CN100490802C - Injection use medicine composition containing water-soluble 17-allylamino-17-demethoxy geldanamycin - Google Patents
Injection use medicine composition containing water-soluble 17-allylamino-17-demethoxy geldanamycin Download PDFInfo
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Abstract
An injection of water-soluble 17-allylamino-17-demethoxy geldanamycin (17-AAG) for treating multiple kinds of cancers is prepared from 17-AAG and polyethanediol for increasing the solubility of 17-AAG in water.
Description
Technical field
The present invention relates to the medicinal composition for injections of 17-allyl amino-17-demethoxylation geldanamycin (17-AAG).
Background technology
Antitumor antibiotic is the chemical substance with active anticancer that is produced by microbial metabolism.The antitumor antibiotic of having reported is of a great variety, wherein be applied to clinical have 10 surplus kind.The antitumor antibiotic of natural origins such as mitomycin, amycin, daunorubicin, bleomycin, Bleomycin A5, dactinomycin and become treatment tumor medicine commonly used through the congener of chemical modification becomes an important component part in cancer therapy drug storehouse.
At present, the antitumor antibiotic that acts on various different target spots is in the news successively, main target spot comprises tumor vessel, dna profiling, matrix metalloproteinase and heat shock protein 90 (HSP90) etc., and wherein, the inhibitor geldanamycin of HSP90 is because its significant anticancer effect is noticeable.(geldanamycin is the excretory a kind of material of moist streptomycete GA) to geldanamycin, belongs to benzoquinone ansamycin (benzoquinone ansamycin) class antibiotic.People find that for a long time GA has the good restraining activity to the growth of tumor cell.Studies show that afterwards, the antiproliferative of GA and antitumor action are because it combines with heat shock protein 90 (HSP90) and suppresses its intrinsic ATPase activity, thereby cause HSP90 to follow proteic degraded.
At present, Chang Yong tumor chemotherapeutic drug has following two serious weak points clinically: 1. owing to the specificity that lacks tumor cell, so side effect is very big.2. easily produce drug resistance of tumor.Present many tumor conventional chemotherapy weak effects, prognosis mala are the clinical important difficult problems of puzzlement, and the key factor that influences chemotherapy effect is that tumor produces drug resistance to chemotherapeutics.
Because tumor has good gene plasticity, cancerous cell can be by multiple modes such as gene mutation and multidrug resistance gene to the injury of chemotherapeutics, activates many cellular signal transduction paths and protect and self avoid the chemotherapeutics injury, thus the generation drug resistance.The approach that solves this contradiction is possibly at the mechanism of tumor to environmental stimulus generation adaptation response.It at first is to realize by the expression that increases multiple molecular chaperones (as heat shock protein) that cell produces various reactions to environmental stimulus.Discovering that heat shock protein is obviously expressed in the kinds of tumors tissue strengthens, so the inhibitor of heat shock protein not only can directly bring into play anti-tumor effect, and might remove the tolerance of tumor to other cancer therapy drug.And because heat shock protein belongs to stress response protein, its content in normal structure is extremely low, so geldanamycin class medicine can be brought into play optionally inhibitory action to tumor.
The advantage of geldanamycin also is the popularity of its effect, HSP90 keep some key carcinogenic follow on proteic conformation, stability and the function extremely important.The albumen of being responsible for maintaining by HSP90 comprises: the p53 of receptor tyrosine kinase, transmembrane conductance regulator, serine/threonine kinase, sudden change, c-erbB, Bcr-Ab1, Raf1, Akt and hypoxic inducing factor-1 α etc., they cause breeding, cell cycle is advanced and the signal transduction pathway of apoptosis in work; In addition, they are also very important for the characteristics of keeping such as malignant tumor phenotypes such as infiltration, angiogenic growth and transfers.Geldanamycin passes through the specific inhibition of heat shock protein, cause the unstable and degraded of these carcinogenic proteins, geldanamycin and derivant thereof equal to have realized inhibition to multiple cancer target spot and approach to the inhibition of HSP90 function, this multipath combination inhibitory action makes geldanamycin possess the broad-spectrum tumor cell resistance.
GA by HSP90 to multiple cancer target spot the time inhibitory action also have the another one advantage, be exactly that tumor cell is difficult for it is produced resistance, because a tumor cell is difficult to change simultaneously the multiple signal pathway of keeping its growth, to escape the lethal effect of medicine.
Though GA shows the good restraining tumor promotion on the animal model of people's tumour transplatation, be applied to be subjected to when clinical its hepatotoxic restriction.For making the HSP90 inhibitor can be used in oncotherapy, the American National ICR screens a series of geldanamycin derivants, obtain a kind of chemical compound 17-allyl amino-17-demethoxylation geldanamycin (17-allylamino-17-demethoxygeldanamycin at last, 17-AAG), its structural formula is shown in (I).
17-AAG has kept GA to the inhibitory action of HSP90 and the anti-tumor activity in cell culture and tumour transplatation model, but liver toxicity is significantly less than GA.Because 17-AAG shows good active and cancer selectivity on preclinical models, now enter the II clinical trial phase in the U.S. and Britain, initial results is encouraging, this comprising with the research of cellulotoxic preparation's use in conjunction, these tests will be determined the therapeutic activity of 17-AAG.
The kind specific character of 17-AAG shows that it might become a kind of comparatively ideal novel chemotherapeutics.But it is dimethyl sulfoxide that the U.S. carries out the employed solvent of the 17-AAG of clinical and experimental study.This solvent is bigger to the toxicity of human body, " in Chinese pharmacopoeia and the ICH pertinent literature in the regulation human injectable drug the high-load of dimethyl sulfoxide can not surpass 50 milligrams/agent.The 17-AAG human preparation of national cancer institute development is a lyophilized formulations, and earlier with 2 milliliters of dmso solutions, in joining 10% G/NS injection, the amount of the dimethyl sulfoxide that uses has surpassed 2000 milligrams/agent then with preceding.
