CN101502486A - Antineoplastic 2-methoxyestradiol injection containing cyclodextrin or cyclodextrin derivates - Google Patents
Antineoplastic 2-methoxyestradiol injection containing cyclodextrin or cyclodextrin derivates Download PDFInfo
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- CN101502486A CN101502486A CNA2009100643382A CN200910064338A CN101502486A CN 101502486 A CN101502486 A CN 101502486A CN A2009100643382 A CNA2009100643382 A CN A2009100643382A CN 200910064338 A CN200910064338 A CN 200910064338A CN 101502486 A CN101502486 A CN 101502486A
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Abstract
The invention relates to 2-methoxyestradiol injection, an anti-tumor drug containing cyclodextrin or cyclodextrin derivatives, and solves the problem that 2-methoxyestradiol is hard to be dissolved in water. The technical scheme to be solved is as follows: the anti-tumor drug, that is, the 2-methoxyestradiol injection containing cyclodextrin or cyclodextrin derivatives, is prepared from 2-methoxyestradiol and cyclodextrin or cyclodextrin derivatives with the mole ratio being 1:(2-10); and the mass concentration of 2-methoxyestradiol in the final water solution of the 2-methoxyestradiol injection is 0.1mg/ml to 25mg/ml. The invention is prepared by mixing 2-methoxyestradiol and cyclodextrin or cyclodextrin derivatives having good water solubility and biocompatibility, thereby effectively solving the problem that 2-methoxyestradiol is hard to be dissolved in water, avoiding the allergic reaction, greatly reducing the hemolytic activity and ensuring good cell inhibitory activity and high stability. The invention is an innovation in the field of medicine.
Description
One, technical field
The present invention relates to medical domain, particularly a kind of antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative.
Two, technical background
2-methoxyestradiol (1,3,5-triolefin-2,3,17 β-trihydroxy-2-methyl ether sterol) be an estradiol physiology metabolite (.J Cancer Res ClinOncol.127:405～410 such as Schumacher G in vivo, (2001)), has tangible anti-tumor activity, its anticancer mechanism may be induced tumor and endothelial cell apoptosis (.Cancer.92:500～509 (2001) such as LinHL), also have antineoplastic vascular form .Invest New Drug.20:183～194 (2002) such as () Figg WD with and can suppress the hypertrophy of tumor cell relevant .Carcinog.31:111～124 (2001) such as () Kumar AP, it is to suppress cell proliferation in dose-dependent mode of time at research 2-methoxyestradiol to myeloma cell's the 2-methoxyestradiol of also finding on that the scholar is arranged, its inhibitory action when 10 μ mol/L the strongest (.Clin CancerRes.8:3948～3954 (2002) such as DingliD), this just requires the 2-methoxyestradiol being used for reaching an effective blood drug level when clinical on the one hand, requires simultaneously can keep an effective blood drug level for a long time in vivo.But the I phase clinical research result of 2-methoxyestradiol shows that the 2-methoxyestradiol is oral irregular, lack dependency (James J etc. between pharmacokinetic parameter and the dosage, Invest New Drugs, 25:41-48 (2006)), the reason that lacks dependency between oral pharmacokinetic parameter and the dosage is that 2-methoxyestradiol dissolubility in water is too little, the cause that medicine can not effectively absorb.The 2-methoxyestradiol is an insoluble drug in a kind of water, dissolubility is less than 0.25mg/L in the water, injection to such medicine, present one is to adopt injection suspension, this injection requires medicine to have higher pharmacologically active, less dosage is promptly arranged, and can only intramuscular and subcutaneous injection, but the conventional dosage of 2-methoxyestradiol need reach more than the 400mg; The 2nd, be that solvent or employing ethanol are that solvent adding polyoxyethylene hydrogenated Oleum Ricini is that solubilizing agent is formed with the organic solvent, the critical defect that with an organic solvent reaches the injection of surface active agent solubilization is to cause haemolysis and anaphylaxis easily, as the product that goes on the market
Can clearly being defined in needs to use the processing of desensitizing earlier of 17-hydroxy-11-dehydrocorticosterone, antihistaminic before the clinical use, develop a kind of injection of 2-methoxyestradiol so, have simultaneously to have better biocompatibility?
