprim (Trimethoprim); ethyl sulfate trimethoprim Pyridine (Trimethoprim Sulfate); triple sulfadiazine (Trisulfapyrimidines); Triacetyl oleandomycin (Troleandomycin); Trospectomycin sulfate; mix Together tyrothricin (Tyrothricin); vancomycin (Vancomycin); vancomycin Su hydrochloride (Vancomycin Hydrochloride); Virginiamycin (Virginiamycin); Zuoer Bo neomycin (Zorbamycin). ...

Anti-virus agent comprises: Acemannan; Acycloguanosine (Acyclovir); Acyclovir Sodium (Acyclovir Sodium); Adefovir; Alovudine; AlvirceptSudotox; Amantadine hydrochloride (Amantadine Hydrochloride); Aranotin (Aranotin); Arildone; The Atevirdine mesylate; Avridine; Cidofovir, Cipamfylline; Arabic cytosine glucosides hydrochloride (CytarabineHydrochloride); The Delavirdine mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine hydrochloride (Famotine Hydrochloride); Fiacitabine; Fialuridine; Fosarilate; Phosphocholine calcium sodium (Foscarnet Sodium); Fosfonet sodium; Ganciclovir; Ganciclovir sodium; Potassium iodomercurate (Idoxuridine); Kethoxal (Kethoxal); Lamivudine; Lobucavir; The Memotine hydrochloride; Methisazone (Methisazone); Nevirapine; Penciclovir; Pirodavir; Ribavirin (Ribavirin); The Rimantadine hydrochloride; The Saquinavir mesylate; The Somantadine hydrochloride; Sorivudine; Pu's branch penicillium (Statolon); Stavudine; Tilorone long-range navigation hydrochloride (Tilorone Hydrochloride); Trifluridine; The Valacyclovir hydrochloride; Vidarabine; Vidarabine phosphate; The Vidarabine na phosphates; Viroxime; Zalcitabine; Zidovudine; Zinviroxime and integrase inhibitor.