Summary of the invention
The present inventor finds unexpectedly, in preparation, add a certain amount of Polyethylene Glycol (PEG) and can improve 17-allyl amino-17-demethoxylation geldanamycin significantly (hereinafter to be referred as 17-AAG, or the amino geldanamycin of 17-allyl) dissolubility in water, and PEG does not react with material medicine 17-AAG, reach the requirement of injection preparation, make things convenient for clinical application, finished the present invention thus.
Unless otherwise indicated, the part term definition of this description is as follows:
The pharmaceutical composition that " medicinal composition for injections " of the present invention used for the injectable that comprises the 17-AAG of pharmaceutically acceptable form and polyethylene glycols cosolvent, it can further comprise other solvent for injection, for example normal saline or glucose solution.In this article, sometimes " medicinal composition for injections " abbreviated as " pharmaceutical composition ".
" injection " of the present invention for comprising the injection of 17-AAG and polyethylene glycols cosolvent, it can only be after normal saline or glucose solution dilution, just can be used for injection, and can not be directly used in injection.In this article, sometimes " injection " abbreviated as " preparation ".
" injection " of the present invention is after the above-mentioned injection that comprises 17-AAG and polyethylene glycols cosolvent is diluted with normal saline or glucose solution, the injection of the be directly used in injection that obtains.
The invention provides the medicinal composition for injections of a kind of 17-AAG of containing, comprise the 17-AAG and the polyethylene glycols cosolvent of the pharmaceutically acceptable form for the treatment of effective dose, 17-AAG is 1～6mg:1ml with the ratio of Polyethylene Glycol.
Drug regimen composition formula of the present invention can significantly improve the 17-AAG water solublity, and in a preferred embodiment of the present invention, when selecting PEG400 as cosolvent for use, the result shows that the water solublity of 17-AAG can increase more than 50 times.
The 17-AAG of the pharmaceutically acceptable form that is fit to comprises pharmaceutically acceptable salt form and pharmaceutically acceptable solvate forms, the pharmaceutically acceptable solvate forms that also comprises pharmaceutically acceptable salt, wherein said 17-AAG is pharmaceutically acceptable amorphous state or crystal habit.
Preferably, 17-AAG is 1～3mg:1ml with the ratio of Polyethylene Glycol, so that obtain to contain the more stable injection of 17-AAG, lowers the use amount of PEG400 simultaneously.
Preferred, 17-AAG is 1.0～1.5mg:1ml with the ratio of Polyethylene Glycol.
In a preferred embodiment of the present invention, 17-AAG is 1.25mg:1ml with the ratio of Polyethylene Glycol.
In pharmaceutical composition of the present invention, described polyethylene glycols cosolvent is to be selected among PEG300, PEG400, the PEG600 one or more.
In a preferred embodiment of the present invention, described polyethylene glycols cosolvent is a PEG400.The dissolubility of 17-AAG in PEG400 can reach 6mg/ml.According to " the highest working concentration of the pertinent regulations PEG400 of Chinese pharmacopoeia is 40%, in order to obtain to contain the more stable injection of 17-AAG, also in order to lower the use amount of PEG400, the concentration of 17-AAG in the PEG400 solution can be adjusted into 1～3mg/ml, preferred 1.0～1.5mg/ml simultaneously.
It will be understood by those skilled in the art that in pharmaceutical composition of the present invention, two or more polyethylene glycols cosolvent combined used that perhaps add other solvent, for example glycerol, propylene glycol, ethanol etc. all can not exceed scope of the present invention.
Pharmaceutical composition of the present invention can also comprise any conventional adjuvant that is used for injection, includes but not limited to diluent, antiseptic, stabilizing agent, pH regulator agent, isotonic agent etc.
Described injection can be intravenous injection, thoracic cavity injection or lumbar injection agent, the intravenous drip administration when being respectively applied for chemotherapy, thoracic cavity drug administration by injection (entering the thoracic cavity), intraperitoneal injection (entering the abdominal cavity).
Need before the injection clinical practice of the present invention with normal saline solution or the dilution of 5% glucose injection.The present invention is according to " pertinent regulations of Chinese pharmacopoeia, the highest working concentration of PEG400 is 40%, therefore, the 17-AAG preparation can be diluted 1.5～10 times.According to the investigation result of formulation soln compatibility test, preferred 17-AAG preparation extension rate is 2～5.
Therefore, pharmaceutical composition of the present invention also can further comprise a kind of solvent, and this solvent is normal saline or glucose solution, and the volume ratio of Polyethylene Glycol and this solvent is 1:1.5～10.Normal saline of the present invention and glucose solution all are aqueous solutions that injectable is used.
Preferably, the volume ratio of Polyethylene Glycol and this solvent is 1:2～5.
In pharmaceutical composition of the present invention, be not particularly limited the consumption of 17-AAG, can be normally used any dosage in injection." treatment effective dose " is meant that the 17-AAG ejection preparation reaches the common consumption of therapeutic effect, and the doctor can make suitable adjustment according to patient's the state of an illness and the situation of others.When being used for various treatment for cancer, the use amount of 17-AAG is generally 0.2～10mg/kg body weight/day, preferred 1～4mg/kg body weight/day.
Therefore, if consider that with medication on the one pharmaceutical composition of unit dosage forms of the present invention can comprise 4～600mg 17-AAG for 1～3 time, preferred 15～240mg (body weight for humans is pressed 60Kg and calculated).
The present invention also further provides the preparation method of aforementioned pharmaceutical compositions, comprises 17-AAG is dissolved in the Polyethylene Glycol, forms the step of injection.17-AAG and Polyethylene Glycol can make clear and bright 17-AAG solution, and it can be used for the intravenous drip administration by with an amount of dilutions such as normal saline.