Three, summary of the invention
At above-mentioned situation, for overcoming the prior art defective, the present invention's purpose just provides a kind of antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative, can effectively solve the 2-methoxyestradiol and be difficult to water-soluble problem, the technical scheme of its solution is, the antineoplastic 2-methoxyestradiol injection of making by 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative that contains cyclodextrin or cyclodextrin derivative, the mole ratio 1:2 of 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative～10,2-methoxyestradiol mass concentration is 0.1mg/ml～25mg/ml in the final aqueous solution of 2-methoxyestradiol injection, and said cyclodextrin derivative is a hydroxypropyl, the ethoxy beta-schardinger dextrin-, the methyl beta-schardinger dextrin-, the glucosyl group beta-schardinger dextrin-, the malt-base beta-schardinger dextrin-, any in the sulfonic group beta-schardinger dextrin-.The cyclodextrin of the present invention's good water solubility, good biocompatibility or cyclodextrin derivative and 2-methoxyestradiol mix system, thereby efficiently solve the 2-methoxyestradiol and be difficult to water-soluble problem, do not have irritated reaction, hemolytic activity obviously reduces and have good cell and suppress active, stability is high, is an innovation in the medical domain.
Four, the specific embodiment
Below in conjunction with practical situation the specific embodiment of the present invention is elaborated.
Provide by technical scheme, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative that the present invention is made by 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative, the mole ratio 1:4 of 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative～7, said 2-methoxyestradiol injection is the water soluble parenteral solution of 2-methoxyestradiol, 2-methoxyestradiol freeze-dried powder, 2-methoxyestradiol aseptic powder injection, the glucose injection of 2-methoxyestradiol, the sodium chloride injection of 2-methoxyestradiol, the Dextrose and Sodium Chloride Inj. of 2-methoxyestradiol.
The water soluble parenteral solution of said 2-methoxyestradiol is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative, add the injection water then, reflux is stirred to the 2-methoxyestradiol and dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made;
As the mole ratio of making 2-methoxyestradiol and hydroxypropyl is the injection of 1:9.85, be to take by weighing 2-methoxyestradiol 140mg, add injection water 5ml suspendible, add hydroxypropyl 7g dissolving, add the injection water then to 10ml, reflux is stirred to the 2-methoxyestradiol and dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, through 0.22 μ m filtering with microporous membrane, packing, at 121 ℃, pressure sterilizing 12 minutes, get the water soluble parenteral solution of 2-methoxyestradiol, 2-methoxyestradiol dissolubility reaches 14g/L in the solution, and dissolubility improves 5.6 ten thousand times in the water, and the 2-methoxyestradiol in the water soluble parenteral solution of 2-methoxyestradiol and the mole ratio of hydroxypropyl are 1:9.85;
Carrying out light durability test according to 2005 editions regulations of Chinese Pharmacopoeia, is contrast with the ethanol solution with the 2-methoxyestradiol of concentration, the results are shown in Table 1;
Table 1 light stability trial drug content (%) changes
As seen from the above table, the water soluble parenteral solution stability of 2-methoxyestradiol significantly improves;
Being contrast with the poly-solution of the oxygen ethylene castor oil hydrogenated dehydrated alcohol of the 2-methoxyestradiol of concentration, carry out whole body initiative allergometry with Cavia porcellus, low dose group 0.7mg/kg, high dose group 2.8mg/kg, the water soluble parenteral solution test sample measurement result of 2-methoxyestradiol is all negative; Reference substance is positive reaction, measure its hemolytic with red cell suspension, the water soluble parenteral solution test sample of 2-methoxyestradiol there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours, and reference substance does not have the red blood cell condensation phenomenon, but erythrocyte hemolysis is obvious, so the water soluble parenteral solution toxicity of 2-methoxyestradiol obviously reduces, toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test for contrast with human lung carcinoma cell line A-549, the half-inhibition concentration IC of contrast liquid
50Be 14.9 μ g/ml, the water soluble parenteral solution test sample half-inhibition concentration IC of 2-methoxyestradiol
50Be 11.4 μ g/ml, the anti-tumor activity that draws the water soluble parenteral solution of 2-methoxyestradiol is better than reference substance.
