CN101091698A - New type antineoplastic medicine, and preparation method - Google Patents
New type antineoplastic medicine, and preparation method Download PDFInfo
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- CN101091698A CN101091698A CNA2006100868984A CN200610086898A CN101091698A CN 101091698 A CN101091698 A CN 101091698A CN A2006100868984 A CNA2006100868984 A CN A2006100868984A CN 200610086898 A CN200610086898 A CN 200610086898A CN 101091698 A CN101091698 A CN 101091698A
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Abstract
The present invention relates to an antineoplastic medicine and its preparation method. The invented antineoplastic medicine is a liposome containing mixture formed from lentinan, mitoxantrone and mitoxantrone hydrochloride according to any mixing ratio. Said invention also provides the concrete steps of its preparation method.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, particularly relate to a kind of antitumor drug and preparation method thereof.
Background technology
Tumor, especially malignant tumor are one of pertinacious diseases of facing of the current whole world, all have every year thousands of people to die from cancer.Lentinan and mitoxantrone are the antitumor drug of current clinical practice, all have untoward reaction in various degree, such as vomiting, diarrhoea etc.Simultaneously, the problems such as allergy shock that the macromole vegetable protein that contains in the lentinan causes, serious threat is to patient's life security.Mitoxantrone is toxic to liver and kidney.
Summary of the invention
In order to solve toxic side effect that existing lentinan and mitoxantrone exist even the defective that threatens patient's life security in as the medicinal application process, improve the curative effect of medicine simultaneously, the invention provides a kind of new type antineoplastic medicine.The present invention also provides described preparing anti-tumor medicine method.
Technical scheme of the present invention is as follows:
The invention provides a kind of new type antineoplastic medicine, is the liposome that is enclosed with the arbitrary proportion mixture of lentinan and mitoxantrone, mitoxantrone hydrochloride, is formed by following feedstock production:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 1-3: 1) 0.03-0.6mol;
Antioxidant 10-20 gram;
Gamma-cyclodextrin 0.01-0.06mol;
18-amine. 0.01-0.07mol;
The mixture 0.003-0.006mol of methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and any ratio of polyethylene glycol 6000;
Tween80 2-5 gram;
Lentinan restrains than mixture 1-22 arbitrarily with mitoxantrone;
Glycine 10-20 gram;
Lentinan wherein calculates molal quantity with molecular weight 20000 dalton.
Described mitoxantrone also can be a mitoxantrone hydrochloride.
Described antioxidant is meant tiopronin.
The present invention also provides described preparing anti-tumor medicine method as follows:
The preparation blank liposome, adjust particle diameter below 200nm, again antioxidant, anti-allergic agent tiopronin are distributed in the liposome solutions, with 18-amine. it is wrapped up in the liposome, the mixture that adds methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrary proportion again, add surfactant Tween80 and excipient glycine at last, purpose is that liposome medicament can better disperse when water-soluble.
The concrete steps of described preparing anti-tumor medicine method are as follows:
(1) with being dissolved at 1: 1 in the mixed solvent of an amount of chloroform and 6: 1 volume ratios of ethyl acetate with mol ratio than mixture arbitrarily of the mixture of soybean lecithin and any ratio of synthesizing PE (Phosphatidyl Ethanolamine) and cupreol, dish sterol, stigmasterol, makes the saturated solution of phospholipid.
(2) solution that step (1) is made steams under the 30-70 ℃ of temperature and removes organic mixed solvent in Rotary Evaporators, at room temperature vacuum drying 4-12 hour, makes exsiccant uniform immobilized artificial membrane.
(3) phosphate buffer of the pH value 5.0-9.0 of adding 0.01M concentration is an amount of in above-mentioned steps (2) gained immobilized artificial membrane, making phospholipid concentration is 0.01-0.015M, smashed to pieces 1-5 minute with tissue mashing machine, and, make blank liposome in ultrasonic Treatment 10-20 minute.
(4) the solution 0.2um membrane filtration that step (3) is made gets the blank liposome of particle diameter less than 200nm.
(5) the arbitrary proportion mixture with lentinan and mitoxantrone is dissolved in the saturated phosphate buffer of gamma-cyclodextrin, wherein lentinan is to be lentinan below 20000 through the isolated molecular weight of the ultrafilter membrane of molecular cut off 20000, mitoxantrone becomes saturated solution with organic solvent dissolution, mix, mitoxantrone is comprised by gamma-cyclodextrin and dissolves, and adjusting the solution pH value is 7.0-7.6.