The invention still further relates to the application of pharmaceutical composition of the present invention in the preparation cancer therapy drug.Described pharmaceutical composition can be used for various treatment for cancer, comprises leukemia, pulmonary carcinoma, hepatocarcinoma, renal carcinoma, breast carcinoma etc.Clinically, also 17-AAG injection provided by the invention and other chemotherapy drugs in combination can be used, with prevention and improve the tolerance situation of tumor other chemotherapeutics.
The present inventor has carried out comprehensive and systematic research to 17-AAG and injection thereof, comprises physicochemical property research, pharmacodynamics evaluation, pharmacokinetics evaluation, acute toxicity evaluation, long term toxicity evaluation about 17-AAG; About the main ingredient Study on Compatibility of 17-AAG injection, hemolytic evaluation, blood vessel irritation evaluation, anaphylaxis evaluation, stability study etc.
The pharmacodynamic study result of 17-AAG shows:
1,17-AAG all has clear and definite growth inhibited effect, IC external to human small cell lung carcinoma, breast carcinoma, hepatocarcinoma 7402
50About 5 μ g/ml.
2,17-AAG is to human small cell lung carcinoma mice with tumor, people's hepatocarcinoma mice with tumor and the good antitumor action of the equal tool of human breast carcinoma mice with tumor, to the human tumor cells IC of mice with tumor load
50Value is 25mg/kg.
3, in the body, the anticancer experiment in vitro result proves that (strain) has good antitumaous effect to 17-AAG to kinds of tumor cells such as pulmonary carcinoma, hepatocarcinoma, and drug safety.
The pharmacokinetic result of 17-AAG shows: 17-AAG is distributed in most of organs and tissue very soon after the administration, wherein, lung Chinese medicine concentration is all the time than its hetero-organization height, drug level is also higher in the liver, thereby the treatment that is used for pulmonary carcinoma, hepatocarcinoma for 17-AAG provides the pharmacokinetics support.
The acute toxicity test of 17-AAG and long term toxicity test result of study show that this drug toxicity is low, better tolerance, and the clinical practice side effect is little.The toxicity test result of study is summarized as follows:
1, the LD of an intravenous injection 17-AAG of mice
50=102.51mg/kg, the approximate lethal dose of an intravenous drip of dog is 30mg/kg.
2,17-AAG by 1,4 and 8mg/kg dosage carry out 2 months for the Beagle dog (intravenous drip was 1 time in per 3 days, administration is 20 times altogether) long term toxicity test, hepatotoxicity and slight lung toxicity appear in the administration process, bone marrow depression, cardiac toxicity and nephrotoxicity do not occur, and do not occur body weight gain during the administration and suppressed.Hepar damnification that 17-AAG causes and injury of lung are a property crossed, and can recover after the drug withdrawal.
The whole body of injection of the present invention initiatively sensitivity test, hemolytic test and blood vessel irritation result of the test shows that preparation clinical vein drop of the present invention administration is safe.The result of study of above-mentioned test is summarized as follows:
1, preparation of the present invention was injected 3 days continuously to tame rabbit ear edge blood vessel, and slight stimulation (the cavity sample degeneration that blood vessel endothelium undertissue is slight) is only arranged, and was reversible change, can recover in 14 days after the drug withdrawal, illustrated that it is safe that this preparation instils at clinical vein.
2, preparation of the present invention does not exert an influence to the erythrocyte normal condition, does not have hemolytic reaction.
3, preparation of the present invention does not make Cavia porcellus anaphylaxis occur.
The quality investigation result of injection of the present invention shows:
1, the PEG400 in the preparation (adjuvant) does not disturb the assay and the discriminating of main constituent (17-AAG).
2, preparation is placed at 2～8 ℃ ,-18 ℃ long-term, the basic no changes of index such as outward appearance, clarity, content, and preparation stability is better.
3, carry out the test of solution compatibility with normal saline and 5% glucose solution dilution preparation, behind preparation and the solution compatibility, equal no change such as face shaping, clarity, content so this preparation clinical practice solution room temperature condition was stablized in following 4 hours, is convenient to the clinical vein drop in 4 hours.
Below, describe part Study result in detail about 17-AAG injection of the present invention.(1) pharmacodynamics evaluation
For 17-AAG being carried out comparatively comprehensively pharmacodynamics evaluation, the present invention has mainly carried out following test:
(1) tumor cell in vitro growth inhibited experiment
(2) mouse entity tumor antitumor action experiment
(3) mouse ascites tumor and P388 medicine for treating leukemia prolongation effect experiment
(4) people's tumor xenotransplantation tumor experiment
Experimental result proves that 17-AAG all has clear and definite growth inhibited effect, IC external to human small cell lung carcinoma, breast carcinoma, hepatocarcinoma 7402
50About 5 μ g/ml.
With the mouse tumor cell tumor-bearing mice is model, the 17-AAG intravenous administration, and dosage 40,80mg/kg successive administration 4 times all have remarkable antitumor action to mice S180 sarcoma, Lewis lung cancer, B16 melanoma, and tangible dose-effect relationship, ED are arranged
50Average is 30.2mg/kg.
The 17-AAG dosage is 40, successive administration 4 times during 80mg/kg, obviously prolongs ascitic type tumor-bearing mice (EAC, H22, P388) survival period, and certain dose-effect relationship, IC are arranged
50Average is 49.3mg/kg, apparently higher than the IC of solid tumor
50Value.
The 17-AAG dosage is 40, successive administration 8 times during 80mg/kg, to human small cell lung carcinoma mice with tumor, people's hepatocarcinoma mice with tumor and the good antitumor action of the equal tool of human breast carcinoma mice with tumor; Different dosing dosage shows tangible dose-effect relationship.
17-AAG is to the IC of the human tumor cells of mice with tumor load
50Value is 25mg/kg.
