CN100518727C - Preparaton method of anticancer medicine colchicin microsphere freeze dried agent - Google Patents
Preparaton method of anticancer medicine colchicin microsphere freeze dried agent Download PDFInfo
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- CN100518727C CN100518727C CNB031214452A CN03121445A CN100518727C CN 100518727 C CN100518727 C CN 100518727C CN B031214452 A CNB031214452 A CN B031214452A CN 03121445 A CN03121445 A CN 03121445A CN 100518727 C CN100518727 C CN 100518727C
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Abstract
A freeze-dried colchicine microsphere as anticancer medicine is prepared through dissolving polyvinyl alcohol in distilled water, adding sodium chloride, quickly adding the solution of colchicine and cyanoacrylate in organic solution, adding surfactant and freeze-drying protecting agent, and vacuum freeze drying. Its advantages are sure culative effect to breast cancer, primary gout, and hepatic injury and fibrosis, and low cost.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, particularly relate to the preparation method of microballoon lyophilized dose of a kind of cancer therapy drug colchicine that is used to prepare the cancer therapy drug new formulation.
Background technology
The closure globule that microsphere (Microparticle) is made up of biodegradable macromolecular material, reported in literature is arranged, microsphere is a kind of novel form of targeting drug delivery system, after entering in the body, microsphere, medicine is accumulated in the abundant histoorgan of macrophages such as liver, spleen and bone marrow mainly by reticuloendothelial system phagocytic.Microsphere has increased local drug concentration, improves curative effect of medication; Reduce the distribution of medicine simultaneously, reduce poisonous side effect of medicine at whole body.The microsphere good biocompatibility, nontoxic or non-immunogenicity, safe and reliable.Microsphere has shown obvious superiority in the treatment of numerous disease, be current advanced the 4th generation drug delivery system.
Colchicine (Colchicin) be bulb powder from liliaceous plant iphigenia indica Iphigenia indica Kunth etBenth. through the 80-90% alcohol reflux, concentrate, extractum extracts with suitable quantity of water, filters.Water liquid 2%H
2SO
4Transferring pH is 2.0, chloroform extraction, 5%NaOH solution washing, Na
2SO
4Dry concentrating gets jelly, through a kind of alkaloid that ethanol, chloroform crystallization obtain, is a kind of Tropolones chemical compound.The clinical cancer that is used for the treatment of, colchicine pair cell mitosis has the obvious suppression effect, the growth of energy anticancer, the clinical cancer that is used for the treatment of, especially breast carcinoma is had certain curative effect, primary gout is had certain effect, colchicine is having effect aspect treatment hepatic injury and the fibrosis.In sum, colchicine is an anticancer traditional drugs that has wide application prospects.The pertinent literature report that does not also have the colchicine microsphere both at home and abroad.Domestic relevant colchicine does not have relevant patent, bibliographical information for microballoon lyophilized dose yet.
Summary of the invention
The purpose of this invention is to provide the preparation method of microballoon lyophilized dose of the cancer therapy drug colchicine of a kind of targeting height, solid type, it is characterized in that: polyvinyl alcohol is dissolved in the distilled water, adds sodium chloride and adjust solution and be and the isoosmotic aqueous solution of blood plasma; Be dissolved in colchicine and cyanoacrylate in the organic solvent altogether; and be injected in the sodium-chloride water solution of polyvinyl alcohol at a high speed; heating; stir; add surfactant at aqueous phase; freeze drying protectant carries out vacuum lyophilization, obtains microballoon lyophilized dose of pulverous solid colchicine of white, loose, good fluidity.Microballoon lyophilized dose of its colchicine is grouped into by the one-tenth of following ratio of weight and number:
Colchicine 100-1000
Polybutylcyanoacrylate 500-1000
Surfactant 50-100
Polyvinyl alcohol 20-100
Sodium chloride 9000
Glycine 100-1000
700-800 milligrams of polybutylcyanoacrylates
10-100 milligrams of polyvinyl alcohol
The described preparation method that is used to prepare microballoon lyophilized dose of cancer therapy drug colchicine may further comprise the steps:
1) the purchase raw material of following weight and volume parts ratio:
200-800 milligrams of colchicine
700-800 milligrams of polybutylcyanoacrylates
10-100 milligrams of polyvinyl alcohol
40-80 milligrams in surfactant
9000 milligrams in sodium chloride
100-1000 milligrams of freeze drying protectants
500-1000 milliliters of organic solvents
1000 milliliters of distilled water
2) polyvinyl alcohol is used earlier water dissolution, aqueous phase adds surfactant, adds sodium chloride, obtains and the isoosmotic aqueous solution of blood plasma;
3) colchicine and cyanoacrylate are dissolved in the organic solvent altogether, and are injected in the above-mentioned aqueous solution at a high speed, and continue to stir, solution temperature maintains 40 ℃～50 ℃;
4) organic facies is diffused into water rapidly, forms O/W or w/o type Emulsion, and magnetic agitation is adopted in heating, and volatilization eliminates organic solvent;
5) suspension that obtains is centrifugal, and be washed with distilled water to organic solvent-free and surfactant is residual;
6) with microsphere solid precipitate 0.9% physiological saline solution that obtains, add freeze drying protectant, stir after 30-50 minutes, carry out vacuum lyophilization;
7) vacuum lyophilization obtains microballoon lyophilized dose of the pulverulent solids type colchicine of white, loose, good fluidity;
8) weigh, be sub-packed in the 10ml ampoule, inflated with nitrogen seals, and sterilization is finished product.