(6) step (5) being made solution sneaks in the solution that step (4) makes, stir down, add an amount of phosphate buffer, reach cumulative volume 1000ml, ultrasonic Treatment 10-20 minute, and under agitation add the alcoholic solution of tiopronin and 18-amine., stir add down methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrarily than mixture, after the dissolving fully, stir adding Tween80 and glycine down, the complete back of dissolving solution is once more through 0.2nm membrane filtration mistake.
(7) solution that step (6) is made is by the dosage packing that allows on the pharmaceutics, in freezer dryer, make lyophilized powder by common freeze-drying, or pulverize after the solution lyophilization that step (6) is made, cross the 60-150 mesh sieve, carry out packing by acceptable dose on the pharmaceutics.
Can also add xylitol in the medicinal liquid that makes, get 5% isosmotic solution, and add hydroxypropyl methylcellulose, making its concentration is 0.05-0.1%, again through 0.2nm membrane filtration mistake, and sterilization, cooling, packing.Adding hydroxypropyl methylcellulose is to make in the colloid solution, and liposome can not condense.
The effect that the present invention realizes is as follows:
By the test of pesticide effectiveness as can be known, drug effect and the molecular weight of lentinan molecular weight in 10,000 to 20,000 scopes is better in 400,000-800,000 lentinan curative effect.Therefore, with molecular cut off is that 20,000 ultrafiltration post is to the lentinan ultrafiltration, isolate the lentinan of molecular weight below 20,000 and be applied to clinically,, thereby eliminated because the allergy shock phenomenon that the vegetable protein molecule causes owing to the vegetable protein molecular weight in the lentinan is eliminated much larger than 20,000.
Lentinan or the mitoxantrone of molecular weight below 20,000 made the liposome medicament with active targeting and passive target, improve therapeutic efficiency, reduce side effect, can also reduce dosage, increase drug safety.
Molecular weight below 20,000 lentinan or mitoxantrone both share, make the compound recipe liposome, both reduce by dosage, and curative effect improves, untoward reaction does not increase the weight of because of both share or produces new untoward reaction.On the contrary, untoward reaction alleviates greatly, and curative effect is higher simultaneously.
The present invention makes liposome medicament to lentinan and mitoxantrone than mixture arbitrarily, can reduce dosage, improves curative effect, reduces toxic and side effects.
The present invention below 20,000, has fundamentally eliminated the allergy effect of the vegetable protein that is mingled with in the lentinan macromole to the lentinan molecular weight control.
The present invention adopts soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) with mol ratio 1-3: 1 mixture makes to make phospholipid bilayer closely as phospholipid material.
The present invention adopts cupreol, dish sterol, 4: 2: 1 mixture of stigmasterol mol ratio mixes with the moles such as mixture of soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine), form liposome bilayer closely, medicine is difficult for leaking, and is more effective than cholesterol " shutoff ".
The present invention comprises the mitoxantrone that is insoluble in water and water-soluble with gamma-cyclodextrin, thereby makes mitoxantrone the same with lentinan, enters the liposome center, rather than in bilayer.
Medicine provided by the present invention tiopronin as antiradiation drug allergic agent in antioxidant and the body.
The present invention makes the liposome of particle diameter less than 200um, is easy to see through tumor cell membrane and enters tumor cell.
Medicine of the present invention is except with the tight alignment films material " shutoff ", and also useful 18-amine., methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 are modified surface of liposome with the mixture of polyethylene glycol 6000 arbitrary proportion.Outstanding advantage is: medicine is difficult for leaking, and makes long circulating liposomes, eliminates the tumor cell that shifts in the blood, the 18-amine. positive charge, surface of liposome is positively charged, is elecrtonegativity with tumor cell and forms initiatively targeting, avoids liposome to assemble simultaneously.
Be added with the tween80 surfactant in the medicine provided by the present invention, when lipid freeze-dry powder dissolves in water, because the synergism of Macrogol 2000 and polyethylene glycol 6000 and Tween80 makes liposome spread out very soon in water, forms even liposome dispersion.
The lyophilized injection of medicine provided by the present invention is as excipient with glycine.
The specific embodiment
Embodiment 1:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 1: 1) 0.03mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.03mol
Tiopronin 10 grams
18-amine. 0.01mol
Methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 (mol ratio 1: 2) 0.003mol
Tween80 2 grams
Lentinan 1 gram
Glycine 10 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Because present embodiment does not add mitoxantrone, so, do not add gamma-cyclodextrin.