Comprehensively above-mentioned, 17-AAG mice with tumor intravenously administrable ED
50Meansigma methods is 34.7 ± 11.5mg/kg, the 95% credible 12.2～68.1mg/kg that is limited to; Comprehensive therapeutic index shows that greater than 5 drug safety is good.17-AAG is in anticancer experiment in vitro, and the suppression ratio that prolongs growth of tumour cell with action time does not have obvious influence; Experiment shows in the body, and the tangible amount-result relation of the equal tool of 17-AAG antitumor increases with administration number of times, obviously increases its curative effect.
Experimental studies have found that 17-AAG can bring into play inhibitory action from many aspects to the generation development of pulmonary carcinoma, except as in other tumor cell, bringing into play antiproliferative and making tumor cell to the effects such as chemotherapy drug susceptibility enhancing, 17-AAG can also make lung carcinoma cell shift phenotype, 17-AAG can obviously remove the expression of a kind of tumor growth factor erB1/erB2, suppress tumor cell secretion MMP-9 and VEGF, strengthen the expression of E-cadherins, thereby suppress the transfer of tumor cell.
Experiment shows in the animal body, and the chemotherapy regimen that contains 17-AAG can obviously dwindle the mouse-borne tumor volume, prolong survival time of mice than other scheme, in the 17-AAG treatment group, the tumor complete obiteration of 50% tumor-bearing mice is arranged approximately, and mice does not have tumor existence for a long time.
Body is interior, anticancer experiment in vitro studies show that 17-AAG has good antitumaous effect to the tumor cell of being studied (strain), and drug safety.
(2) pharmacokinetics evaluation
By beasle dog single and multiple dosing, rat single and multiple dosing, macaque single-dose, tissue distribution, drainage, human plasma protein fraction combination rate, the influence of liver drug enzyme and metabolite are inferred that research estimates for kinetic property the clinical prodrug of 17-AAG.
In vivo pharmacokinetics process meets two chamber models behind beasle dog, male Wistar rat, the macaque single intravenous injection 17-AAG; Beasle dog single intravenous injection 0.4,1.6 and 3.2mgkg
-1T1/2 α behind the 17-AAG of three kinds of dosage (ratio is 1:4:8) is respectively 0.11 ± 0.10,0.13 ± 0.06,0.24 ± 0.13h, t
1/2β is respectively 1.05 ± 0.21,1.43 ± 0.51,1.39 ± 0.92h, plasma clearance CL after each dosage group administration
SBe respectively 1.77 ± 0.27,1.66 ± 0.32,1.85 ± 0.52Lkg
-1H
-1, t through between t check various dose
1/2α, t
1/2β, CL
SBetween no difference of science of statistics (p〉0.05).Area under the drug-time curve AUC under three kinds of dosage
0-
tTrapezoidal method is respectively 0.21 ± 0.04,0.91 ± 0.26,1.60 ± 0.54mghL
-1(ratio is 1:4.33:7.62), with dosage increase in direct ratio, prompting single intravenous injection 17-AAG presents the linear kinetics feature in the intravital disposal of beasle dog.The t of male Wistar rat and macaque
1/2The basically identical of β and beasle dog.
Can be distributed in most of organs and tissue very soon in vivo after the 17-AAG administration, the content of dispersion of many tissues all is higher than plasma drug level.After the 17-AAG administration, the drug level in the lung is high than other tissue all the time.In brain, only can measure a spot of 17-AAG, illustrate that 17-AAG original shape medicine is difficult for seeing through blood brain barrier and enters cerebral tissue.Along with the prolongation of time, intestinal contents Chinese medicine concentration increases gradually, 4hr to the administration, and intestinal contents Chinese medicine concentration is only second to lung Chinese medicine concentration, illustrates that high amount of drug has entered enteral through bile.Renal drug concentration is higher all the time, illustrates that 17-AAG and metabolite thereof mainly excrete through kidney.Give the Wistar rat vein and inject 17-AAG (5mgkg
-1) drain research.The result shows that behind the 17-AAG intravenously administrable, the medicine original shape is very limited through the excretion of bile, urine and feces, and most of medicine may be converted into multiple metabolite in vivo.
The plasma protein binding rate of 17-AAG and people, rat and beasle dog is all higher, greater than 90%.The plasma protein binding rate of 17-AAG does not more all have significant difference between kind and between variable concentrations.The 17-AAG that rat vein is studied dosage does not cause the variation of liver drug enzyme content, and not show dose dependence effect.The metabolite of 17-AAG in bile, urine sample separated, and carry out Preliminary Identification.Result of study shows, has multiple metabolite in rat urine, bile, and wherein 17-AAG takes off pi-allyl and oxidation product accounts for major part in rat urine, bile.
(3) long term toxicity evaluation
After 17-AAG dissolved with PEG400, with the normal saline dilution, the proportionate solution of size preparation according to dosage was for intravenous drip or lumbar injection usefulness.17-AAG by 1,4 and the 8mg/kg dosed administration carry out 2 months (intravenous drip was 1 time in per 3 days, altogether administration 20 times), convalescent period observed 1 month.The result of Beagle dog long term toxicity test shows that heavy dose of treated animal has 1 example dead, and other animal also shows serious toxic reaction.Be that animal appearance activity reduces, vomiting, loose stool, the sound of stridulating appears in breathing, can recover after the drug withdrawal, but body weight gain is suppressed during administration.Heavy dose of present biochemical indicators such as GOT, GPT, ALP, K-ALP to 3 weeks treated animal 1 week of administration and raise unusually, from the 4th week back GOT, GPT recover gradually normally, recover normally after ALP, the K-ALP drug withdrawal.Hematology, electrocardiogram, routine urianlysis no abnormality seen.Unusual pathological change appears in heavy dose of treated animal of putting to death in 24 hours after the drug withdrawal, mainly contains liver portal area inflammatory cell infiltration, hepatic congestion, pulmonary venous pleonaemia, septal thickening, kitchen range pneumonia, pathological changes such as digestive tract mucosa congestion.The bone marrow examination no abnormality seen, the pathologic finding of heart is no abnormality seen also.Heavy dose of treated animal that convalescent period puts to death has slight hepatocellular degeneration necrosis, abnormal changes such as kitchen range pneumonia.Middle dosage treated animal occurs one and crosses the slight liver toxicity reaction of property.Any toxic reaction was not seen in the 1mg/kg intravenous drip in 2 months, belonged to safe dose.