Said 2-methoxyestradiol freeze-dried powder is to add injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux is stirred to the 2-methoxyestradiol and dissolves fully, the clear and bright aqueous solution of 2-methoxyestradiol, make through 0.22 μ m filtering with microporous membrane degerming, aseptic subpackaged, lyophilization;
As the mole ratio of making 2-methoxyestradiol and glucosyl group beta-schardinger dextrin-is the injection of 1:7, be to take by weighing 2-methoxyestradiol 200mg, with 5ml water for injection suspendible, add glucosyl group beta-schardinger dextrin-6g dissolving again, add the injection water again to 10ml, reflux is stirred to the 2-methoxyestradiol and dissolves fully, get the clear and bright aqueous solution of 2 methoxyestradiols, the concentration of 2-methoxyestradiol is 20g/L in the solution, improve 80,000 times than dissolubility in the water, the clear and bright aqueous solution of 2-methoxyestradiol is through 0.22 μ m filtering with microporous membrane degerming, aseptic subpackaged 1ml/ only, lyophilizing gets the freeze-dried powder of 2-methoxyestradiol.The 2-methoxyestradiol in the freeze-dried powder of 2-methoxyestradiol and the mole ratio of glucosyl group beta-schardinger dextrin-are 1:7, and it is that 0.9% (W/V) sodium chloride solution can dissolve fast that dried frozen aquatic products adds 1ml concentration;
According to 2005 editions regulations of Chinese Pharmacopoeia dried frozen aquatic products being carried out the light durability test, is contrast with 2-methoxyestradiol crude drug, the results are shown in Table 2:
Table 2 light stability trial drug content (%) changes and outward appearance
Drawn by last table, the light stability of the freeze-dried powder of 2-methoxyestradiol obviously improves;
With the polyoxyethylene hydrogenated Oleum Ricini ethanol solution with the 2-methoxyestradiol of concentration is contrast, the freeze-dried powder of 2-methoxyestradiol is 0.9% sodium chloride (W/V) dissolving with 1ml concentration, carry out whole body initiative allergometry with Cavia porcellus, low dose group 1mg/kg, high dose group 4mg/kg, the freeze-dried powder test sample measurement result of 2-methoxyestradiol is all negative, and the reference substance measurement result is positive reaction; Measure its hemolytic with red cell suspension, the freeze-dried powder test sample of 2-methoxyestradiol there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours, contrast liquid has tangible erythrocyte hemolysis phenomenon, draw thus, the toxicity of the freeze-dried powder of 2 methoxyestradiols obviously reduces than reference substance, and toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test for contrast with human lung carcinoma cell line A-549, contrast liquid product half-inhibition concentration IC
50Be 14.9 μ g/ml, the freeze-dried powder test sample half-inhibition concentration IC of 2-methoxyestradiol
50Be 10.2 μ g/ml, the anti-tumor activity that draws the freeze-dried powder of 2-methoxyestradiol is better than reference substance.
Said 2-methoxyestradiol aseptic powder injection is to add injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative, add the injection water again, reflux, being stirred to the 2-methoxyestradiol dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, through 0.22 μ m filtering with microporous membrane degerming, aseptic spray drying, aseptic subpackaged making;
As the mole ratio of making 2-methoxyestradiol and dimethyl-is the injection of 1:4.9, be to take by weighing 2-methoxyestradiol 500mg, with 25ml water for injection suspendible, add dimethyl-19g dissolving, add the injection water again to 50ml, reflux, being stirred to the 2-methoxyestradiol dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, the concentration of 2-methoxyestradiol is 10g/L in the solution, and clear and bright aqueous solution is through 0.22 μ m filtering with microporous membrane degerming, aseptic spray drying, get white powder, the aseptic subpackaged 2-methoxyestradiol aseptic powder injection that gets of white powder.Powder 500mg/ props up, containing 2-methoxyestradiol 25mg/ props up, the mole ratio of 2-methoxyestradiol and dimethyl-is 1:4.9 in the aseptic powder injection; get one of this product and add 0.9% sodium chloride (W/V) solution 2ml; can dissolve fast, the 2-methoxyestradiol reaches 12.5mg/ml in the solution;
According to 2005 editions regulations of Chinese Pharmacopoeia aseptic powder injection being carried out the light durability test, is contrast with 2-methoxyestradiol crude drug, the results are shown in Table 2, and the light stability that draws 2-methoxyestradiol aseptic powder injection obviously improves;
With the polyoxyethylene hydrogenated Oleum Ricini ethanol solution with concentration 2-methoxyestradiol is contrast, 2-methoxyestradiol aseptic powder injection is 0.9% sodium chloride dissolving with 2ml concentration, carry out whole body initiative allergometry with Cavia porcellus, low dose group 0.62mg/kg, high dose group 2.5mg/kg, 2-methoxyestradiol aseptic powder injection test sample measurement result is all negative, and reference substance is positive reaction; Measure its hemolytic with red cell suspension, 2-methoxyestradiol aseptic powder injection test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours, contrast liquid has tangible erythrocyte hemolysis phenomenon, the toxicity that draws 2-methoxyestradiol aseptic powder injection obviously reduces than reference substance, and toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test for contrast with human lung carcinoma cell line A-549, contrast liquid product half-inhibition concentration IC
50Be 14.9 μ g/ml, 2-methoxyestradiol aseptic powder injection test sample half-inhibition concentration IC
50Be 9.7 μ g/ml, the anti-tumor activity that draws 2-methoxyestradiol aseptic powder injection is better than reference substance.