Neurological agents, including anti-psychotic agents, including but not limited to: acetyl Fen Are static maleate (Acetophenazine Maleate); Alentemol hydrobromide; Alpertine; Azaperone; Batelapine maleate; phenyl ketone prazosin (Benperidol); benzyl indole pyridine hydrochloride (Benzindopyrine Hydrochloride); Brofoxine; bromine piperazine alcohol (Bromperidol); bromine piperazine decyl alcohol Salt (Bromperidol Decanoate); Dink do hydrochloride (Butaclamol Hydrochloride); butyrylcholinesterase TFP (Butaperazine); butyrylcholinesterase TFP maleate (Butaperazine Maleate); propylene perphenazine maleate (Carphenazine Maleate); Carvotroline hydrochloride; chlorpromazine (Chlorpromazine); chlorine Promazine hydrochloride (Chlorpromazine Hydrochloride); chlorpromazine sulfur anthracene (Chlorprothixene); Gui pair risperidone (Cinperene); Ke Mailan (Cintriamide); phosphate Kemai Lan (Clomacran Phosphate); chlorothioxanthone (Clopenthixol); Clopimozide; Clopipazan mesylate; Cloroperone Hydrochloride; chlorthalidone level (Clothiapine); Clothixamide maleate; chlorine Olanzapine (Clozapine); Cyclophenazine hydrochloride; reach Piperidinol (Droperidol); Yiddish yl ester hydrochloride (Etazolate Hydrochloride); Fenimide; Flucindole; fluorine test Long (Flumezapine); hydroxyethyl piperazine fluorine oxaprozin decanoate Salt (Fluphenazine Decanoate); hydroxyl piperazine fluorine oxaprozin Enanthate; hydroxyl piperazine fluoropropylthio Piperazine hydrochloride; Fluspiperone; fluorine SPINNER Ling (Fluspirilene); Flutroline; Gevotroline hydrochloride; Halopemide; haloperidol (Haloperidol); fluorine Piperidinol caprate (Haloperidol Decanoate); Iloperidone; chlorobenzene trazodone Amine hydrochloride (Imidoline Hydrochloride); Lenperone; Mazapertine Succinate; methyl sulfone pyridazine (Mesoridazine); methyl sulfone pyridazine Besylate; Metiapine; Milenperone; Milipertine; indolone hydrochloride (Molindone Hydrochloride); Naranol hydrochloride; Neflumozide hydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol (Penfluridol); Pentiapine maleate; hydroxyl prochlorperazine (Perphenazine); dual-fluorophenyl Ding piperazine Benzimidazolone piperidine (Pimozide); Pinoxepin hydrochloride; amide-piperidone (Pipamperone); acetyl piperazine hydrochloride (Piperacetazine); Pipotiazine Palm Salts; Piquindone hydrochloride; prochlorperazine Edisylate (Prochlorperazine Edisylate); prochlorperazine maleate (Prochlorperazine Maleate); hydrochloride oxaprozin (Promazine Hydrochloride); Remoxipride; Remoxipride hydrochloride; Rimcazole Hydrochloride; Seperidol hydrochloride; Sertindole; Setoperone; spiral-shaped piperazine Piperidone (Spiperone); thioridazine (Thioridazine); thioridazine hydrochloride Compounds (Thioridazine Hydrochloride); Mepiquat sulfur propylthiouracil anthracene (Thiothixene); A sulfur propylthiouracil anthracene piperazine hydrochloride (Thiothixene Hydrochloride); Tioperidone Hydrochloride; Tiospirone hydrochloride; trifluoperazine hydrochloride hydrochloride friends (Trifluoperazine Hydrochloride); three haloperidol (Trilfuperidol); three Fluorine oxaprozin (Triflupromazine); trifluoropropionaldehyde triazine hydrochloride (Trilfupromazine Hydrochloride); Ziprasidone hydrochloride; benzene tropine mesylate (Benztropine Mesylate); Anchorage spasm (Biperiden); Anchorage spasm hydrogen chloride Matter (Biperiden Hydrochloride); lactic Anchorage spasm (Biperiden Lactate); Ah Ding adamantane pyridine carboxylic acid (Carmantadine); Ciladopa hydrochloride; Dopamantine: Portuguese Ruffin amine hydrochloride (Ethopropazine Hydrochloride); Lazabemide; Levodopa; Lometraline hydrochloride; Mofegiline hydrochloride; Naxagolide hydrochloride; Pareptide sulfate; Cape pyridine ring hydrochloride (Procyclidine Hydrochloride); Quinelorane hydrogen Chloride; Ropinirole hydrochloride; Selegiline hydrochloride: Tolcapone; Trihexyphenidyl hydrochloride (Trihexyphenidyl Hydrochloride); Felbamate; Loreclezole; Tolgabide; Adatanserin hydrochloride: Adinazolam; Adinazolam methanesulfonate; Arab lactose (Alaproclate); allyl phenethylamine Hydrogen chloride (Aletamine Hydrochloride); phenyl propylamine hydrochloride indanone (Amedalin Hydrochloride); amitriptyline hydrochloride Lin (Amitriptyline Hydrochloride); chlorine piperazine oxygen (Amoxapine); Aptazapine maleate; Azaloxan fumarate; Azepindole; Azipramine hydrochloride; Bipenamol hydrochloride; bupropion hydrochloride (Bupropion Hydrochloride); Ding vinegar aniline (Butacetin); Ding hydrochloride for the forest (Butriptyline Hydrochloride); vinegar amine benzene evil ketone (Caroxazone); cards It yl ester (Cartazolate); benzil (Ciclazindol); cis-propoxyphene hydrochloride Cho Compounds (Cidoxepin Hydrochloride); Cilobamine mesylate; Clodazon Hydrochloride; Clomipramine hydrochloride; N-methyl-2 ,5 - pyrrolidone fumaric Cable salt (Cotinine Fumarate); Cyclindole; Cypenamine hydrochloride; Benzhydrol hydrochloride (Cyprolidol Hydrochloride); Cyproximide; Daledalin toluenesulfonate; Dapoxetine hydrochloride; Dazadrol maleate Salt; Dazepinil hydrochloride; desipramine hydrochloride (Desipramine Hydrochloride); dextral four imidazole (Dexamisole); Deximafen; diphenyl Benzodiazepine hydrochloride (Dibenzepin Hydrochloride); Dioxadrol hydrogen chloride Things; Dothiepin hydrochloride; Doxepin hydrochloride; Duloxetine hydrochloride Things; Eclanamine maleate; Encyprate; Etoperidone hydrochloride; Fantridone hydrochloride; Fenmetozole hydrochloride; Fenmetramide; Fezolamine fumarate; Fluotracen hydrochloride; Fluoxetine; Fluoxetine hydrochloride; Fluparoxan hydrochloride; Gamfexine; phenoxy C guanidine sulfate (Guanoxyfen Sulfate); Imafen hydrochloride; Imiloxan hydrogen Chloride; imipramine hydrochloride (Imipramine Hydrochloride); Indeloxazine hydrochloride; Intriptyline hydrochloride; Iprindole; isoxazole Hydrazide (Isocarboxazid); Ketipramine fumarate; Lofapramine hydrogen Chloride; Lortalamine; maprotiline (Maprotiline); maprotiline hydrochloride Compounds (Maprotiline Hydrochloride); tetramethyl anthracene propylamine hydrochloride (Melitracen Hydrochloride); Milacemide hydrochloride; Minaprine hydrochloride; Mirtazapine; Moclobemide; Modaline sulfate; Napactadine hydrogen chloride Things; Napamezole hydrochloride; Nefazodone hydrochloride; Tennyson acid (Nisoxetine); Nitrafudam hydrochloride; Nomifensine maleate; go A amitriptyline hydrochloride (Nortriptyline Hydrochloride); Octriptyline Phosphate; Opipramol hydrochloride; Oxaprotiline hydrochloride; oxybenzone send indole Indole (Oxypertine); Paroxetine; phenelzine sulfate (Phenelzine Sulfate); Pirandamine hydrochloride; Pizotyline; Pridefine hydrochloride; phenyl pentane Snow acid hydrochloride (Prolintane Hydroehloride); alanyl cycloheptene hydrochlorothiazide Compound (Protriptyline Hydrochloride); quinolizin maleate (Quipazine Maleate); cyclopropylamine (Rolicyprine); Seproxetine hydrochloride; Sertraline Hydrochloride; Sibutramine hydrochloride; Sulpiride; Suritozole; Tametraline hydrochloride; Tampramine fumarate; Tandamine hydrochlorothiazide Compounds; Thiazesim hydrochloride; Thozalinone; Tomoxetine hydrochloride; Trazodone hydrochloride; Trebenzomine hydrochloride; trimipramine (Trimipramine); trimipramine maleate (Trimipramine Maleate); Venlafaxine hydrochloride; phenetyloxycarbonyl methylmorpholine hydrochloride (Viloxazine Hydrochloride); Zimeldine hydrochloride; Zometapine; Ding properly due to sulfur (Albutoin); Ameltolide; Atolide; under ethyl amine (Buramate); acyl Amine imipramine (Carbamazepine); bezoar compound preparation (Cinromide); diphenyl Cycloheptene amide (Citenamide); metformin ketone (Dimethadione); Divalproex Sodium; Eterobarb; ethosuximide (Ethosuximide); ethylbenzene phenytoin (Ethotoin): Fluorine diethylaminoethyl stability (Flurazepam ydrochloride); Fluzinamide: Fosphenytoin sodium; Gabapentin; Ilepcimide; Lamotrigine; magnesium (Magnesinm Sulfate); MEPHENYTOIN (Mephenytoin); toluene Barbieri Properly (Mephobarbital); Methetoin; A Hu amine (Methsuximide); Milacemide hydrochloride; Nabazenil; Nafimidone hydrochloride; nitro Stability (Nitrazepam); benzene aceturea (Phenacemide): Phenobarbital; Phenobarbital sodium; benzene Hu amine (Phensuximide); two phenyl hydantoin (Phenytoin); two phenyl hydantoin sodium (Phenytoin Sodinm); deoxygenated benzene Barbiturates (Primidone); Progabide; Ralitoline; Remacemide hydrochlorothiazide Compounds; Ropizine; Sabeluzole; Stiripentol; sulfur thiazide (Sulthiame); E Sulfur sodium pentobarbital (Thiopental Sodium); Tiletamine hydrochloride; Topiramate; three pairs ketone (Trimethadione); 2 - valproate (Valproate Sodium); Valproic Acid; Vigabatrin; Zoniclezole hydrochloride; Zonisamide; Alverinc citrate: Anisotropine methyl bromide; atropine (Atropine); atropine oxide hydrochloride (Atropine Oxide Hvdrochloride); atropine sulfate (Atropine Sulfate); belladonna preparations (Belladonna); Benapryzine hydrochloride; under piperazine hydrochloride benzene risperidone (Benzetimide Hydrochloride); benzene slightly bromide (Benzilonium Bromide); Anchorage spasm (Biperiden); Anchorage spasm hydrochloride (Biperiden Hydrochloride); Anchorage spasm lactate (Biperiden Lactate); Clidinium Bromides; cyclopentolate hydrochloride (Cyclopentolate Hydrochloride); Right Dextrose (Dexetimide); bicyclic amine hydrochloride (Dicyclomine Hydrochloride); Dihexyverine hydrochloride; Domazoline fumarate; tensiomin diphenyl Zhuo (Elantrine); Elucaine; B under the care products (Ethybenztropine); excellent Cato Product hydrogen chloride (Eucatropine Hydrochloride); Glycopyrrolate; Heteronium bromide; homatropine hydrobromide (Homatropine Hydrobromide); homatropine methyl bromide (Homatropine Methylbromide); Hyoscyamine (Hyoscyamine); hydrobromide hyoscyamine (Hyoscyamine Hydrobromide); hyoscyamine sulfate (Hyoscyamine Sulfate); isopropyl Amine iodide (Isopropamide Iodide); bromide Mepiquat Junior ester (Mepenzolate Bromide); atropine methyl nitrate (Methylatropine Nitrate); Metoquizine; Oxybutynin chloride; Parapenzolate bromide; Pentapiperium dimethyl sulfate; benzene Kabbah ammonium (Phencarbamide); Poldine Dimethyl sulfate; C glutamine (Proglumide); propantheline bromide (Propantheline Bromide); Propenzolate hydrochloride; scopolamine hydrogen Bromide (Scopolamine Hydrobromide); Tematropium dimethyl sulfate Esters; Tiquinamide hydrochloride; Tofenacin hydrochloride; Toquizine; Triampyzine sulfate; trihexyphenidyl hydrochloride (Trihexyphenidyl Hydrochloride); off amide (Tropicamide). ...

Psychosis reagent comprises preferably: chlorine temazepam (Lorazepam); Clopoxide (chlordiazepoxide); Chlorine nitrogen (clorazepate); Diazepam (diazepam); Alprazolam; Hydroxyzine (hydroxyzine); Buspirone (buspirone); Yenlafaxine; Mephobarbital (mephobarbital); Meprobamate (meprobamate); Doxepin (doxepin); Fluphenazine (perphenazine); The two naphthoates (hydroxyzine pamoate) of hydroxyzine; Venlafaxine; Mirtazapine; Nefazodone; BUP (bupropion); Phenelzine (phenelzine); Tranylcypromine (tranylcypromine); Citalopram; Paraxefine; Sertraline; Amitrptyline; MK-240 (protriptyline); Divalproex; Ammonia disappears stable (clonazepam); Clozapine (clozapine); Chloperastine alcohol (haloperidol); Loxapine (loxapine); Molindone (molindone); Thiothixene (thiothixene); Pimozide (pimozide); Risperidone; Quefiapine; Thiothixen; Olanzapine; Quetiapine; Prochlorperazine mesylate (prochlorperazine); Mesoridazin; Trifluoperazine (trifluoperazine); Chlorpromazine (chlorpromazine); Fluphenazine (perphenazine); Fluvoxamine. best stable reagent comprises: clozapine (clozapine); Venlafaxine; Risperidone; Quefiapine; Thiothixen; Olanzapine.

Chemical compound of the present invention when using when independent use or with the cocktail form, is all taken to treat effective dose.Effective dose is determined according to the parameter of following discussion in the treatment; But it all is to have established in tumor region suppressing the amount of the effective medication amount of tumor growth that effective dose is gone up in treatment under any circumstance.