Carry out the long term toxicity evaluation for rats by intraperitoneal injection (per 3 days 1 time, totally 20 times) 17-AAG 13,5 and 2mg/kg.The serious toxicity reaction similar to dog appears in heavy dose of treated animal, and the observation period recovers normal gradually.Slight liver toxicity reaction appears in the 5mg/kg treated animal.2mg/kg continues lumbar injection and did not see any toxic reaction in 2 months, belongs to safe dose.
(4) blood vessel irritation evaluation
Get the 17-AAG preparation, be mixed with injection with 4 times of normal saline dilutions, 17-AAG preparation blood vessel irritation is estimated in the injection of rabbit auricular vein.Animal general state no abnormality seen during the administration and between convalescent period.The auricular vein inserting needle position of matched group and administration group shows that all local vein has mild hyperaemia and swelling.The 17-AAG injection was injected 3 days continuously to tame rabbit ear edge blood vessel, only there is 1 routine animal to be tried position venous endothelial undertissue and slight cavity sample degeneration occurs, all the other administration groups and control animals auricular vein wall all do not have and thicken, no endotheliocytic swelling, come off, do not have inflammatory cell infiltration around the blood vessel, no thrombosis forms in the lumen of vessels.After the drug withdrawal in 14 days administration group and matched group auricular vein there is no abnormal change.Experimental result shows that the 17-AAG injection is safe on clinical vein instils.
(5) hemolytic evaluation
Adopt improved external hemolytic test method(s) (spectrophotography) to carry out the 17-AAG preparation and have or not the haemolysis evaluation.Test specimen is the 17-AAG preparation, with 4 times of normal saline dilution preparations.The negative control medicine is a normal saline.Positive control drug is a distilled water.Result of study shows that the 17-AAG injection does not exert an influence to the erythrocyte normal condition, does not have hemolytic reaction.
(6) anaphylaxis evaluation
The 17-AAG preparation is carried out the Cavia porcellus hypersensitive test.Test specimen is the 17-AAG preparation, with 4 times of normal saline dilution preparations.Positive control drug is a horse serum.The next day intravenous injection 17-AAG injection and horse serum, inject altogether 3 times, excited in the 14th day and the 21st day.The injection back was observed 30 minutes.The 17-AAG injection does not make Cavia porcellus anaphylaxis occur.
Water solublity 17-AAG injection of the present invention has the following advantages:
1, efficient, the anti-tumor effect of broad-spectrum.
2, special tumor-selective killing effect.
3, hypotoxicity.
4, good water-solubility makes things convenient for intravenous administration.
5, preparation and clinical administration stability of solution are good.
6, wide application prospect is expected to be used for the treatment of various proliferative diseasees.
In order to understand essence of the present invention better,,, describe in detail but do not limit the present invention by description to better embodiment of the present invention below in conjunction with accompanying drawing.
Brief description of drawings
Fig. 1 is the process chart of 17-AAG injection preparation of the present invention.
The specific embodiment
Employed 17-AAG provides by Shenzhen Sheng Eryi industry development Co., Ltd in following test, and its concrete preparation method is referring to Chinese patent 02132163.9 and Chinese patent application 02818718.0.17-AAG also can buy by commercial sources, for example: A.G.Scientific, Inc.6450 Lusk Blvd.Suite E102, San Diego, CA 92121 (CAS No.CAS[75747-14-7]).
Used other test material of the present invention if no special instructions, is commercially available purchase product.
The physicochemical property research of 17-AAG
[embodiment 1]
One, the 17-AAG influence factor tests the foundation of HPLC assay method
With octadecylsilane chemically bonded silica is filler; Phosphate buffer [is got sodium dihydrogen phosphate (NaH
2PO
42H
2O) 2g is dissolved in water and dilutes and make 1000ml]-acetonitrile-methanol-triethylamine (40:50:10:0.2) regulates pH to 5.0 with phosphoric acid and is mobile phase; Flow velocity is 1.2ml/min; The detection wavelength is 303nm.Number of theoretical plate should be not less than 2000 by 17-AAG; The separating degree of 17-AAG peak and adjacent impurity peaks should meet the requirements.
Two, test method and result
1, sample controlled trial
The lucifuge operation.Get the about 15mg of 17-AAG, the accurate title, decide, and puts in the 50ml measuring bottle, and it is an amount of to add mobile phase, supersound process 5min adds mobile phase and is diluted to scale, shakes up, measure 20 μ l and inject chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time, and total impurities counts 1.26% by normalization method.
2, acid degradation test
The lucifuge operation.Get 17-AAG 15mg, accurate claim surely, put in the 50ml measuring bottle, after adding 0.1mol/L hydrochloric acid solution 1ml and placing 6hr, it is an amount of to add mobile phase, and supersound process 5min adds mobile phase and is diluted to scale, shakes up, and destroys solution as acid; Measure and destroy solution 20 μ l injection chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time; Other gets 0.1mol/L hydrochloric acid solution 1ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, as sour blank solution, measures blank solution 20 μ l and injects chromatograph of liquid, the record chromatogram.17-AAG places in the 0.1mol/L hydrochloric acid solution and produced degradation impurity in 6 hours, shows that 17-AAG is unstable under acidic condition.