Described vacuum lyophilization is at-50 ℃～-60 ℃, carries out under 0.5～0.1mPa condition.
The preferred chloroform of described organic solvent, dichloromethane, ethanol or any two kinds mixture.
Described surfactant is selected from Tween-80, Tween-20, Span-80, Span-20, Poloxamer or their mixture.
Described freeze drying protectant is selected from glycine, sorbose, sorbitol, glucose, lactose or their mixture.
The invention has the beneficial effects as follows with the colchicine of method for preparing and use 0.9% physiological saline solution for microballoon lyophilized dose, then be dispersed into uniform colchicine microsphere aqueous solution immediately, its effective active composition is a colchicine microsphere wherein, scanning electron microscope records the mean diameter of liposome after the hydration less than 1 μ m, and 75% particle diameter is between 200-300 μ m.Because after microballoon lyophilized dose of hydration of colchicine of the present invention, the particle diameter of colchicine microsphere is little, can be compatible in vivo.By microsphere is medicine degradable, the avirulence in vivo of carrier, has the characteristics such as targeting that can discern mutant.The particle diameter of colchicine microsphere is little, and liver, spleen tissue are had natural targeting, has therefore improved the accumulation of anti-liver cancer drug colchicine in hepatic tissue, has improved the therapeutical effect of colchicine to hepatocarcinoma.The safety investigation of sample has been carried out in this experiment, comprises the test of irritation test and hemolytic, and result of the test shows that experimental animal there is no stimulates the sexual abnormality reaction, and microballoon lyophilized dose of colchicine is safe and reliable, nonirritant, and do not have hemolytic reaction.The method technology that the present invention produces microballoon lyophilized dose of colchicine is simple, does not need special equipment, thereby production cost is low, is suitable for large-scale industrial production.
Description of drawings
Fig. 1 is colchicine standard substance HPCE figure.
Fig. 2 is colchicine blood plasma standard substance HPCE figure.