When taking, prescription of the present invention is useful in the pharmacy acceptable composition with the acceptable amount of pharmacy.Such preparation can contain salt routinely, buffer reagent, antiseptic, compatibility carrier and other treatment composition at random.When using in medicine, salt should be that pharmacy is acceptable, but the acceptable salt of non-pharmacy can be used to prepare the acceptable salt of its pharmacy traditionally, and such salt also is not precluded within the scope of the present invention.The acceptable salt of such pharmacology and pharmacy includes, but not limited to be equipped with the salt of taking from following processed with acid: hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-benzoic acid, sulfonic acid, tartaric acid, citric acid, methanesulfonic acid, fumaric acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid.Equally, the acceptable salt of pharmacy can be prepared into alkali metal or alkali salt, as sodium, and potassium or calcium salt.

Suitable buffer reagent comprises: acetic acid and salt (1-2%W/V); Citric acid and salt (1-3%W/V); Boric acid and salt (0.5-2.5%W/V); With phosphoric acid and salt (0.8-2%W/V).

Suitable preservatives comprises chloro benzalkonium (0.003-0.03%W/V); Methaform (0.3-0.9%W/V); Parabens (0.01-0.25%W/V); And thimerosal (0.004-0.02%W/V).

Reactive compound of the present invention can be the pharmaceutical composition that the conjugate of the present invention of effective dose is gone up in treatment that contains that at random is included in the pharmaceutically acceptable carrier." pharmaceutically acceptable carrier ", as used herein, mean and be suitable for one or more compatibility solid or liquid filler materials, diluent or the capsule bag material taken to human or other animals." carrier " refers to the organic or inorganic composition, and be natural or synthetic, and active component combines so that use with it.The composition of pharmaceutical composition can mix in the interactional mode that can significantly not damage required curative effect of medication each other with molecule of the present invention.

The compositions that is suitable for non-enterally administer generally includes the sterile preparation product of conjugate of the present invention.This preparation can be according to known method preparation.Can be for the taxane prescription at FL33431, N.W.Boca Raton, 2000 Corporate main roads, CRC publishes the TAXOL of company limited: the chapter 9 of science and application finds.Usually, TAXOL is mixed with Cremophor EL (the polyoxyethylenated castor oil)/alcohol mixture of 6 mg/ml, and it is diluted to whole solution with saline commonly used or 5% glucose.The Taxotere solution of 15 mg/ml is formulated in polysorbate80 (polyoxyethylene sorbitol acid anhydride list oleic acid)/alcohol cpd, dilutes with 5% glucose.This prescription with contrast than prescription described herein.

Therefore the sterile preparation product can be the sterile solution or the suspension of non-intestinal acceptable diluent of avirulence or solvent.In addition, aseptic fixedly oil is traditionally also as solvent or suspension media.For this reason, any gentleness fixedly oil can be used, comprise synthetic single or two-glyceride.In addition, fatty acid such as oleic acid also can use in preparation injectable product.Be suitable for oral medication, subcutaneous medication, intravenous administration, the carrier compound of muscle medication etc. can find PA, the Mack publishing company of Easton in the Remington pharmaceutical science.

The employed body that tried of this paper is meant the mankind, primates, horse, cattle, pig, sheep, goat, Canis familiaris L., cat and rodent.

Conjugate of the present invention can be taken by effective dose.Effective dose is meant and postpones outbreak, holds back the development, and stops outbreak or development simultaneously, or diagnoses the needed amount of the concrete patient's condition for the treatment of.Usually, the effective dose of treatment cancer is to suppress the required amount of mammalian cancer cells original position propagation.When giving when being tried body and taking, effective dose depends on the concrete patient's condition for the treatment of certainly; The seriousness of the patient's condition; The individual patient parameter comprises the age, health, height and body weight; The treatment of carrying out simultaneously; The frequency of treatment; And application method.These factors are well-known to the those of ordinary skill in this field, only use routine test just can implement.Body should use maximal dose usually preferably, i.e. the maximum safe dose of the reliable medical judgment of basis.

Dosage should suitably be regulated to obtain medication amount oral or that system's medication is required.Generally, oral dose every day of reactive compound is from about 0.01 milligram/kg/day to 1000 milligram/kg/day.Expectation should be effective at the IV dosage of about 1 to 1000 milligram/square metre/day scope.Tried under this dosage under the unconspicuous situation of reaction of body, even the degree that can use higher dosage (or by different more partial route of administration, dosage that effectiveness is higher) to stand permission to the patient.Through as 24 hours continuous IV takes medicine or the multi-agent of every day is taken medicine considers to obtain the suitable system content of chemical compound.The scheme of taking medicine preferably comprises and uses concentration that time span etc. are described (referring to embodiment) in the other places of this paper.

Can use multiple route of administration.The concrete mode of choosing depends on the concrete medicine of choosing, the dosage that severity of disease for the treatment of and therapeutic effect are required certainly.In general, method of the present invention can use any medically acceptable application method to implement, and promptly produces any way of the reactive compound of effective dose under the situation that does not have to cause unacceptable side effect clinically.Such application method comprises oral medication, rectal application, Sublingual medication, local application, nose medication, percutaneous medication, Intradermal medication or non-enterally administer." non-enterally administer " comprises subcutaneous medication, intravenous medication, intramuscular medication or perfusion.For taxane, the intravenous route of administration is better.

Compositions can be present in the single medicament easily, can be by well-known any method preparation in the pharmaceutical field.All methods all comprise conjugate of the present invention are joined step in the combination with the carrier of being made up of one or more auxiliary elements.Usually, compositions is by evenly closely joining chemical compound and liquid-carrier, the careful solid carrier that separates, or in the combination of two kinds of carriers, formed product prepares if desired then.

The compositions that is suitable for oral medication can be made into indivedual unit dosage forms, as capsule, and cachet, tablet or lozenge, every kind of reactive compound that contains scheduled volume.Other compositionss comprise the suspension in water-soluble liquid or the non-aqueous solution body, as syrup, and elixir, or emulsion.

Other drug-supplying systems can comprise regularly release, postpone to discharge or the sustained release administration system.Such system can avoid reactive compound repeated drug taking of the present invention, gives to be tried body and the doctor increases facility.Many kinds of release administration systems can use, and they are known for those of ordinary skill in this field.They comprise polymer-matrix system such as polylactic acid and polyglycolic acid, polyanhydride and polycaprolactone; The non-polymer system that is lipid comprises steroid such as cholesterol, cholesteryl ester and fatty acid or neutral fat such as list, two and triglyceride; The hydrogel delivery system; The silicone rubber system; The peptide based system; Wax coating, the compressed tablets of use conventional junction mixture and excipient, partially fused implant or the like.In addition, pump base hardware drug-supplying system also can use, and some are applicable to implantation.

The long-term release implant that continues also can use." for a long time " discharges, and be as used herein, is meant the active component at least 30 days of the implant feed therapeutic dose that makes up and arrange, at least 60 days preferably.Long-term lasting release implant is well-known to the those of ordinary skill in this field, comprises more above-described delivery systems.Such implant can use especially in the treatment solid tumor, by implant being placed near tumor or directly being placed in the tumor, thereby the local high dose of The compounds of this invention is worked.

Can more fully understand the present invention by the following example.Yet these embodiment only are intended to demonstrate embodiment of the present invention, should not be interpreted as limitation of the scope of the invention.