3, alkaline degradation test
The lucifuge operation.Get 17-AAG 15mg, accurate claim surely, put in the 50ml measuring bottle, after adding 0.1mol/L sodium hydroxide solution 1ml and placing 6hr, it is an amount of to add mobile phase, and supersound process 5min adds mobile phase and is diluted to scale, shakes up, and destroys solution as alkali; Measure and destroy solution 20 μ l injection chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time; Other gets 0.1mol/L sodium hydroxide solution 1ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, as the alkali blank solution, measures blank solution 20 μ l and injects chromatograph of liquid, the record chromatogram.17-AAG places in the 0.1mol/L sodium hydroxide solution and produced degradation impurity in 6 hours, shows that 17-AAG is unstable under alkali condition.
4, oxidative degradation test
The lucifuge operation.Get 17-AAG15mg, accurate claim surely, put in the 50ml measuring bottle, after adding 30% hydrogenperoxide steam generator 1ml and placing 6hr, it is an amount of to add mobile phase, and supersound process 5min adds mobile phase and is diluted to scale, shakes up, and destroys solution as oxidation; Measure and destroy solution 20 μ l injection chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time; Other gets 30% hydrogenperoxide steam generator 1ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, as the oxidation blank solution, measures blank solution 20 μ l and injects chromatograph of liquid, the record chromatogram.17-AAG places in 30% hydrogenperoxide steam generator and did not see obvious destruction in 6 hours, so 17-AAG is at 30% H
2O
2In stable.
The acid of table 1 17-AAG crude drug, alkali, oxidation failure test result
| Experimental condition | Result's (content is in the peak area normalization method) |
| The sample controlled trial | Total impurities is 1.26, and main peak goes out the peak in 10.43min, in 2.54,3.10,3.34,3.69,4.46,4.67,6.57,7.21,7.48,8.09,8.89,9.47, the 12.89min place goes out impurity peaks. |
| 0.1mol/L HCl, 1ml, 6 hours | Increase 0.48% 4.47min locate impurity peaks, other impurity peaks is not seen increase.So 17-AAG places the 6hr instability in 0.1mol/L HCl. |
| 0.1mol/L NaOH, 1ml, 6 hours | Total impurities increases to 22.12% by 1.26%, so 17-AAG places the 6hr instability in 0.1mol/L NaOH solution. |
| 30%H 2O 2, 1ml, 6 hours | Each impurity has no significant change, so 17-AAG is at 30%H 2O 2In stable. |
5, highlight test
The lucifuge operation.Get 17-AAG sample 100mg, through 4500 ± 500Lx irradiation 10 days; Get the about 15mg of postradiation sample, the accurate title, decide, and puts in the 50ml measuring bottle supersound process 5min, add mobile phase and be diluted to scale, shake up, measure 20 μ l and inject chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time, as seen from the figure, do not produce new impurity, former impurity has increased by 0.53%, so 17-AAG is to photo-labile.
6, hot accelerated decomposition test
The lucifuge operation.Get 17-AAG sample 50mg respectively, heated 1 day in 10 days or 105 ℃ through 60 ℃ of heating of high temperature; The about 15mg of sample of above-mentioned processing learns from else's experience respectively, the accurate title, decide, put in the 50ml measuring bottle, supersound process 5min adds mobile phase and is diluted to scale, measure 20 μ l and inject chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time, and the result shows that 17-AAG new impurity do not occur in 60 ℃ of conditions, former impurity is also basicly stable, so 17-AAG is stable under 60 ℃ of conditions; Placed one day under the 17-AAG105 ℃ of condition, related substance increases to 1.55%.
7, high wet test
The lucifuge operation.Get 17-AAG sample 50mg, in 25 ± 2 ℃, be to investigate 10 days at 90% ± 5% o'clock at relative humidity; The about 15mg of 17-AAG after the fixed processing of accurate title, put in the 50ml measuring bottle, supersound process 5min, add mobile phase and be diluted to scale, measure 20 μ l and inject chromatograph of liquid, the record chromatogram is to 3 times of main constituent peak retention time, and measurement result shows that new impurity does not appear in 17-AAG, so 17-AAG is stable under super-humid conditions.
Three, test brief summary
By above result of the test as can be known, the HPLC method specificity of being set up is good, degradation impurity effectively can be separated, and highly sensitive.17-AAG meets photo-labile, does not produce new impurity, and former impurity increases; Unstable under acid, alkali condition, do not see that new impurity produces, former total impurities increases; Stable under oxidizing condition; Stable under 60 ℃ and super-humid conditions.The solution of 17-AAG is seen photo-labile, answers the lucifuge operation when adopting liquid phase process to measure content or impurity.
17-AAG and adjuvant PEG400 repercussion study
[embodiment 2]
Get 17-AAG, the adjuvant PEG400 of different proportionings, under illumination and temperature effect condition, investigate the interaction of crude drug and adjuvant respectively.With the variation before and after HPLC method inspection 17-AAG content and the related substance placement, observe the variation of medicine character such as outward appearance, color and luster simultaneously, to estimate the compatibility situation of crude drug and adjuvant.
One, 17-AAG preparation related substance HPLC detection method
With octadecylsilane chemically bonded silica is filler; Phosphate aqueous solution (it is 3.0 that water intaking is regulated pH value with phosphoric acid) for mobile phase A, is a Mobile phase B with the acetonitrile; Flow velocity is per minute 1.0ml, gradient elution; Detect wavelength 303nm.Number of theoretical plate should be not less than 2000 by 17-AAG; The separating degree of 17-AAG peak and adjacent impurity peaks should meet the requirements.This HPLC detection method can be destroyed illumination impurity and effectively separate with solvent peak.