Preparation process:
(1) with the mixture of soybean lecithin and any ratio of synthesizing PE (Phosphatidyl Ethanolamine) and cupreol, dish sterol, being dissolved at 1: 1 in the mixed solvent of an amount of chloroform and 6: 1 volume ratios of ethyl acetate with mol ratio than mixture arbitrarily of stigmasterol made the saturated solution of immobilized artificial membrane material.
(2) solution that step (1) is made removes organic mixed solvent to steam under the 30-40 ℃ of temperature in the rotary evaporation view, at room temperature vacuum drying 4-5 hour, makes exsiccant uniform immobilized artificial membrane.
(3) phosphate buffer of the pH value 5.0 of adding 0.01M concentration is an amount of in above-mentioned (2) step gained immobilized artificial membrane, and making phospholipid concentration is 0.01-0.015M, smashs to pieces 1-5 minute with tissue mashing machine, and in ultrasonic Treatment 10-20 minute, makes blank liposome.
(4) the solution 0.2um membrane filtration that step (3) is made gets the blank liposome of particle diameter less than 200nm, and regulating pH value is 7.0.
(5) lentinan is dissolved in the phosphate buffer, wherein lentinan is to be lentinan below 20000 through the isolated molecular weight of the ultrafilter membrane of molecular cut off 20000.
(6) step (5) is made solution and sneak in the solution that step (4) makes, stir down, add an amount of phosphate buffer, reach cumulative volume 1000ml, ultrasonic Treatment 10-20 minute, and under agitation add the alcoholic solution of tiopronin and 18-amine..After the dissolving fully, stir add down methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine or methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrarily than mixture, after the dissolving fully, stirring adds tween80 and glycine down, and solution is once more through 0.2um membrane filtration mistake after the dissolving fully.
(7) solution that step (6) is made makes lyophilized powder by the dosage packing that allows on the pharmaceutics by common freeze-drying.
With rat liver cancer model, the treatment group is the medicine of the present invention of 4mg/kg dosage, and matched group is the common lentinan freeze dried powder of 8mg/kg dosage.All press fixedly medicinal liquid volume of 1.0ml/20g body weight, carry out the tail vein injection administration.Per 3 days single administrations, the administration fortnight.Experimental result is as follows:
As seen, drug administration dosage of the present invention only is half of existing medicine, and curative effect exceeds 27%, and irritated rate and side effect incidence rate all reduce greatly.
Embodiment 2:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 2: 1) 0.05mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.05mol
Tiopronin 15 grams
18-amine. 0.03mol
Methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine 0.04mol
Tween80 3 grams
Lentinan 2 grams
Glycine 15 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Because present embodiment does not add mitoxantrone, so, do not add gamma-cyclodextrin.
Preparation process:
Step (1)-(7) are referring to embodiment 1.
Step (8): the medicinal liquid that step (6) is made adds xylitol and water for injection, and being made into 5% xylitol isosmotic solution and lentinan concentration is the solution of 1mg, 2ml.And the adding hydroxypropyl methylcellulose, its concentration is 0.2%, again through 0.2um membrane filtration mistake, packing.
With rat liver cancer model, the treatment group is the medicine of the present invention of 8mg/kg dosage, and matched group is the common lentinan freeze dried powder of 16mg/kg dosage.All press fixedly medicinal liquid volume of 1.0ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Experimental result is as follows:
As seen, drug administration dosage of the present invention only is half of existing medicine, and curative effect exceeds 26%, and irritated rate and side effect incidence rate all reduce greatly.
Embodiment 3:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 3: 1) 0.2mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.2mol
Tiopronin 20 grams
18-amine. 0.07mol
γ cyclodextrin 0.066mol
Methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 (mol ratio 1: 4) 0.006mol
Tween80 3 grams
Mitoxantrone restrains than mixture 10 arbitrarily with mitoxantrone hydrochloride
Glycine 20 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
(1) with the mixture of soybean lecithin and any ratio of synthesizing PE (Phosphatidyl Ethanolamine) and cupreol, dish sterol, being dissolved at 1: 1 in the mixed solvent of an amount of chloroform and 6: 1 volume ratios of ethyl acetate with mol ratio than mixture arbitrarily of stigmasterol made the saturated solution of immobilized artificial membrane material.
(2) solution that step (1) is made removes organic mixed solvent to steam under the 50-60 ℃ of temperature in the rotary evaporation view, at room temperature vacuum drying 4-5 hour, makes exsiccant uniform immobilized artificial membrane.