Embodiment

Material and method

The crystallization of DHA-Paclitaxel

Mentioned as other places in this application, the present invention is chemical compound preferably, " Taxoprexin ^TM", be the covalent conjugates of DHA and Paclitaxel.Its chemical constitution, synthetic, purify and interaction in vitro at United States Patent (USP) 5,795, be described in 909, its whole disclosures are all by being incorporated in this piece of writing in this citation.In addition, the crystal form of this conjugate uses following scheme to obtain:

The weight (W) of the DHA-paclitaxel conjugate (as United States Patent (USP) 5,795, the preparation described in 909) that the record chromatography is purified.The required alcoholic acid amount of DHA-paclitaxel conjugate of using following Equation for Calculating crystallization chromatography to purify:

Ethanol milliliter number=DHA-paclitaxel gram number (W) * 5 is to 8 (being preferably 8)

About 3/4 volume of ethanol (E) is joined in the garden base cone shape flask that contains DHA-paclitaxel and stirring rod.Conical flask is placed on the mixing platform.Content is at room temperature stirred or is warming to when being no more than 40 ℃, remaining 1/4 volume of ethanol is added.If the initial amount of alcohol (E) that adds is not dissolved whole DHA-paclitaxel, can add the extra ethanol of increment, up to forming clear solution.Yet, write down employed total amount ethanol (EFin).Use the required water yield of following Equation for Calculating crystallization:

Water milliliter number=ethanol milliliter number (EFin) * 0.5 is to 1.5

In the water yield that records as above to be calculated and the alcoholic solution that is added dropwise to conical flask.Continuous stirring in whole dropping process.Even finish add water after, stir and also will continue.Stir and at room temperature continue at least 4 hours.The recording start crystallization stops crystallization and total crystallization time.If after stirring 4-18 hour, crystal growth no longer occurs, can be placed on conical flask in the refrigerator or between cold-room at least 24 hours.

Then, under vacuum, (pass through vacuum pump), be filled in the filter flask of suitable size with the content of the Buchner funnel that is equipped with filter paper with conical flask.In case the content of conical flask (" mother solution ") passes through in the clean flask, break vacuum, and with mother solution to getting back in the conical flask.With the mother solution spin rinse in the conical flask to any attached to the residual crystal on the flask limit, reuse contains the crystalline Buchner funnel of first process and filters under vacuum.In case mother solution passes the Buchner funnel for the second time, with the crystal (in the funnel filter) collected once, wash once with ice-cold hexane (being placed on subzero at least 1 hour hexane below 15 ℃ in advance) with ice-cold ethanol (being placed on subzero at least 1 hour ethanol below 15 ℃ in advance) flushing.Assistance with a scraper and a reinforcement funnel scrapes crystal in the clean flask from the Buchner funnel.All flasks covered and are placed under the high vacuum with aluminium foil, with crystal drying at least 24 hours.Then these crystal are used as pure DHA-paclitaxel prescription source.

DHA-paclitaxel crystallizes into monoclinic space group P2 ₁(system lacks the 0k0:k=odd number), a=18.6418 (2) A, b=17.8806 (4) A, c=18.9812 (3) A ,=90.3920 (10) A, V=6326.8 (2) A, Z=4 (two molecules are arranged in asymmetric cell), d _Calculate=1.222 gram/cubic centimetres.

The active component of DHA-paclitaxel:Taxoprexin

Form	Molecular weight	DHA-paclitaxel％
			????DHA	????328	????27％
????paclitaxel	????854	????73％
			????DHA-paclitaxel	????1164	????100％

Animal is tried body and is tested: embodiment 1-7

Embodiment 1:Taxoprexin and paclitaxel are to the effect of Mus M109 pulmonary carcinoma

With the Mus lung tumor is that M (Madison) 109 is the homogenic Mus of flank subcutaneous injection.Tumor was implanted after 4 days, when heavily about 30 milligram hours of tumor, in continuous five days every day (the 4th day to the 8th day), Taxoprexin (OD=120 milligram/kg/day * 5 day) or paclitaxel (OD=20 milligram/kg/day * 5 day) are injected with the thing piece by tail vein.Two kinds of medicines all are dissolved in 10%Cremophor EL/10% ethanol/80% saline.Width and length evaluation gross tumor volume by tumor.The result shows that paclitaxel postpones about 4 days of tumor growth.On the contrary, taxoprexin has fully eliminated whole detectable tumors in eight Mus.

Embodiment 2:Taxoprexin and paclitaxel are to the effect of Mus M109 pulmonary carcinoma

With the Mus lung tumor is that M (Madison) 109 is the homogenic Mus of flank subcutaneous injection.Tumor was implanted after 5 days, than a last embodiment late one day, when tumor growth to 10 times big 300 milligram hours, Taxoprexin (OD=120 milligram/kg/day * 5 day) or paclitaxel (OD=20 milligram/kg/day * 5 day) are injected with the thing piece by tail vein.Two kinds of medicines all are dissolved in 10%Cremophor EL/10% ethanol/80% saline.Width and length evaluation gross tumor volume by tumor.As in previous test, paclitaxel postpones about 4 days of tumor growth (LCK=1.0).On the contrary, taxoprexin has fully eliminated the whole detectable tumor of seven (C/T=7/8) in eight Mus when 120 milligrams/kg/day * 5 day, taxoprexin has eliminated in seven Mus four whole detectable tumor fully when 80 milligrams/kg/day * 5 day.The tissue that shows tumor is carried out histological examination does not have tumor cell, has only scar tissue.These data show taxoprexin cures the disease in this pattern.

Embodiment 3: human NCI-H522 lung tumor is to using in Mus

The reaction of Taxoprexin and paclitaxel treatment

Taxoprexin has studied to being grown in the anti-tumor activity of the human NCI-H522 lung tumor in the nude mice in south research association.With the subcutaneous implantation of tumor.Determine tumor quality from the width and the length computation of tumor.Medicine dissolution is fed in the tail vein in 12.5%cremophorEL/12.5% ethanol/75% saline and by intravenously administrable, once a day, totally 5 days, implanted the back the 15th day to the 19th day in tumor.The result shows that 50 milligrams/kg/day * 5 a day Taxoprexin and 20 milligrams/kg/day * 5 a day paclitaxel have eliminated whole detectable tumors in 10 Mus.

Embodiment 4: Taxoprexin and paclitaxel in the vole

Pharmacokinetic parameter

Took 6.8 milligrams/kilogram Taxoprexin to vole through 3 minutes by tail vein.With medicine dissolution in 10%Cremophor EL/10% ethanol/80% saline.Measure the serum-concentration of Taxoprexin and paclitaxel with the reverse hplc method.From these data, calculate pharmacokinetic parameter.Taxoprexin has low 100 times clearance rate and distribution volume (referring to table 1).

Table 1

The pharmacokinetic parameter of Taxoprexin in the vole
				Medicine	Clearance rate	Blood plasma t 1/2(hour) (n=3)	Distribution volume
paclitaxel	28.2 ml/min/kilogram	????4.8±2.6	4.3 liter/kilogram
				Taxoprexin	0.3 ml/min/kilogram	????4.8±0.1	0.058 liter/kilogram

Embodiment 5: after vein is taken Taxoprexin, in the vole

The plasma concentration of Taxoprexin and paclitaxel

In 0 moment, injected Taxoprexin for the vole vein through 3 minutes by tail vein.Medicine dissolution is in 10%Cremophor EL/10% ethanol/80% saline.Dosage is 6.8 milligrams/kilogram.Measure Taxoprexin and concentration and the time relation (referring to table 2) of paclitaxel in serum with the reverse hplc method.

Table 2

Take behind the Taxoprexin plasma concentration (ng/ml) of Taxoprexin and paclitaxel in the vole
			Time (hour)	????paclitaxel	????Taxoprexin
????0	????200	????100,000
			????1	????100	????95,000
????2	????70	????90,000
			????5	????40	????70,000
????24	????10	????40,000

Embodiment 6: give the Mus vein taking dose that carries M109 or M5076 tumor 50 millis

The blood plasma of the deutero-paclitaxel of Taxoprexin of gram/kilogram and tumor concentration

0 constantly, take the agent of Taxoprexin piece for the Mus of carrying the tumor that generates from M109 or M5076 by tail vein.Medicine dissolution is in 10%Cremophor EL/10% ethanol/80% saline.Behind the injectable drug, along with the variation of time is killed Mus and tumor resection immediately.With the tumor tissues homogenizing and extract paclitaxel.Measure the concentration of paclitaxel with the reverse hplc method.Collect blood at the same time, determine the amount of paclitaxel.The result shows that the concentration from the deutero-paclitaxel of Taxoprexin is about 3 μ M after 24 hours, and is higher 40 times than blood plasma degree 70nM.Each data point is average (n=3) of three measured values.Annotate: the t of paclitaxel in identical tumor system _1/2＜8 hours.