The specific embodiment
The present invention is the preparation method of microballoon lyophilized dose of the cancer therapy drug colchicine of a kind of targeting height, solid type.Polyvinyl alcohol is dissolved in the distilled water, and adding sodium chloride is adjusted solution and is and the isoosmotic aqueous solution of blood plasma; Colchicine and cyanoacrylate are dissolved in the machine solvent altogether; and be injected in the sodium-chloride water solution of polyvinyl alcohol at a high speed; heating; stir; add surfactant and freeze drying protectant at aqueous phase; carry out vacuum lyophilization, obtain microballoon lyophilized dose of pulverous solid colchicine of white, loose, good fluidity, the one-tenth of the ratio of weight and number that its colchicine is microballoon lyophilized dose is grouped into:
Colchicine 100-1000
Polybutylcyanoacrylate 500-1000
Polyvinyl alcohol 20-100
Surfactant 50-100
Sodium chloride 9000
Glycine 100-1000
500-1000 milliliters of organic solvents
1000 milliliters of distilled water
Wherein, preferably be grouped into by the one-tenth of following ratio of weight and number:
Colchicine 200-800
Polybutylcyanoacrylate 700-800
Polyvinyl alcohol 10-100
Surfactant 40-80
Sodium chloride 9000
Glycine 100-1000
700-800 milliliters of organic solvents
1000 milliliters of distilled water
The described preparation method that is used to prepare microballoon lyophilized dose of cancer therapy drug colchicine may further comprise the steps:
1) the purchase raw material of following weight and volume parts ratio:
200-800 milligrams of colchicine
800 milligrams of polybutylcyanoacrylates
20 milligrams of polyvinyl alcohol
40-80 milligrams in surfactant
9000 milligrams in sodium chloride
100-1000 milligrams of freeze drying protectants
500-1000 milliliters of organic solvents
1000 milliliters of distilled water
2) polyvinyl alcohol is used earlier water dissolution, aqueous phase adds surfactant, adds sodium chloride, obtains and the isoosmotic aqueous solution of blood plasma;
3) colchicine and cyanoacrylate are dissolved in the organic solvent altogether, and are injected in the above-mentioned aqueous solution at a high speed, and continue to stir, solution temperature maintains 40 ℃～50 ℃;
4) organic facies is diffused into water rapidly, forms O/W or w/o type Emulsion, and magnetic agitation is adopted in heating, and volatilization eliminates organic solvent;
5) suspension that obtains is centrifugal, and be washed with distilled water to organic solvent-free and surfactant is residual;
6) with microsphere solid precipitate 0.9% physiological saline solution that obtains, add freeze drying protectant, stir after 30-50 minutes, carry out vacuum lyophilization;
7) vacuum lyophilization obtains microballoon lyophilized dose of the pulverulent solids type colchicine of white, loose, good fluidity;
8) weigh, be sub-packed in the 10ml ampoule, inflated with nitrogen seals, and sterilization is finished product.
The present invention will be further described below in conjunction with specific embodiment.
1), the purchase raw material of following weight and volume
250 milligrams of colchicine
800 milligrams of polybutylcyanoacrylates
20 milligrams of polyvinyl alcohol
40 milligrams in surfactant
9000 milligrams in sodium chloride
500 milligrams of glycines
500 milliliters of chloroforms
1000 milliliters of distilled water
2), accurate weighing polyvinyl alcohol is 20 milligrams, earlier with the abundant swelling of 500ml redistilled water, after treating the abundant swelling of polyvinyl alcohol, continue to add other 500ml water and 40 milligrams of surfactants, add 9.0g sodium chloride again and adjust aqueous solution to oozing with blood plasma etc., magnetic stirring apparatus 500rpm stirs, and keeps solution temperature to maintain 20 ℃;
3), the preparation 1.0mg/ml colchicine chloroformic solution 250ml, place the 500ml large beaker, standby;
4), with chloroform 250ml fully dissolve the preparation 800 milligrams of polybutylcyanoacrylates, place another 500ml large beaker, standby;
5), the colchicine and the cyanoacrylate organic solvent mixed together of getting equivalent be even, places the 1000ml large beaker, and be standby.
6), inject the polyvinyl alcohol water solution of magnetic agitation at a high speed with the gradation of 100ml syringe, can obtain the emulsion of translucent colchicine, aqueous temperature maintains 40 ℃～50 ℃;
7), continue the Ex-all of extremely organic solvent being volatilized of heating (40 ℃～50 ℃) and the above-mentioned emulsion of high-speed stirred, finally obtain white suspension;
8), the suspension that obtains is centrifugal, and repeatedly wash with distilled water, residual to organic solvent-free and surfactant;
9), with nanoparticle solid sediment 0.9% physiological saline solution that obtains, add freeze drying protectant, stir;
10), the colchicine microsphere suspension that will contain freeze drying protectant places the large diameter Flat bottom container of wide-mouth;-55 ℃; 0.3mPa vacuum lyophilization is 24 hours under the condition, promptly gets microballoon lyophilized dose of the pulverulent solids type colchicine of white, loose, good fluidity.