(3) phosphate buffer of the pH value 5.0 of adding 0.01M concentration is an amount of in above-mentioned (2) step gained immobilized artificial membrane, and making phospholipid concentration is 0.01-0.015M, smashs to pieces 1-5 minute with tissue mashing machine, and in ultrasonic Treatment 10-20 minute, makes blank liposome.
(4) the solution 0.2um membrane filtration that step (3) is made gets the blank liposome of particle diameter less than 200nm, and regulating pH value is 7.0.
(5), in the phosphate buffer of 0.01M concentration, add gamma-cyclodextrin at pH value 3.5-5.0, the preparation saturated solution, mitoxantrone is insoluble in water, becomes saturated solution with anhydrous alcohol solution, the alcoholic solution that under agitation drips mitoxantrone is regulated pH value 3.5-5.5 to gamma-cyclodextrin solution.
(6) step (5) is made solution and sneak in the solution that step (4) makes, stir down, add an amount of phosphate buffer, reach cumulative volume 1000ml, ultrasonic Treatment 10-20 minute, and under agitation add the alcoholic solution of tiopronin and 18-amine..After the dissolving fully, stir add down methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine or methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrarily than mixture, after the dissolving fully, stirring adds tween80 and glycine down, and solution is once more through 0.2um membrane filtration mistake after the dissolving fully.
(7) solution that step (6) is made makes lyophilized powder by the dosage packing that allows on the pharmaceutics by common freeze-drying.
The solution that step (6) is made is made injection by the dosage packing that allows on the pharmaceutics.
With rat liver cancer model, the treatment group is the medicine of the present invention of 1.25mg/kg dosage, and matched group is the common lentinan freeze dried powder of 2.5mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
As seen, drug administration dosage of the present invention only is half of existing medicine, and curative effect exceeds 18%, and irritated rate and side effect incidence rate all reduce greatly.
Embodiment 4:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 3: 1) 0.6mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.6mol
Tiopronin 18 grams
18-amine. 0.06mol
γ cyclodextrin 0.060mol
Methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine 0.005mol
Tween80 4 grams
Mitoxantrone restrains than mixture 20 arbitrarily with mitoxantrone hydrochloride
Glycine 18 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
Referring to embodiment 3.
With rat liver cancer model, the treatment group is the medicine of the present invention of 1.5mg/kg dosage, and matched group is the common mitoxantrone hydrochloride freeze dried powder of 4mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
Embodiment 5:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 1: 1) 0.2mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.2mol
Tiopronin 16 grams
18-amine. 0.055mol
γ cyclodextrin 0.033mol
Methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 (mol ratio 1.6: 4.5) 0.04mol
Tween80 3.3 grams
Lentinan 1 gram
Mitoxantrone restrains than mixture 10 arbitrarily with mitoxantrone hydrochloride
Glycine 17 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
(1) with the mixture of soybean lecithin and any ratio of synthesizing PE (Phosphatidyl Ethanolamine) and cupreol, dish sterol, being dissolved at 1: 1 in the mixed solvent of an amount of chloroform and 6: 1 volume ratios of ethyl acetate with mol ratio than mixture arbitrarily of stigmasterol made the saturated solution of immobilized artificial membrane material.
(2) solution that step (1) is made removes organic mixed solvent to steam under the 40-50 ℃ of temperature in the rotary evaporation view, at room temperature vacuum drying 4-5 hour, makes exsiccant uniform immobilized artificial membrane.
(3) phosphate buffer of the pH value 3.5 of adding 0.01M concentration is an amount of in above-mentioned (2) step gained immobilized artificial membrane, and making phospholipid concentration is 0.01-0.015M, smashs to pieces 1-5 minute with tissue mashing machine, and in ultrasonic Treatment 10-20 minute, makes blank liposome.
(4) the solution 0.2um membrane filtration that step (3) is made gets the blank liposome of particle diameter less than 200nm, and regulating pH value is 7.0.
(5) in the phosphate buffer of pH value 3.5-5.0, add gamma-cyclodextrin, the preparation saturated solution, under agitation drip mitoxantrone and mitoxantrone hydrochloride arbitrarily than the alcoholic solution of mixture to gamma-cyclodextrin solution, regulate pH value 3.5-5.5.