The glucose injection of said 2-methoxyestradiol is to add injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water, reflux is stirred to the 2-methoxyestradiol and dissolves fully, adds the injection water again and gets 2-methoxyestradiol solution, add the glucose stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made;
As the mole ratio of making 2-methoxyestradiol and malt-base beta-schardinger dextrin-is the injection of 1:2, be to take by weighing 2-methoxyestradiol 500mg, with 12.5ml water for injection suspendible, add malt-base beta-schardinger dextrin-5.4g dissolving again, the mole ratio of 2-methoxyestradiol and malt-base beta-schardinger dextrin-is 1:2, add the injection water to 25ml, reflux, being stirred to the 2-methoxyestradiol dissolves fully, the concentration of 2-methoxyestradiol is 20g/L in the solution, adds the injection water again to 250ml, obtains the 2-methoxyestradiol solution of 2mg/ml, add 12.5g glucose stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing is at 115 ℃, pressure sterilizing 30 minutes, the glucose injection of 2-methoxyestradiol;
Carrying out light durability test according to 2005 editions regulations of Chinese Pharmacopoeia, is contrast with the ethanol solution of 2-methoxyestradiol, the results are shown in Table 1, and the light stability that draws the glucose injection of 2-methoxyestradiol obviously improves;
Get the polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol, with being contrast after the 5% glucose injection dilution, carry out whole body initiative allergometry with Cavia porcellus, low dose group 0.5mg/kg, high dose group 2mg/kg, the glucose injection test sample measurement result of 2-methoxyestradiol is all negative, and reference substance is positive reaction; Measure its hemolytic with red cell suspension, the glucose injection test sample of 2-methoxyestradiol there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours, and reference substance does not have the red blood cell condensation phenomenon, but erythrocyte hemolysis is obvious, the toxicity that draws the glucose injection of 2-methoxyestradiol significantly is lower than reference substance, and toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test for contrast with human lung carcinoma cell line A-549, the half-inhibition concentration IC of contrast liquid
50Be 14.9 μ g/ml, the glucose injection half-inhibition concentration IC of 2-methoxyestradiol
50Be 8.5 μ g/ml, the anti-tumor activity that draws the glucose injection of 2-methoxyestradiol is better than reference substance.
The sodium chloride injection of said 2-methoxyestradiol is to add injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux is stirred to the 2-methoxyestradiol and dissolves fully, add the injection water again, get 2-methoxyestradiol solution, add the sodium chloride stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing get the sodium chloride injection of 2-methoxyestradiol;
In the mole ratio of making 2-methoxyestradiol and hydroxypropyl is the injection of 1:5, be to take by weighing 2-methoxyestradiol 500mg, with 12.5ml water for injection suspendible, add hydroxypropyl 12.7g dissolving again, the mole ratio of 2-methoxyestradiol and hydroxypropyl is 1:5, add the injection water again to 25ml, reflux, being stirred to the 2-methoxyestradiol dissolves fully, the concentration of 2-methoxyestradiol is 20g/L in the solution, add the injection water again to the 2-methoxyestradiol solution that 250ml obtains 2mg/ml, add 2.25g sodium chloride stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, at 121 ℃, pressure sterilizing 12 minutes, the sodium chloride injection of 2-methoxyestradiol;
Carrying out light durability test according to 2005 editions regulations of Chinese Pharmacopoeia, is contrast with the ethanol solution of 2-methoxyestradiol, the results are shown in Table 1, and the light stability that draws the sodium chloride injection of 2-methoxyestradiol obviously improves;
Get the polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol, be contrast with 0.9% sodium chloride (W/V) injection dilution back, carry out whole body initiative allergometry with Cavia porcellus, low dose group 0.5mg/kg, high dose group 2mg/kg, the sodium chloride injection test sample measurement result of 2-methoxyestradiol is all negative; Reference substance is positive reaction; Measure its hemolytic with red cell suspension, the sodium chloride injection test sample of 2-methoxyestradiol there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours, and reference substance does not have the red blood cell condensation phenomenon, but erythrocyte hemolysis is obvious, the sodium chloride injection toxicity that draws the 2-methoxyestradiol obviously reduces, and toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test for contrast with human lung carcinoma cell line A-549, the half-inhibition concentration IC of contrast liquid
50Be 14.9 μ g/ml, the sodium chloride injection test sample half-inhibition concentration IC of 2-methoxyestradiol
50Be 11.9 μ g/ml, the anti-tumor activity that draws the sodium chloride injection of 2-methoxyestradiol is better than reference substance.