Identical with the step of embodiment 1, the prescription of different is raw material is as follows:
400 milligrams of colchicine
600 milligrams of polybutylcyanoacrylates
40 milligrams of polyvinyl alcohol
50 milligrams in surfactant
9000 milligrams in sodium chloride
800 milligrams of glycines
800 milliliters of organic solvents
1000 milliliters of distilled water
Identical with the step of embodiment 1, the prescription of different is raw material is as follows:
800 milligrams of colchicine
500 milligrams of polybutylcyanoacrylates
50 milligrams of polyvinyl alcohol
40 milligrams in surfactant
9000 milligrams in sodium chloride
1000 milligrams of glycines
1000 milliliters of organic solvents
1000 milliliters of distilled water
The foundation of embodiment 3, colchicine microsphere analytical method
Set up high performance capillary electrophoresis in the test and measured the biological drug disposition dynamics methods of colchicine, the required test specimen amount of this method is little, lowest detection is limited to 0.03mg/ml, sample peak type is good, colchicine and biological sample impurity good separation, the detection of high performance capillary electrophoresis is online, quick, rapid.The typical color spectrogram as shown in Figure 1 and Figure 2.
From Fig. 1 and Fig. 2 as can be seen, under above chromatographic condition, the colchicine appearance time is short, and the sample peak had all gone out in 5 minutes, and the peak type is sharp, no conditions of streaking.Impurity went out the peak at 1～3.47 minute in the plasma sample, and colchicine went out the peak at 4～5 minutes, and biological sample impurity and colchicine good separation meet separation requirement, can be used as the biological drug disposition kinetics measuring method of colchicine.The condition of microballoon lyophilized dose of biological vivo sample high performance capillary electrophoresis of colchicine (HPCE) detection method is as follows.
Separating medium: 30mmol.L
-1Boric acid solution (NaOH transfers to pH10.0); Separation voltage: 15.0KV, 20 ℃ of column temperatures, pressure sample introduction 2.0sec detects wavelength: 254nm, capillary tube: 47cm * 50 μ m; Effective length: 40cm.
The particle size determination that embodiment 4, colchicine are microballoon lyophilized dose
Get the colchicine microsphere, the redistilled water dissolving is observed with zeta potential particle diameter instrument.Zeta potential particle diameter instrument records the mean diameter of liposome after the colchicine microsphere of the present invention hydration less than 1 μ m, and 75% particle diameter is between 200-300nm.
The irritation test that embodiment 5, colchicine are microballoon lyophilized dose
1) white mice intravenous injection
Test method: select 10 of healthy Kunming kind white mice, body weight 20.0～25.0g divides two groups at random.One group of 5 mice, the microballoon lyophilized remover liquid injection of tail vein injection 0.2ml colchicine, 5 mices of matched group, tail vein injection is with dosage 0.9% normal saline.In one hour, observe the administration mice and do not have any Deviant Behavior after the administration, the nonirritant reaction, mice is movable and diet is unaffected, and the microballoon lyophilized remover liquid injection of the colchicine of being injected is to the blood vessel nonirritant; After giving mouse tail vein injection, the mice vascular venous is organized non-stimulated damaging action.
2) mice by intraperitoneal injection method
Test method: select 10 of healthy Kunming kind white mice, body weight 20.0-25.0g divides two groups at random.One group of 5 mice, lumbar injection 0.1ml colchicine microsphere injection liquid, 5 mices of matched group, lumbar injection is with dosage 0.9% normal saline.Observe after the administration to the administration and in one hour, observe the administration mice and do not have any Deviant Behavior, the nonirritant writhing response, mice is movable and diet is unaffected, the colchicine microsphere injection liquid nonirritant of being injected.
This experiment has simultaneously been carried out the safety of prepared sample is investigated, and comprises that irritation test and hemolytic test result show, microballoon lyophilized dose of safety of colchicine, reliable, and nonirritant, and do not have hemolytic reaction.
In above-mentioned each experiment, experimental animal there is no stimulates the sexual abnormality reaction.Result of the test shows that microballoon lyophilized dose of colchicine is safe and reliable.
Because after microballoon lyophilized dose of hydration of colchicine of the present invention, the particle diameter of colchicine microsphere is little, liver, spleen tissue there are natural targeting, have therefore improved the accumulation of anti-liver cancer drug colchicine in hepatic tissue, improved the therapeutical effect of colchicine hepatocarcinoma.Therefore colchicine of the present invention is a kind of cancer therapy drug novel form for microballoon lyophilized dose.Simultaneously,, face with preceding adding disperse medium and disperse formation solution-type microsphere, made things convenient for storage, transportation because microballoon lyophilized dose of colchicine is stored with solid form.