Embodiment 7: the Taxoprexin in multiple animal species except that the people and

The dosage of paclitaxel is (MTD and EstLD relatively ₄₀)

Mus, the dosage that carries out Taxoprexin and paclitaxel in vole and the Canis familiaris L. compares.In milligram/kilogram, Mus, vole and Canis familiaris L. are high about 4-5 times to the maximum tolerated dose (MTD) of maximum tolerated dose (MTD) the comparison paclitaxel of Taxoprexin, or in mole paclitaxel equivalent, high about 3-3.5 is doubly.The maximum toxicity that allows of the dosage of vole and Canis familiaris L. should reduce in neutrophil cell and the lymphocyte in platelet.For Mus, the toxicity of vole and Canis familiaris L. Taxoprexin littler than paclitaxel (referring to table 3).

Table 3

Dosage compares: paclitaxel and Taxoprexin in different plant species
				Species Mus vole Canis familiaris L.	Dosage (milligram/kilogram) *	Dosage rate: Taxoprexin/paclitaxel
Taxoprexin?paclitaxel	By weight	With the taxane molar concentration meter **
			MTD＝100×?????????MTD＝20× 5＝500????????5＝100 EstLD 40＝420?LD 40＝85 MTD＝80???????EstMTD＝20		????5 ????5 ????4 ????4.7	????3.6 ????3.6 ????2.9 ????3.4
Meansigma methods

^*MTD is a maximum tolerated dose

^*The MW=1164 of Taxoprexin; The MW=854 of paclitaxel; MW ratio=0.73

Make us uncannily, for Taxoprexin dosage and pharmacokinetics advantage, aforementioned data has been established the safety deduction.Compare the bigger MTD of Taxoprexin with paclitaxel and be sure of to release the bigger safety of Taxoprexin and bigger effectiveness.The less distribution volume of Taxoprexin be sure of that release is including, but not limited to nerve, hair follicle, and the infringement that Taxoprexin implements in the perienchyma of GI cell etc. is less.Taxoprexin time of staying in tumor is long to be sure of to release and reaches the optimum treatment effect and need the less number of times of taking, and this can be sure of to release and reduces system toxicity.Therefore Taxoprexin demonstrates clearance rate and the distribution volume than low 100 times of paclitaxel.In addition, stable with the amount maintenance in 24 hours of the paclitaxel in the tumor of Taxoprexin treatment, and keep maintenance level to be less than 8 hours with this amount in the tumor of paclitaxel treatment.At last, Taxoprexin shows the human HCT colon tumor cured in 8 Mus 3, and paclitaxel has cured 0 Mus.HCT is anti-paclitaxel tumor.

Human subject test: embodiment 8-9

Material and method:

Medication (process 1 and 2) before the TAXOPREXIN input

Before the process of carrying out 1 and 2, in order to minimize the anaphylaxis to the Cremophor composition of Taxoprexin input, the patient accepts the preceding medication of following treatment.It is this that to relate to the preceding therapeutic regimen of the treatment that contains Cremophor treatment product be well-known in this field.

An embodiment is as follows:

Dexamethasone (dexamethasone) is 20 milligrams of PO before 12 hours, 20 milligrams of PO before 6 hours

Diphenhydramine (diphenhydramine) before 30-60 minute vein advance 50 milligrams

H ₂Vein before blocker 30-60 minute (as cimetidine Cimetidine300 milligram)

Medication before the replaceable treatment (process 3 and except that the process it)

If do not have anaphylaxis in process 1 and 2, subsequent process can use medication before the following replaceable treatment, according to the judgement of researcher:

Dexamethasone (dexamethasone) or: 1) 8 milligrams of PO before 12 hours, 8 milligrams of PO before 6 hours, perhaps: 2) 10 milligrams of intravenous administration before 30-60 minute

Diphenhydramine (diphenhydramine) before 30-60 minute vein advance 25 milligrams

H ₂Intravenous administration before blocker 30-60 minute (as cimetidine Cimetidine300 milligram)

The TAXOPREXIN that the human vein takes ^Dilution

Two kinds of different bottles are provided.First kind of bottle, TAXOPREXIN ^CONCENTRATE (" concentrate "), the alcoholic solution that contains 200 milligrams of DHA-paclitaxel, concentration is second kind of bottle of 100 mg/ml (2.0 milliliters of cumulative volumes), the DILUENT of TAXOPREXIN concentrate (dilution) contains the mixture of 30 milliliters of Cremophor EL and ethanol 4: 1 (volume ratio).Before use, the concentrate of two parts of (2) volumes and the dilution of three parts of volumes are blended in the aseptic dry glass hybrid bottle.Then the DHA-paclitaxel " preparation " that makes being diluted to the aqueous solution (D5W) of 5% glucose or the standard vein of Sterile Saline commonly used (NS) solution imports in the solution.The concentration of DHA-paclitaxel in D5W and NS must be adjusted in the scope of 0.8 to 8.0 mg/ml.TAXOPREXIN ^Dosage in body surface area.Height and body weight according to the patient determine that correct body surface area is very important (before each takes the cycle).

First dilution: premix preparation

1. the concentrate bottle with right quantity takes out from refrigerator.Bottle was remained on room temperature one hour.Check that each bottle is to guarantee that solution is transparent crystal or the granule of not containing.If there is granule, with bottle ultrasonic degradation 30 minutes and reexamining at room temperature.If there is crystal, if or still have granule behind the ultrasonic degradation, bottle is abandoned.

2. use 21 metering syringe needles and do not contain the scale syringe of latex, size is enough to comprise volume required concentrate, the concentrate of required dosage is extracted out from the concentrate bottle cleanly continuously, up to cumulative volume entirely in syringe.

3. content in the syringe carefully is distributed in the aseptic empty glass hybrid bottle, the size of hybrid bottle is enough big so that it can hold the concentrate and the dilution of cumulative volume, slowly drips content to reduce foam along the bottle inwall.

4. use another 21 scale syringe that measures syringe needle and do not contain latex, syringe size is enough big so that it can hold volume required dilution, and the volume of dilution equals the concentrate volume of 1.5 times extraction.

5. the content that will contain the syringe of dilution is distributed in the hybrid bottle carefully, slowly drips content to reduce foam along the bottle inwall.

6. the mixed content thing with hybrid bottle softly rotates to guarantee the mixing fully of concentrate and dilution.Make the premix preparation of 40 milligrams of DHA-paclitaxel/ milliliters like this.

7.TAXOPREXIN premix preparation (40 milligrams of DHA-paclitaxel) should be transparent; Yet, because Cremophor EL-P may have some foams at the solution top.Cross the Cheng Qian in serial dilution, the premix preparation is kept 5 minutes up to most of foam dissipates.

Dilution eventually: input solution

1. with whole TAXOPREXIN ^Premix preparation (40 milligrams of DHA-paclitaxel) content is transferred in the glass input bottle of D5W or NS cleanly with new 21 metering syringe needles and the syringe that do not contain latex, and the input bottle is long-pending enough imports solution concentration between 0.8 to 8.0 milligram of DHA-paclitaxel/ milliliter to prepare greatly eventually.

2. fully mix input solution by manual rotation.

3. as all non-intestinal goods, check TAXOPREXIN in the medication anterior optic ^Particulate matter or metachromatism.If TAXOPREXIN ^Premix preparation or input solution are opaque or present precipitation, and solution should not use.

TAXOPREXIN ^Input solution is taken through two (2) hours intravenouss under ambient room temperature and illumination condition.Medication speed depends on the final volume of input solution eventually, and those of ordinary skill can be determined this speed easily.

Store and stability:

Kai Feng TAXOPREXIN not ^The CONCENTRATE bottle is stored in the refrigerator, and 2-8 ℃ (36-46 degrees Fahrenheit), in their original packaging, lucifuge.TAXOPREXIN ^The bottle that do not break a seal of the dilution of concentrate is stored in their original packaging, under controlled room temperature (15-30 ℃).TAXOPREXIN ^Premix preparation (40 milligrams of DHA-paclitaxel) or the TAXOPREXIN input solution of making fully, in D5W or NS, (necessary) taking out TAXOPREXIN in refrigerator ^Use in 24 hours behind the concentrate bottle.TAXOPREXIN ^Or TAXOPREXIN ^The Kaifeng of input solution or premix necessarily can not be freezing or put back in the refrigerator.