The Dextrose and Sodium Chloride Inj. of said 2-methoxyestradiol is to add injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux is stirred to the 2-methoxyestradiol and dissolves fully, add the injection water again, get 2-methoxyestradiol solution, add sodium chloride, glucose stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made;
As the mole ratio of making 2-methoxyestradiol and gamma-cyclodextrin is the injection of 1:6, be to get 2-methoxyestradiol 500mg, with 12.5ml water for injection suspendible, add gamma-cyclodextrin 12.8g dissolving again, the mole ratio of 2-methoxyestradiol and gamma-cyclodextrin is 1:6, add the injection water again to 25ml, reflux, being stirred to the 2-methoxyestradiol dissolves fully, the concentration of 2-methoxyestradiol is 20g/L in the solution, adds the injection water again to 250ml, obtains the 2-methoxyestradiol solution of 2mg/ml, add 2.25g sodium chloride again, 12.5g glucose stirring and dissolving, through 0.22 μ m filtering with microporous membrane, packing is at 115 ℃, pressure sterilizing 30 minutes, the Dextrose and Sodium Chloride Inj. of 2-methoxyestradiol;
Carrying out light durability test according to 2005 editions regulations of Chinese Pharmacopoeia, is contrast with the ethanol solution of 2 methoxyestradiols, the results are shown in Table 1, and the light stability that draws the Dextrose and Sodium Chloride Inj. of 2-methoxyestradiol obviously improves;
Get the polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol, with being contrast after the Dextrose and Sodium Chloride Inj. dilution, carry out whole body initiative allergometry with Cavia porcellus, low dose group 0.5mg/kg, high dose group 2mg/kg, the Dextrose and Sodium Chloride Inj. test sample measurement result of 2-methoxyestradiol is all negative, and reference substance is positive reaction; Measure its hemolytic with red cell suspension, the Dextrose and Sodium Chloride Inj. test sample of 2-methoxyestradiol there is no the red blood cell condensation phenomenon in 3 hours, but slight erythrocyte hemolysis is arranged, and reference substance does not have the red blood cell condensation phenomenon, but erythrocyte hemolysis is obvious, the Dextrose and Sodium Chloride Inj. toxicity that draws the 2-methoxyestradiol is lower than reference substance, and toxicity is little;
The polyoxyethylene hydrogenated Oleum Ricini ethanol solution of 2-methoxyestradiol carries out anti-tumor activity test with human lung carcinoma cell line A-549, the half-inhibition concentration IC of reference substance for contrast
50Be 14.9 μ g/ml, the Dextrose and Sodium Chloride Inj. test sample half-inhibition concentration IC of 2-methoxyestradiol
50Be 11.1 μ g/ml, the anti-tumor activity that draws is better than reference substance.
By the above as can be known, major advantage of the present invention is that 2ME2 and cyclodextrin or cyclodextrin spread out Biological mole ratio is 1:2～10, and preferred 1:4～7 can make 2ME2 molten in water Xie Du reaches 10～25g/L, improves 40,000～100,000 times than solubility in the 2ME2 raw material liquid medicine, The 2ME2 parenteral solution can satisfy the dependent pharmacological action mould of time-dose of 2ME2 Type; The present invention has preferably biocompatibility, with organic solvent and the surface-active of 2ME2 The parenteral solution of agent solubilising is compared, and no allergic reaction generation, hemolytic activity obviously reduce; The extracorporeal anti-tumor cell The activity test result shows that injection of the present invention also has good cell inhibitory activity; Good stability of the present invention, This is also significant to the security that improves the 2ME2 injection, and economic and social benefit is huge.