(6) step (5) is made solution and sneak in the solution that step (4) makes, stir down, add an amount of phosphate buffer, reach cumulative volume 1000ml, ultrasonic Treatment 10-20 minute, and under agitation add the alcoholic solution of tiopronin and 18-amine..After the dissolving fully, stir add down poly-7 glycol 2000 of methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine or methoxyl group and polyethylene glycol 6000 arbitrarily than mixture, after the dissolving fully, stirring adds tween80 and glycine down, and solution is once more through 0.2um membrane filtration mistake after the dissolving fully.
(7) solution that step (6) is made makes lyophilized powder by the dosage packing that allows on the pharmaceutics by common freeze-drying.
(8) solution that step (6) is made is made injection by the dosage packing that allows on the pharmaceutics.
With mouse lymphocyte leukemia L1210 model, the treatment group is the medicine of the present invention (in lentinan) of 0.1mg/kg dosage, and matched group is the common mitoxantrone freeze dried powder and 1mg/kg lentinan lyophilized powder mixing administration of 10mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
Embodiment 6:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 3: 1) 0.15mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.16mol
Tiopronin 11 grams
18-amine. 0.05mol
γ cyclodextrin 0.3mol
Methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine 0.003mol
Tween80 3 grams
Lentinan 1.5 grams
Mitoxantrone restrains than mixture 4.5 arbitrarily with mitoxantrone hydrochloride
Glycine 12 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
With reference to embodiment 5.
With mouse lymphocyte leukemia L1210 model, the treatment group is the medicine of the present invention (in lentinan) of 3mg/kg dosage, and matched group is the common mitoxantrone freeze dried powder and 4.5mg/kg lentinan lyophilized powder mixing administration of 15mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
Embodiment 7:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 2: 1) 0.6mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.6mol
Tiopronin 13 grams
18-amine. 0.07mol
γ cyclodextrin 0.059mol
Methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine 0.006mol
Tween80 5 grams
Lentinan 17 grams
Restraining than mixture 5 arbitrarily of mitoxantrone hydrochloride
Glycine 20 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
With reference to embodiment 5.
With mouse lymphocyte leukemia L1210 model, the treatment group is the medicine of the present invention (in lentinan) of 3mg/kg dosage, and matched group is the common mitoxantrone hydrochloride freeze dried powder and 68mg/kg lentinan lyophilized powder mixing administration of 10mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
Embodiment 8:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture (mol ratio 1: 1) 0.06mol
Cupreol, dish sterol, stigmasterol mixture (mol ratio 4: 2: 1) 0.06mol
Tiopronin 11 grams
18-amine. 0.01mol
γ cyclodextrin 0.01mol
Methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine (mol ratio 1: 1) 0.003mol
Tween80 2 grams
Lentinan 0.8 gram
Mitoxantrone 0.2 gram
Glycine 10 grams
Phosphate buffer 0.01M, pH value 3.5-7.6 to 1000ml.
Preparation process:
With reference to embodiment 5.
With mouse lymphocyte leukemia L1210 model, the treatment group is the medicine of the present invention (in lentinan) of 0.8mg/kg dosage, and matched group is the common mitoxantrone freeze dried powder and 0.8mg/kg lentinan lyophilized powder mixing administration of 0.2mg/kg dosage.All press fixedly medicinal liquid volume of 0.5ml/20g body weight, carry out tail passages through which vital energy circulates drug administration by injection.Per 3 days single administrations, the administration fortnight.Every group each 60.Experimental result is as follows:
Claims (8)
1. a new type antineoplastic medicine is characterized in that, described antitumor drug is the liposome that is enclosed with the arbitrary proportion mixture of lentinan and mitoxantrone, mitoxantrone hydrochloride.
2. according to the described antitumor drug of claim 1, it is characterized in that described antitumor drug is formed by following feedstock production:
Soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) mixture 0.03-0.6mol;
Antioxidant 10-20 gram;
Gamma-cyclodextrin 0.01-0.06mol;
18-amine. 0.01-0.07mol;
The mixture 0.003-0.006mol of methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and any ratio of polyethylene glycol 6000;
Tween80 2-5 gram;
Lentinan restrains than mixture 1-22 arbitrarily with mitoxantrone;
Glycine 10-20 gram;
Lentinan wherein calculates molal quantity with molecular weight 20000 dalton.
3. according to the described antitumor drug of claim 2, it is characterized in that the mol ratio of soybean lecithin and synthesizing PE (Phosphatidyl Ethanolamine) is 1-3 in described soybean lecithin and the synthesizing PE (Phosphatidyl Ethanolamine) mixture: 1.