Presentation mode:

TAXOPREXIN ^Concentrate is aseptic, and not containing in the single dose bottle of pyrogen provides with 2.0 milliliters of non-hydrotropic solutions.TAXOPREXIN ^The dilution of concentrate (4: 1 volume ratio Cremophor ^EL-P and alcoholic acid mixture) aseptic, not containing in the single dose bottle of pyrogen provides with 3.0 milliliters.

Sum up:

A bottle: TAXOPREXIN Concentrate (alcoholic solution of DHA-paclitaxel)	B bottle: TAXOPREXIN Dilution (1: 4 ethanol: Cremophor )
		200 milligrams/2 milliliters bottles	In 10 milliliters of bottles 3 milliliters
1,000 milligram/10 milliliters bottles	In 50 milliliters of bottles 15 milliliters

Preparation and take points for attention:

With undiluted concentrate be used for preparing that plastized polyvinyl chloride (PVC) device of importing solution or equipment contacts is inadvisable.Contact plasticizer DEHP (two-2-ethylhexyl phthalic acid ester) in order to minimize the patient, plasticizer can leach from PVC input bag or device, so TAXOPREXIN ^Input solution should be stored in the vial, and takes by being lined with the mobile nitroglycerine administration set of poly omnidirectional, uses the pressure filter that does not contain latex in the embedded pipeline of Abbott No.4524 that has 0.22 micron microporous membrane.

TAXOPREXIN ^Be the cytotoxicity cancer therapy drug, as other genotoxic potential chemical compounds, should be careful when handling and prepare TAXOPREXIN solution.Should use the method for correct processing and disposal cancer therapy drug.Should use glove.If TAXOPREXIN ^Concentrate, the premixing preparation, or the input solution touch skin or mucosa, should use soap and water cleaning down contact area immediately.The Guide Book of several relevant these themes is published (Am.J.Hosp.Pharm 1986:43 (5): 1193-1204; Am.J.Hosp.Pharm 1990; 47 (5): 1033-1049; JAMA1985; 253 (11); 1590-1592; ONS 1988; 2-14; NIH publishes No.83-2621; The National Research Council and cytotoxicity expose to the open air-to handling the suggestion that cytotoxicity relates to, from Louis P.Jeffry, ScD, chairman, the National Research Council and cytotoxicity expose to the open air, pharmacy and publilc health science Massachusetts institute, 179Longwood Avenue, Boston, MA02115; Australia's medical journals, 1983; 1:426-428; CA-clinician's cancer periodical 1983; 33 (5); 258-263).

Embodiment 8: TAXOPREXIN pharmacokinetic parameter among the human receptor

Use WinNonlin2.0 version software (Pharsight company limited, MountainView, CA, the U.S.) to implement whole statistical analysiss.

Table 4TAXOPREXIN ^Pharmacokinetic parameter patient dose C _MaximumAUC %AUCID (milligram/square metre) (μ g/ milliliter) (μ g * little deduction

The time/milliliter) 1 200 110 1,433 122 400 115 1,845 233 400 150 3,710 594 660 138 8,527 715 660 183 5,563 436 660 279 8,825 568 660 179 5,117 489 660 211 5,811 467 880 326 9,091 46 abbreviations: maximal plasma concentration (C_Maximum), the area under the Cot curve (AUC)

Table 5

TAXOPREXIN Pharmacokinetic parameter
					The patient	Dosage	T 1/2	v Ss	Cl
ID (milligram/square metre) (hour) (liter) (ml/min) 1 200 7.8 2.7 4.2 2 400 10 5.1 6.0 3 400 31 8.3 3.2 4 660 52 9.5 2.1 5 660 21 6.9 3.6 6 660 26 5.2 2.2 8 660 24 7.8 4.1 9 660 24 8.3 4.1 7 880 23 6.6 3.5
					All dosage 24 (13) 6.7 (2.1) 3.7 (1.2)
Numerical value is meansigma methods (SD).Abbreviation: t1/2 (T 1/2); Distribution volume (V under the steady statue Ss); System Cleaning rate (Cl).

TAXOPREXIN ^The pharmacokinetics conclusion:

DHA-paclitaxel has little distribution volume (about 7 liters), low clearance rate (about 4 ml/min) and long t1/2 (about 24 hours, be about 30% than the t1/2 of independent paclitaxel).

Along with TAXOPREXIN ^The increase DHA-paclitaxel of DHA-paclitaxel dosage exposes increase to the open air.Embodiment 9: take TAXOPREXIN in human subject ^After,

The pharmacokinetic parameter of paclitaxel

Table 6 is taken TAXOPREXIN ^After, the pharmacokinetic parameter patient dose C of paclitaxel _MaximumAUC T _1/2Time Paclitaxel:

＞0.05???TAXOPREXIN

μ M AUC ratio ID (milligram/flat (ng/ (Ng ^*Hour/(hour) (hour) (%)

Side's rice) milli milliliter)+

Rise) 1 200 40------2---2 400 21------0---3 400 74------3---4 660 68 1,596 32 3 0.0195 660 61 1,576 35 3 0.0286 660 251 2,209 20 16 0.0258 660 73 4,479 81 5 0.0889 660 192 2,592 46 4 0.0457 880 134 2,433 27 8 0.027 abbreviations: maximal plasma concentration (C_Maximum), the area under the Cot curve (AUC) ,+value obtains from visual inspection plasma concentration curve.

Table 7

Take TAXOPREXIN and paclitaxel *After, the pharmacokinetic parameter of paclitaxel: A contrast
				Scheme	C Maximum(μM)	AUC(μM *Hour)	Time＞0.05 μ M (hour)
Intravenous administration TAXOPREXIN
				200 milligrams/square metre (n=1)	0.047	---	?2.0+
400 milligrams/square metre (n=2)	0.056±0.045	---	?2.5+
				660 milligrams/square metre (n=5)	0.15±0.10	2.9±1.4	?6.1±5.6+
880 milligrams/square metre (n=1)	0.16	2.9	?＞8.0+
				Intravenous administration paclitaxel
1 hour (the 80-108 milligram/square metre) 1	4.5±1.7	---	?＞6.0
				3 hours (175 milligrams/square metre) 2	5.9±0.9	19±3.0	?24±3.5
24 hours (175 milligrams/square metre) 2	0.5±0.1	16±4.4	?34±5.8
				96 hours (140 milligrams/square metre) 3	0.060±0.003 **	---	?---

^*Value representation meansigma methods ± SD

^**C _ss

+ value obtains from visual inspection plasma concentration curve.

1.Seidman Deng the people, Journal of Clinical Oncology, 1998

2.Gianni Deng the people, Journal of Clinical Oncology, 1995

3.Wilson Deng the people, Journal of Clinical Oncology, 1994

Paclitaxel pharmacokinetics conclusion

Paclitaxel exposes the Taxoprexin of dosage＜1% to the open air.

Using Taxoprexin 660﹠amp; After 880 milligrams of/square metre treatments, obtain the relevant Paclitaxel plasma concentration (＞0.05 μ M) of pharmacology.

When 660 milligrams of/square metre dosage levels, the diversity that between the patient Paclitaxel is exposed to the open air is 3-4 times.

After with the Taxoprexin treatment, the T of Paclitaxel _1/2Performance prolongs (average ± SD, 40 ± 22 hours).

The time plasma concentration that remains on the threshold concentration (as 0.01 μ M) may be relevant with neutropenia.

All documents disclosed herein are all by being incorporated in this paper in this citation.

Claims (174)

1. give the compositions tried the fatty acid-anticancer chemical compound conjugate that body takes for one kind, be included in at least a fatty acid-anticancer compound composition that is tried in the packing material that body takes, wherein in packing material the amount of fatty acid-anticancer chemical compound than the maximum tolerated dose (MTD) about at least 10% of unconjugated at least a anticancer compound.

2. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 20% of unconjugated at least a anticancer compound.

3. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 30% of unconjugated at least a anticancer compound.

4. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 40% of unconjugated at least a anticancer compound.

5. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 50% of unconjugated at least a anticancer compound.

6. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 75% of unconjugated at least a anticancer compound.

7. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 100% of unconjugated at least a anticancer compound.

8. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 200% of unconjugated at least a anticancer compound.

9. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 300% of unconjugated at least a anticancer compound.

10. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein the amount in the packing material is than the maximum tolerated dose (MTD) about at least 400% of unconjugated at least a anticancer compound.

11. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein packing material is the packing material of intravenous medication.

12. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein anticancer compound is a taxane.

13. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 12, wherein taxane is paclitaxel and docetaxel.

14. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein conjugate does not have capsule to wrap in the liposome.

15. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 1, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

16. according to the compositions of the fatty acid-anticancer chemical compound conjugate of claim 15, wherein fatty acid is a docosahexenoic acid.

17. a treatment suffers from the method for being tried body of abnormal mammalian cell propagation pathological changes, comprises to being tried body and takes the fatty acid-anticancer chemical compound conjugate composition of the amount of the maximum tolerated dose (MTD) about at least 10% than unconjugated at least a anticancer compound.

18. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 20% of unconjugated at least a anticancer compound.

19. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 30% of unconjugated at least a anticancer compound.

20. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 40% of unconjugated at least a anticancer compound.

21. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 50% of unconjugated at least a anticancer compound.

22. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 75% of unconjugated at least a anticancer compound.

23. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 100% of unconjugated at least a anticancer compound.

24. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 200% of unconjugated at least a anticancer compound.

25. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 300% of unconjugated at least a anticancer compound.

26. according to the method for claim 17, the amount of the fatty acid-anticancer chemical compound conjugate composition of wherein taking is than the maximum tolerated dose (MTD) about at least 400% of unconjugated at least a anticancer compound.

28. according to the method for claim 17, wherein anticancer compound is a taxane.

29. according to the method for claim 28, wherein taxane is paclitaxel and docetaxel.

30. according to the method for claim 17, wherein conjugate does not have capsule to wrap in the liposome.

31. according to the method for claim 17, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

32. according to the method for claim 17, wherein fatty acid is a docosahexenoic acid.

33. give and to be tried body and take the test kit that fatty acid-anticancer chemical compound conjugate composition is used for one kind, comprise: contain the packing material of at least a fatty acid-anticancer chemical compound conjugate composition and give at least a fatty acid-anticancer chemical compound conjugate that body is taken the amount of the maximum tolerated dose (MTD) about at least 10% than unconjugated at least a anticancer compound that tried of this treatment of needs.

34. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 20% of unconjugated at least a anticancer compound.

35. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 30% of unconjugated at least a anticancer compound.

36. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 40% of unconjugated at least a anticancer compound.

37. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 50% of unconjugated at least a anticancer compound.

38. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 75% of unconjugated at least a anticancer compound.

39. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 100% of unconjugated at least a anticancer compound.

40. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 200% of unconjugated at least a anticancer compound.

41. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 300% of unconjugated at least a anticancer compound.

42. according to the test kit of claim 33, the amount of wherein at least a fatty acid-anticancer chemical compound conjugate is than the maximum tolerated dose (MTD) about at least 400% of unconjugated at least a anticancer compound.

43. according to the test kit of claim 33, wherein at least a fatty acid-anticancer chemical compound conjugate is a taxane.

44. according to the test kit of claim 43, wherein taxane is paclitaxel and docetaxel.

45. according to the test kit of claim 33, wherein conjugate does not have capsule to wrap in the liposome.

46. according to the test kit of claim 33, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

47. according to the test kit of claim 33, wherein fatty acid is a docosahexenoic acid.

48. an increase is tried the method for the therapeutic index of vivo antitumor chemical compound, comprises fatty acid and anticancer compound are puted together formation fatty acid-anticancer chemical compound conjugate;

Give and to be tried body and take fatty acid-anticancer chemical compound conjugate, thereby with respect to the therapeutic index that prescription has improved anticancer compound of not puting together of anticancer compound.

49. according to the method for claim 48, wherein anticancer compound is a taxane.

50. according to the method for claim 49, wherein taxane is paclitaxel and docetaxel.

51. according to the method for claim 48, wherein conjugate does not have capsule to wrap in the liposome.

52. according to the method for claim 48, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

53. according to the method for claim 52, wherein fatty acid is a docosahexenoic acid.

54. according to the method for claim 48, it is human wherein being tried body.

55. give the method that body is taken fatty acid-taxane conjugate of being tried that needs this treatment, be included in to be less than in 3 hours and import conjugate for one kind.

56. according to the method for claim 55, wherein conjugate is at 2 hours or be less than in 2 hours input.

57. the injectable preparation of at least a fatty acid-taxane conjugate composition comprises at least a fatty acid-taxane conjugate composition greater than about 6 mg/ml.

58. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 7 mg/ml.

59. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 8 mg/ml.

60. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 10 mg/ml.

61. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 15 mg/ml.

62. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 20 mg/ml.

63. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 40 mg/ml.

64. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 60 mg/ml.

65. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 80 mg/ml.

66. according to the injectable preparation of claim 57, wherein preparation comprises at least a fatty acid-taxane conjugate composition greater than about 100 mg/ml.

67. according to the injectable preparation of claim 57, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

68. according to the injectable preparation of claim 67, wherein fatty acid is a docosahexenoic acid.

69. the Injectable composition of at least a fatty acid-taxane conjugate comprises at least a fatty acid-taxane conjugate that is less than about 0.3 mg/ml.

70. fatty acid-taxane conjugate composition comprises at least a fatty acid-taxane conjugate greater than about 6 mg/ml, and surfactant.

71. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 7 mg/ml.

72. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 8 mg/ml.

73. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 10 mg/ml.

74. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 15 mg/ml.

75. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 20 mg/ml.

76. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 40 mg/ml.

77. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 60 mg/ml.

78. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 80 mg/ml.

79. according to the fatty acid-taxane conjugate composition of claim 70, the amount of wherein at least a fatty acid-taxane conjugate is greater than about 100 mg/ml.

80. according to the fatty acid-taxane conjugate composition of claim 70, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

81. according to the fatty acid-taxane conjugate composition of claim 80, wherein fatty acid is a docosahexenoic acid.

82. according to the fatty acid-taxane conjugate composition of claim 70, wherein surfactant is Cremophor EL or EL-P.

83. according to the fatty acid-taxane conjugate composition of claim 82, wherein the concentration of Cremophor arrives between about 49.7% (volume ratio) about 9.6%.

84. fatty acid-taxane conjugate composition, comprise at least a fatty acid-taxane conjugate and surfactant, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 50 mg/ml.

85. according to the fatty acid-taxane conjugate composition of claim 84, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 60 mg/ml.

86. according to the fatty acid-taxane conjugate composition of claim 84, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 70 mg/ml.

87. according to the fatty acid-taxane conjugate composition of claim 84, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 80 mg/ml.

88. according to the fatty acid-taxane conjugate composition of claim 84, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 90 mg/ml.

89. according to the fatty acid-taxane conjugate composition of claim 84, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of surfactant is at least about 100 mg/ml.

90. according to the fatty acid-taxane conjugate composition of claim 84, wherein surfactant is Cremophor EL or EL-P.

91. according to the fatty acid-taxane conjugate composition of claim 84, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

92. according to the fatty acid-taxane conjugate composition of claim 91, wherein fatty acid is a docosahexenoic acid.

93. according to the fatty acid-taxane conjugate composition of claim 84, wherein taxane is paclitaxel or docetaxel.

94. the fatty acid-taxane conjugate composition according to claim 84 further comprises solvent.

95. according to the fatty acid-taxane conjugate composition of claim 94, wherein solvent is an ethanol.

96. according to the fatty acid-taxane conjugate composition of claim 95, wherein the ratio that exists of solvent and surfactant is about 1: 1.

97. fatty acid-taxane conjugate composition comprises at least a fatty acid-taxane conjugate and solvent, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 42 mg/ml.

98. according to the fatty acid-taxane conjugate composition of claim 97, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 50 mg/ml.

99. according to the fatty acid-taxane conjugate composition of claim 97, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 60 mg/ml.

100. according to the fatty acid-taxane conjugate composition of claim 97, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 70 mg/ml.

101. according to the fatty acid-taxane conjugate composition of claim 97, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 80 mg/ml.

102. according to the fatty acid-taxane conjugate composition of claim 97, the ratio of the wherein at least a fatty acid-weight of taxane conjugate and the volume of solvent is at least about 100 mg/ml.