A: the aqueous solution B that transfers to pH3.0 with phosphoric acid: acetonitrile
0min 60％ 40％
30min 30％ 70％
35min 60％ 40％
Two, test method and result
The lucifuge operation.It is standby that No. 9 sieve backs are crossed in an amount of 17-AAG powder grinding back.Take by weighing 17-AAG and adjuvant Polyethylene Glycol-400 (chemical plant, the southeast, PVG) according to table 2 Central Plains ratio of adjuvant, promptly get red sticky clear liquid, through 0.2 μ m degerming membrane filtration.In the 25ml of cleaning sterile cillin bottle, loading amount is that 8ml/ props up with each proportioning filled with solution.
The interaction sample supplementary material prescription of table 2 crude drug and adjuvant
Sample was placed freezing, cold preservation, 60 ℃ and 4500Lx condition following 10 days, respectively at 0 day, 5 days, 10 days observation sample outward appearances; And from sample solution, get 5.5g, and add methanol and be diluted to 10ml, shake up, measure each 20 μ l of above-mentioned solution respectively and inject chromatograph of liquid, the record chromatogram; The results are shown in Table 3.
Table 3 interaction measurement result
Three, test brief summary
The HPLC measurement result shows the 17-AAG crude drug to light, thermo-responsive, and influence of light solution and temperatures involved solution are investigated degraded in 5 days obviously, so do not continue to investigate.Simultaneously, do not have interaction between above-mentioned result of the test proof raw material and the adjuvant, adjuvant is selected correct.
The preparation of 17-AAG injection
[embodiment 3]
Precision takes by weighing 1000 milligrams of 17-AAG, joins in 800 milliliters of PEG400 (Gao Nan chemical plant, PVG, lot number 040448) solution to dissolve.The room temperature lucifuge is carried out aseptic filtration.Under aseptic condition, the preparation branch is filled in the sterilization cillin bottle.
Join before the clinical practice in 0.9% sodium chloride injection or the 5% or 10% G/NS injection, make the final concentration of PEG400 reach 30%～40% or 10%～30%, the 17-AAG in this injection is stable with interior maintenance at 4 hours.
Fig. 1 is seen in the technological process of 17-AAG injection preparation.
Pharmaceutical formulation of the present invention can significantly improve the 17-AAG water solublity, and the result shows that the water solublity of 17-AAG can increase more than 50 times.
[embodiment 4]
Precision takes by weighing 1200 milligrams of 17-AAG, joins in 400 milliliters of PEG400 solution to dissolve.The room temperature lucifuge is carried out aseptic filtration.Under aseptic condition, the preparation branch is filled in the sterilization cillin bottle.
[embodiment 5]
Precision takes by weighing 1000 milligrams of 17-AAG, joins in 500 milliliters of PEG400 solution to dissolve.The room temperature lucifuge is carried out aseptic filtration.Under aseptic condition, the preparation branch is filled in the sterilization cillin bottle.
The research of solvent load
[embodiment 6]
Polyethylene Glycol-400 chemical property is stable, can mix with water, ethanol arbitrary proportion.PEG-400 is 1%～50% as the typical concentrations of solvent for injection.PEG-400 drug administration by injection toxicity is lower, and is low to the stimulation of skin, mice by intraperitoneal injection LD
50Be 4.2g/kg.In order to ensure the safety of 17-AAG preparation, determine PEG-400 content in the clinical drop medication liquid is controlled between 10～40%.
According to above-mentioned Polyethylene Glycol-400 character, prepare the sample of the different proportionings of 5 parts of supplementary materials, preparation method is with method under the supplementary material interaction item.Behind the sample shake well, under different condition, investigate sample stability.The results are shown in Table 4.
Table 4 supplementary product consumption result of study
Annotate: 0.9% NC, i.e. normal saline solution; 5%Glu, i.e. 5% glucose solution; 10%Glu, i.e. 10% glucose solution.
Three, test brief summary
Above-mentioned result of the test shows, the better stability of preparation of 17-AAG and PEG-400 preparation, and the 1.5mg/ml preparation dilutes 4 times with 10% glucose solution or normal saline solution respectively, room temperature normal illumination 6 hours, appearance character is stable.1.0mg/ml preparation is respectively with 5 times of 10% glucose solution or normal saline solution dilutions, under the room temperature normal illumination condition, solution keeps clarification in 20 hours.
[embodiment 7]
1.25mg/ml 17-AAG injection is carried out the investigation of solution compatibility test stability.With reference to 17-AAG combination drug clinically is that (injection: compatibility solution), the 17-AAG preparation dilutes 5 times with 5% glucose solution or normal saline solution respectively to 1:4, room temperature normal illumination 4 hours, the appearance character and the related substance of investigation solution.
One, test method and result
Get 1.25mg/ml17-AAG injection (press embodiment 3 method preparation) 5.5g, add normal saline respectively, 5% glucose solution is diluted to 25ml, promptly gets need testing solution.Sample solution is placed down in room temperature condition, respectively at investigating its appearance character, clarity in the 0th hour, 4 hours.
Content assaying method is: get 1.25mg/ml 17-AAG injection 5.5g, be transferred in the 100ml measuring bottle with normal saline, 5% glucose solution 25ml respectively, place down in room temperature condition, in 0,4hr adds methanol respectively and be diluted to scale.Get 20 μ l and inject chromatograph of liquid, HPLC measures related substance and content, the results are shown in Table 5.
Table 5 17-AAG injection solution compatibility test stability
| The investigation condition | Appearance character | Clarity | Related substance (%) | Content (%) |
| 0.9％NC(0h) | Red clear and bright liquid | Be shallower than turbidity standard No. 0.5 | 1.02 | 100.8 |
| 0.9％NC(4h) | Red clear and bright liquid | Be shallower than turbidity standard No. 0.5 | 1.02 | 101.0 |
| 5％Glu(0h) | Red clear and bright liquid | Be shallower than turbidity standard No. 0.5 | 1.11 | 101.4 |
| 5％Glu(4h) | Red clear and bright liquid | Be shallower than turbidity standard No. 0.5 | 1.23 | 102.1 |
Annotate: 0.9%NC, i.e. normal saline solution; 5%Glu, i.e. 5% glucose solution.