4. antitumor drug according to claim 2 is characterized in that, described mitoxantrone also can be a mitoxantrone hydrochloride.
5. antitumor drug according to claim 2 is characterized in that described antioxidant is meant tiopronin.
6. any described preparing anti-tumor medicine method of claim 1-5 is as follows:
The preparation blank liposome, adjust particle diameter below 200nm, again antioxidant, anti-allergic agent tiopronin are distributed in the liposome solutions, with 18-amine. it is wrapped up in the liposome, add the mixture of methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrary proportion again, add surfactant Tween80 at last.
7. according to the described preparing anti-tumor medicine method of claim 6, it is characterized in that concrete steps are as follows:
(1) with the mixture of soybean lecithin and any ratio of synthesizing PE (Phosphatidyl Ethanolamine) and cupreol, dish sterol, being dissolved at 1: 1 in the mixed solvent of an amount of chloroform and 6: 1 volume ratios of ethyl acetate with mol ratio than mixture arbitrarily of stigmasterol made the saturated solution of phospholipid;
(2) solution that step (1) is made steams under the 30-70 ℃ of temperature and removes organic mixed solvent in Rotary Evaporators, at room temperature vacuum drying 4-12 hour, makes exsiccant uniform immobilized artificial membrane;
(3) phosphate buffer of the pH value 5.0-9.0 of adding 0.01M concentration is an amount of in above-mentioned steps (2) gained immobilized artificial membrane, making phospholipid concentration is 0.01-0.015M, smashed to pieces 1-5 minute with tissue mashing machine, and, make blank liposome in ultrasonic Treatment 10-20 minute;
(4) the solution 0.2um membrane filtration that step (3) is made gets the blank liposome of particle diameter less than 200nm;
(5) the arbitrary proportion mixture with lentinan and mitoxantrone is dissolved in the saturated phosphate buffer of gamma-cyclodextrin, wherein lentinan is to be lentinan below 20000 through the isolated molecular weight of the ultrafilter membrane of molecular cut off 20000, mitoxantrone becomes saturated solution with organic solvent dissolution, mix, mitoxantrone is comprised by gamma-cyclodextrin and dissolves, and the solution pH value is 7.0-7.6;
(6) step (5) being made solution sneaks in the solution that step (4) makes, stir down, add an amount of phosphate buffer, reach cumulative volume 1000ml, ultrasonic Treatment 10-20 minute, and under agitation add the alcoholic solution of tiopronin and 18-amine., stir add down methoxy poly (ethylene glycol) monophosphatide acyl ethanolamine, methoxy poly (ethylene glycol) 2000 and polyethylene glycol 6000 arbitrarily than mixture, after the dissolving fully, stir adding Tween80 and glycine down, the complete back of dissolving solution is once more through 0.2nm membrane filtration mistake;
(7) solution that step (6) is made is by the dosage packing that allows on the pharmaceutics, in freezer dryer, make lyophilized powder by common freeze-drying, or pulverize after the solution lyophilization that step (6) is made, cross the 60-150 mesh sieve, carry out packing by acceptable dose on the pharmaceutics.
8. preparing anti-tumor medicine method according to claim 7 is characterized in that, can also add xylitol in the medicinal liquid that makes, and gets 5% isosmotic solution, and the adding hydroxypropyl methylcellulose, making its concentration is 0.05-0.1%, again through 0.2nm membrane filtration mistake, sterilization, cooling, packing.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010111807A1 (en) * | 2009-04-03 | 2010-10-07 | 武汉大安制药有限公司 | A polysaccharide liposome, the preparation method and use of it |
| CN104324001A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Mitoxantrone lipidosome combined drug, and large-scale production technology and application thereof |
-
2006
- 2006-06-22 CN CNA2006100868984A patent/CN101091698A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010111807A1 (en) * | 2009-04-03 | 2010-10-07 | 武汉大安制药有限公司 | A polysaccharide liposome, the preparation method and use of it |
| JP2012522730A (en) * | 2009-04-03 | 2012-09-27 | ウーハン ダーアン ジーイャオ ヨウシェンゴンス | Polysaccharide liposomes, their preparation and use |
| KR101395858B1 (en) * | 2009-04-03 | 2014-05-15 | 우한 도칸 파마슈티컬 컴퍼니 리미티드 | A polysaccharide liposome, the preparation method and use of it |
| CN104324001A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Mitoxantrone lipidosome combined drug, and large-scale production technology and application thereof |
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