Claims (5)
1. the preparation method of microballoon lyophilized dose of a cancer therapy drug colchicine, it is characterized in that: concrete preparation process is as follows:
1) the purchase raw material of following weight and volume parts ratio:
200-800 milligrams of colchicine,
700-800 milligrams of cyanoacrylates,
10-100 milligrams of polyvinyl alcohol,
40-80 milligrams in surfactant,
9000 milligrams in sodium chloride,
100-1000 milligrams of freeze drying protectants,
500-1000 milliliters of organic solvents,
1000 milliliters of distilled water;
2) polyvinyl alcohol is used earlier dissolved in distilled water, aqueous phase adds surfactant, adds sodium chloride, obtains and the isoosmotic aqueous solution of blood plasma;
3) colchicine and cyanoacrylate are dissolved in the organic solvent altogether, and are injected in the above-mentioned aqueous solution at a high speed, and continue to stir, solution temperature maintains 40 ℃～50 ℃;
4) organic facies is diffused into water rapidly, forms O/W or w/o type Emulsion, and magnetic agitation is adopted in heating, and volatilization eliminates organic solvent;
5) suspension that obtains is centrifugal, and be washed with distilled water to organic solvent-free and surfactant is residual;
6) with colchicine microsphere 0.9% physiological saline solution that obtains, add freeze drying protectant, stir after 30-50 minutes, carry out vacuum lyophilization;
7) vacuum lyophilization obtains microballoon lyophilized dose of the pulverulent solids type colchicine of white, loose, good fluidity;
8) weigh, be sub-packed in the 10ml ampoule, inflated with nitrogen seals, and sterilization is finished product.
2. according to the preparation method of microballoon lyophilized dose of the described cancer therapy drug colchicine of claim 1, it is characterized in that: described vacuum lyophilization is at-50 ℃～-60 ℃, carries out under 0.5～0.1MPa condition.
3. according to the preparation method of microballoon lyophilized dose of the described cancer therapy drug colchicine of claim 1, it is characterized in that: described organic solvent is selected from chloroform, dichloromethane, ethanol or any two kinds mixture.
4. according to the preparation method of microballoon lyophilized dose of the described cancer therapy drug colchicine of claim 1, it is characterized in that: described surfactant is selected from tween 80, tween 20, Arlacel-80, Arlacel-20, poloxamer or their mixture.
5. according to the preparation method of microballoon lyophilized dose of the described cancer therapy drug colchicine of claim 1, it is characterized in that: described freeze drying protectant is selected from glycine.
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|---|---|---|---|
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|---|---|---|---|
| CNB031214452A CN100518727C (en) | 2003-03-31 | 2003-03-31 | Preparaton method of anticancer medicine colchicin microsphere freeze dried agent |
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| CN1533765A CN1533765A (en) | 2004-10-06 |
| CN100518727C true CN100518727C (en) | 2009-07-29 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1311872C (en) * | 2004-12-29 | 2007-04-25 | 山东蓝金生物工程有限公司 | Anticancer combination of medication |
| CN101045162B (en) * | 2006-12-11 | 2011-12-14 | 台山市友顺化工有限公司 | Method for preparing medicine carryed nanometer particle of polycyanoacrylate |
| CN101444491B (en) * | 2008-12-11 | 2010-04-14 | 海南数尔药物研究有限公司 | Ozagrel sodium microballoon lyophilized preparation and preparation method thereof |
| CN103721176B (en) * | 2012-10-12 | 2016-12-07 | 上海中医药大学附属龙华医院 | Chinese medicine preparation for the treatment of breast cancer relapse transfer and preparation method thereof |
| CN109908356B (en) * | 2017-12-13 | 2021-02-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyanoacrylate material loaded with antitumor drug |
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2003
- 2003-03-31 CN CNB031214452A patent/CN100518727C/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
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| 柔红霉素毫微粒冻干针剂的研究. 彭应旭等.中国药房，第10卷第2期. 1999 |
| 柔红霉素毫微粒冻干针剂的研究. 彭应旭等.中国药房，第10卷第2期. 1999 * |
| 秋水仙碱纳米控释微粒抗肿瘤的实验研究. 孙铭等.天津医药，第29卷第12期. 2001 |
| 秋水仙碱纳米控释微粒抗肿瘤的实验研究. 孙铭等.天津医药，第29卷第12期. 2001 * |
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