Claims (10)
1, a kind of antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative, it is characterized in that, contain cyclodextrin or cyclodextrin derivative in the 2-methoxyestradiol injection, the mole ratio of 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative is 1:2～10.
2, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 1, it is characterized in that, contain cyclodextrin or cyclodextrin derivative in the said 2-methoxyestradiol injection, the mole ratio of 2-methoxyestradiol and cyclodextrin or cyclodextrin derivative is 1:4～7.
3, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 1 and 2, it is characterized in that said cyclodextrin derivative is any in hydroxypropyl, ethoxy beta-schardinger dextrin-, methyl beta-schardinger dextrin-, glucosyl group beta-schardinger dextrin-, malt-base beta-schardinger dextrin-, the sulfonic group beta-schardinger dextrin-.
4, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 1 and 2, it is characterized in that the glucose injection of the water soluble parenteral solution that said 2-methoxyestradiol injection is the 2-methoxyestradiol, 2-methoxyestradiol freeze-dried powder, 2-methoxyestradiol aseptic powder injection, 2-methoxyestradiol, the sodium chloride injection of 2-methoxyestradiol, the Dextrose and Sodium Chloride Inj. of 2-methoxyestradiol.
5, the antineoplastic agent 2 methoxyestradiol injections that contain cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, the water soluble parenteral solution of said 2-methoxyestradiol is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative, add the injection water then, reflux is stirred to the 2-methoxyestradiol and dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made.
6, the antineoplastic agent 2 methoxyestradiol injections that contain cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, said 2-methoxyestradiol freeze-dried powder is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux is stirred to the 2-methoxyestradiol and dissolves fully, the clear and bright aqueous solution of 2-methoxyestradiol, make through 0.22 μ m filtering with microporous membrane degerming, aseptic subpackaged, lyophilization.
7, the antineoplastic agent 2 methoxyestradiol injections that contain cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, said 2-methoxyestradiol aseptic powder injection is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative, add the injection water again, reflux, being stirred to the 2-methoxyestradiol dissolves fully, get the clear and bright aqueous solution of 2-methoxyestradiol, through 0.22 μ m filtering with microporous membrane degerming, aseptic spray drying, aseptic subpackaged making.
8, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, the glucose injection of said 2-methoxyestradiol is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water, reflux, being stirred to the 2-methoxyestradiol dissolves fully, add the injection water again and get 2-methoxyestradiol solution, add the glucose stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made.
9, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, the sodium chloride injection of said 2-methoxyestradiol is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux, being stirred to the 2-methoxyestradiol dissolves fully, add the injection water again, get 2-methoxyestradiol solution, add the sodium chloride stirring and dissolving again, through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing get the sodium chloride injection of 2-methoxyestradiol.
10, the antineoplastic 2-methoxyestradiol injection that contains cyclodextrin or cyclodextrin derivative according to claim 4, it is characterized in that, the Dextrose and Sodium Chloride Inj. of said 2-methoxyestradiol is by adding injection water suspendible in the 2-methoxyestradiol, add the dissolving of cyclodextrin or cyclodextrin derivative again, add the injection water again, reflux, being stirred to the 2-methoxyestradiol dissolves fully, add the injection water again, get 2 methoxyestradiol solution, add sodium chloride again, the glucose stirring and dissolving is through 0.22 μ m filtering with microporous membrane, packing, pressure sterilizing is made.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI419695B (en) * | 2011-11-29 | 2013-12-21 | Chi Mei Foundation Hospital | Use 2-methoxy estradiol to treat sepsis |
| CN110420336A (en) * | 2019-08-13 | 2019-11-08 | 郑州大学 | A kind of linarin inclusion compound and its preparation method and application |
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2009
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI419695B (en) * | 2011-11-29 | 2013-12-21 | Chi Mei Foundation Hospital | Use 2-methoxy estradiol to treat sepsis |
| CN110420336A (en) * | 2019-08-13 | 2019-11-08 | 郑州大学 | A kind of linarin inclusion compound and its preparation method and application |
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| Publication number | Publication date |
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| CN101502486B (en) | 2010-12-29 |
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