Two, test brief summary
By above result of the test as can be known, behind 17-AAG and the solution compatibility, appearance character, clarity, related substance and content all do not change in 4 hours, and is then behind 17-AAG and normal saline and the 5% glucose solution compatibility, stable in following 4 hours of room temperature condition.
Thereby, determine that tentatively 17-AAG injection prescription consists of PEG-400 8ml, 17-AAG 10mg; Before the injection with normal saline or 5% glucose injection with 5 times of preparation dilutions, the liquid after the dilution under room temperature normal illumination condition 4 hours stable.
Influence factor's test of 17-AAG injection
[embodiment 6]
According to the experimental technique of influence factor in the medicine stability guideline, carry out sample respectively and under illumination, acid, alkali, oxidation and heat affecting condition, investigate.Adopt the variation of related substance in the 17-AAG preparation related substance HPLC detection method sample for reference.
One, test method
1, controlled trial
Get 17-AAG injection (by the method preparation of embodiment 3) 5.5g and put in the 10ml measuring bottle, add methanol and be diluted to scale, shake up, get 20 μ l and inject chromatograph of liquid, measure its related substances.
2, acid, alkali, oxidation failure test
Get 17-AAG injection (pressing the method preparation of embodiment 3) 5.5g, put respectively in the 10ml measuring bottle, each adds 1mol/L hydrochloric acid solution, 1mol/L sodium hydroxide solution, each 1ml of 30% hydrogenperoxide steam generator, place after 6 hours, add methanol and be diluted to scale, shake up, destroy solution, alkali destruction solution, oxidation destruction solution as acid; Measure sour destruction, alkali destruction, each 20 μ l injection chromatograph of liquid of oxidation destruction solution, write down chromatogram.Other gets 1mol/L hydrochloric acid solution, 1mol/L sodium hydroxide solution, each 1ml of 30% hydrogenperoxide steam generator, puts in the 10ml measuring bottle, adds methanol and is diluted to scale, as sour blank solution, alkali blank solution, oxidation blank solution; Measure each 20 μ l of above-mentioned blank solution and inject chromatograph of liquid, measure its related substances.
3, illumination failure test
Get 17-AAG injection (by the method preparation of embodiment 3) 5.5g and put and be put in the 10ml measuring bottle under the lamp inspection canopy, the intensity of illumination of measuring setting-out product place is 4500LX, places 5 days.Add methanol and be diluted to scale, shake up, destroy solution as illumination.Measure and destroy solution 20 μ l injection chromatograph of liquid, measure its related substances.
4, temperature is investigated test
Get 17-AAG injection (pressing the method preparation of embodiment 3) 5.5g, put respectively in the 10ml measuring bottle.Place freezing refrigerator-freezer, cold storage refrigerator, indoor (25 ℃ of control temperature), 40 ℃ of calorstats, 60 ℃ of calorstats to investigate 5 days respectively.Add methanol and be diluted to scale, shake up, as temperature effect solution; Measure each 20 μ l of above-mentioned solution and inject chromatograph of liquid, measure its related substances.
Two. result of the test
The results are shown in Table 6.By the result as can be known, the injection sample is unstable under acid, alkali, oxidizing condition; Sample is to photaesthesia, and illumination destroys serious, notes the lucifuge operation in preservation and the use; Ambient temperature is influential to sample, so 17-AAG injection of the present invention should under freezing conditions be preserved.
Table 6 influence factor result of the test
The acute toxicity testing of 17-AAG
[embodiment 7]
After 17-AAG dissolved with PEG400, with the normal saline dilution, the proportionate solution of size preparation was according to dosage given mice, rat, Beagle dog (tieing up tonneau China experimental animal center by Beijing provides) intravenous injection or intravenous drip.Three all animal toxicities react and dead quantity after observing administration.With BLISS legally constituted authority meter half lethal dose and approximate lethal dose.The once intravenous LD of mice
50=102.51mg/kg, 95% credibility interval is 92.99～113.00mg/kg; The once intravenous LD of rat
50=127.99mg/kg, 95% credibility interval is 113.62～144.16mg/kg; The approximate lethal dose of an intravenous drip of dog is 30mg/kg.
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (9)
1, a kind of medicinal composition for injections that contains 17-allyl amino-17-demethoxylation geldanamycin is characterized in that,
Said composition comprises the 17-allyl amino-17-demethoxylation geldanamycin and the polyethylene glycols cosolvent PEG400 of the pharmaceutically acceptable form for the treatment of effective dose;
17-allyl amino-17-demethoxylation geldanamycin is 1～6mg:1ml with the ratio of PEG400.
2, the described medicinal composition for injections of claim 1 is characterized in that, 17-allyl amino-17-demethoxylation geldanamycin is 1～3mg:1ml with the ratio of PEG400.
3, the described medicinal composition for injections of claim 1 is characterized in that, described compositions further comprises a kind of solvent, and this solvent is normal saline or glucose solution, and the volume ratio of PEG400 and this solvent is 1:1.5～10.
4, the described medicinal composition for injections of claim 3 is characterized in that, the volume ratio of PEG400 and this solvent is 1:2～5.
5, the described medicinal composition for injections of one of claim 1～4 is characterized in that, the dosage form of said composition is an injection.
6, the described medicinal composition for injections of claim 5 is characterized in that, said composition comprises 17-allyl amino-17-demethoxylation geldanamycin of 4～600mg.
7, the described medicinal composition for injections of claim 6 is characterized in that, said composition comprises 17-allyl amino-17-demethoxylation geldanamycin of 15～240mg.
8, the described medicinal composition for injections of claim 5 is characterized in that, this injection is intravenous injection, thoracic cavity injection or lumbar injection agent.
9, the application of the medicinal composition for injections of one of claim 1～4 in the preparation cancer therapy drug.
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