103. according to the fatty acid-taxane conjugate composition of claim 97, wherein solvent is Cremophor EL.

104. according to the fatty acid-taxane conjugate composition of claim 97, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

105. according to the fatty acid-taxane conjugate composition of claim 104, wherein fatty acid is a docosahexenoic acid.

106. according to the fatty acid-taxane conjugate composition of claim 97, wherein taxane is paclitaxel or docetaxel.

107. the fatty acid-taxane conjugate composition according to claim 97 further comprises surfactant.

108. according to the fatty acid-taxane conjugate composition of claim 107, wherein surfactant is Cremophor.

109. according to the fatty acid-taxane conjugate composition of claim 108, wherein the ratio that exists of solvent and surfactant is about 1: 1.

110. fatty acid-taxane conjugate composition comprises at least a fatty acid-taxane conjugate at least about 37 mg/ml.

111. according to the fatty acid-taxane conjugate composition of claim 110, the amount of wherein at least a fatty acid-taxane conjugate is at least about 40 mg/ml.

112. according to the fatty acid-taxane conjugate composition of claim 110, the amount of wherein at least a fatty acid-taxane conjugate is at least about 50 mg/ml.

113. according to the fatty acid-taxane conjugate composition of claim 110, the amount of wherein at least a fatty acid-taxane conjugate is at least about 60 mg/ml.

114. according to the fatty acid-taxane conjugate composition of claim 110, the amount of wherein at least a fatty acid-taxane conjugate is at least about 80 mg/ml.

115. according to the fatty acid-taxane conjugate composition of claim 110, the amount of wherein at least a fatty acid-taxane conjugate is at least about 100 mg/ml.

116. according to the fatty acid-taxane conjugate composition of claim 110, wherein fatty acid is that C8-C26 is unbranched, spontaneous fatty acid.

117. according to the fatty acid-taxane conjugate composition of claim 110, wherein fatty acid is a docosahexenoic acid.

118. according to the fatty acid-taxane conjugate composition of claim 110, wherein taxane is paclitaxel or docetaxel.

119. a treatment suffers from the method for being tried body of unusual mammal propagation pathological changes, comprising: taken fatty acid-taxane conjugate to trying body, the amount of conjugate is at least 250,275,300,350,400,450,500,550,600,650,700,750,800,850,900,950,1000,1050,1100,1150,1200,1250,1300,1350 or 1400 milligrams/square metre.

120. according to the method for claim 119, wherein this amount is through 24 hours or be less than 24 hours, and 6 hours or be less than 6 hours, 3 hours or be less than 3 hours, or 2 hours or be less than 2 hours and give and tried body and take.

121. according to the method for claim 119, wherein fatty acid is the fatty acid of C8-C26.

122. according to the method for claim 119, wherein fatty acid is the unbranched of C16-C22, spontaneous fatty acid.

123. according to the method for claim 119, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

124. according to the method for claim 123, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

125. according to the method for claim 119-124, wherein taxane is paclitaxel.

126. according to the method for claim 125, wherein fatty acid is conjugated on 2 ' the OH position of paclitaxel.

127. according to the method for claim 126, wherein fatty acid is a docosahexenoic acid.

128. a composition substance comprises: the pure basically crystal of the conjugate of C8-C26 fatty acid and anticancer compound.

129. according to the composition substance of claim 128, wherein fatty acid is the fatty acid of C16-C22.

130. according to the composition substance of claim 129, wherein fatty acid is spontaneous unbranched fatty acid.

131. according to the composition substance of claim 129, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

132. according to the composition substance of claim 129, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

133. according to any one composition substance of claim 128-132, wherein anticancer compound is a taxane.

134. according to the composition substance of claim 133, wherein taxane is paclitaxel.

135. according to the composition substance of claim 134, wherein fatty acid is conjugated on 2 ' the OH position of paclitaxel.

136. according to the composition substance of claim 135, wherein fatty acid is a docosahexenoic acid.

137. the method for the conjugate of separation of C 8-C22 fatty acid and anticancer compound comprises: fatty acid and anticancer compound covalency are puted together the formation conjugate, form the conjugate crystal, isolation of crystalline.

138. according to the method for claim 137, wherein fatty acid at room temperature is buttery.

139. according to the method for claim 137, fatty acid polymerization unsaturated fatty acid wherein.

140. according to the method for claim 139, wherein fatty acid is the fatty acid of C16-C22.

141. according to the method for claim 137, wherein fatty acid is that C16-C22 is unbranched, spontaneous fatty acid.

142. according to the method for claim 137, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

143. according to the method for claim 137, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

144. according to any one method of claim 137-143, wherein anticancer compound is a taxane.

145. according to the method for claim 144, wherein taxane is paclitaxel.

146. according to the method for claim 145, wherein fatty acid is conjugated on 2 ' the OH position of paclitaxel.

147. according to the method for claim 146, wherein fatty acid is a docosahexenoic acid.

148. a test kit comprises

A kind of packing comprises first packing material of the solution of the conjugate that contains the fatty acid that is dissolved in first solvent and taxane, produces second packing material of the chemical compound of second solvent and surfactant, second solvent easily with first solvent and

The indication of combination solution and mixture.

149. according to the test kit of claim 148, wherein first solvent is an ethanol.

150. according to the test kit of claim 148, wherein surfactant is Cremophor.

151. according to the test kit of claim 148, wherein second solvent is an ethanol.

152. according to the test kit of claim 151, wherein the ratio that exists of the Cremophor and second solvent was at least 1: 1, and 2: 1,3: 1, or 4: 1.

153. according to any one test kit of claim 148-152, wherein fatty acid is the C8-C26 fatty acid, C16-C22 fatty acid, or spontaneous unbranched C16-C22 fatty acid.

154. according to any one test kit of claim 148-152, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

155. according to any one test kit of claim 148-152, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

156. according to the test kit of claim 153, wherein taxane is paclitaxel.

157. according to the test kit of claim 156, wherein fatty acid is a docosahexenoic acid.

158. according to the test kit of claim 152, wherein the conjugate concentration in the solvent is about 100 mg/ml.

159. medication preparation product comprise: the intravenous administration solution of the conjugate of C8-C26 fatty acid and taxane, wherein solution is substantially free of liposome.

160. according to the medication preparation product of claim 159, wherein fatty acid is that C16-C22 is unbranched, spontaneous fatty acid.

161. according to the medication preparation product of claim 159, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

162. according to the medication preparation product of claim 159, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

163. according to any one medication preparation product of claim 159-162, wherein taxane is paclitaxel.

164. according to the method for claim 163, wherein fatty acid is conjugated on 2 ' the OH position of paclitaxel.

165. according to the method for claim 164, wherein fatty acid is a docosahexenoic acid.

166. one kind prepares to the method for being tried the intravenous administration solution that body takes of suffering from the mammalian cell proliferation pathological changes, comprise: will be dissolved in the fatty acid in first solvent and the conjugate solution of taxane, with second solvent and surfactant mixtures combination, easy and first solvent of second solvent, described combination results premix joins premix in the intravenous administration solution.

167. according to the method for claim 166, wherein first solvent is an ethanol.

168. according to the method for claim 166, wherein surfactant is Cremophor.

169. according to the method for claim 166, wherein second solvent is an ethanol.

170. according to the method for claim 168, wherein the ratio that exists of the Cremophor and second solvent was at least 1: 1, and 2: 1,3: 1, or 4: 1.

171. according to any one method of claim 166-170, wherein fatty acid is the C8-C26 fatty acid, C16-C22 fatty acid, or spontaneous unbranched C16-C22 fatty acid.

172. according to any one method of claim 166-170, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, docosahexenoic acid, 2-caprylate, 2-caproate, CH ₃-caproate, CH ₃-butyrate, or oleic acid.

173. according to any one method of claim 166-170, wherein fatty acid is a linoleic acid, Palmic acid, arachidonic acid, 20 diene acid, or docosahexenoic acid.

174. according to the test kit of claim 171, wherein taxane is paclitaxel.

175. according to the method for claim 174, wherein fatty acid is a docosahexenoic acid, fatty acid is conjugated on 2 ' the OH position of paclitaxel.

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