CN101461787B - Preparation method of hydroxycamptothecin nano crystal lyophilized powder for injection preparation - Google Patents
Preparation method of hydroxycamptothecin nano crystal lyophilized powder for injection preparation Download PDFInfo
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- CN101461787B CN101461787B CN2008100497076A CN200810049707A CN101461787B CN 101461787 B CN101461787 B CN 101461787B CN 2008100497076 A CN2008100497076 A CN 2008100497076A CN 200810049707 A CN200810049707 A CN 200810049707A CN 101461787 B CN101461787 B CN 101461787B
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Abstract
The invention discloses a method for preparing a nanometer hydroxycamptothecin crystal freeze-dried powder preparation. Main raw materials of the nanometer hydroxycamptothecin crystal freeze-dried powder preparation consist of an active raw material, namely hydroxycamptothecin, phospholipids, a surfactant, namely poloxamer 188 or polyethylene glycol stearate-15, and a freeze-dried auxiliary material excipient. The method for preparing the nanometer hydroxycamptothecin crystal freeze-dried powder preparation comprises the following steps: after the hydroxycamptothecin is added into an alkaline solution to be dissolved, the phospholipids are added in an ultrasonic water bath, and the poloxamer 188 or the polyethylene glycol stearate-15 is added into the mixture under magnetic stirring to be dissolved; the pH value of glacial acetic acid is adjusted to be between 4.0 and 6.0, and hydroxycamptothecin crystals are precipitated; and then the high-pressure homogenization is performed to obtain a nanometer hydroxycamptothecin crystal suspension, and then the freeze-dried auxiliary material excipient is added to be freezely dried to obtain the nanometer hydroxycamptothecin crystal freeze-dried powder preparation. The method is simple and easy to operate. Nanometer crystal freeze-dried powder has the advantages of high dispersity, good stability and so on. The average size of the crystals is 355.6nm, the average content of the hydroxycamptothecin in a sample is 98.5 percent of labeled amount, and the effect of inhibiting and killing liver cancer and gastric cancer cells of the preparation is remarkably stronger than that of a hydroxycamptothecin injection.
Description
Technical field
The present invention relates to a kind of cancer therapy drug, be specifically related to a kind of hydroxycamptothecin nano crystal lyophilized powder for injection preparation, the invention still further relates to the preparation method of said preparation.
Background technology
Hydroxy camptothecin is the strongest micro-alkaloid of antitumaous effect in the similar antitumor monomer that extracts from Chinese Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) in the 60-70 age in last century, belongs to cell cycle specific agents, mainly acts on DNA synthesis stage (S-phase).HCPT is topoisomerase I (Topo I) specific inhibitor, by suppressing the Connection Step again in the DNA superhelix relaxation, causes the fracture of strand and double-stranded DNA, triggers cell death.The clinical chemicotherapy that is mainly used in malignant tumor such as primary hepatocarcinoma, gastric cancer, incidence cancer, gland originality epithelial cancer, leukemia, bladder cancer; Toxic reaction mainly shows the inhibition of urinary system, digestive system and hemopoietic function etc., but its toxicity is starkly lower than camptothecine, and particularly the urinary system reaction is few, easily is accepted clinically.At present, mainly with injection application clinically, the subject matter that injection exists in clinical practice has hydroxy camptothecin: short (intravenous injection distribution half-life (t of (1) half-life
1/2a) be 4.5min, eliminate half-life (t
1/2 β) be 29min), need repetitively administered or extend the period of treatment, cause dose-limiting toxicity-bone marrow depression and gastrointestinal toxicity also to increase thereupon.(2) mainly be distributed in gallbladder behind the intravenously administrable, and that cancer is often sent out the distribution of tissues such as histoorgan such as liver, lung, stomach is unsatisfactory.(3) the fat-soluble water solublity of hydroxy camptothecin is all bad, and the active anticancer of making the water solublity sodium salt reduces by 90%, and toxic and side effects increases; Poor stability, the lactonic ring of medicine are to light, pH sensitivity, and it is the more weak open loop carboxylate structure of function that anti-tumor biological is learned the stronger closed loop lactone thaumatropy of function, and pharmacologically active descends greatly.For above-mentioned reasons, hinder hydroxy camptothecin and given full play to antitumor action, limited its clinical practice.
The existing both at home and abroad at present method that adopts solvent evaporation method to prepare hydroxy camptothecin fabaceous lecithin nanometer lyophilized formulations; though the hydroxy camptothecin fabaceous lecithin nanometer lyophilized formulations of this method preparation can overcome the deficiency of existing injection to a certain extent; but this method need be with a large amount of lower boiling organic solvents; unfavorable to environmental conservation; and easily cause organic solvent residual in preparation, influence the therapeutic effect of medicine.
Summary of the invention
The objective of the invention is to overcome above shortcomings in the prior art, a kind of hydroxycamptothecin nano crystal lyophilized powder for injection preparation is provided, hydroxy camptothecin exists with the nanocrystal state in the preparation, the heavy good dispersion of preparation, and stability is high.
The present invention also aims to provide a kind of method for preparing hydroxycamptothecin nano crystal lyophilized powder for injection preparation, this method adopts the alkali dissolution medicine in preparation process, do not make organic solvent, avoided in environmental pollution and the preparation residual organic solvent the influence of curative effect of medication.
The objective of the invention is to be achieved through the following technical solutions:
Hydroxycamptothecin nano crystal lyophilized powder for injection preparation of the present invention, it mainly contains the raw material of following weight parts and makes:
Hydroxy camptothecin 1～6 weight portion
Phosphatidase 12～12 weight portions
Poloxamer 188 or polyglycol distearate-150～10 weight portions
Lyophilizing auxiliary material excipient 0.5～10 weight portion.
Phospholipid described in the present invention is a kind of in soybean lecithin or the Ovum Gallus domesticus Flavus lecithin.Described lyophilizing auxiliary material excipient is a kind of in mannitol or glucose for injection or the injection lactose.
The preparation method of hydroxycamptothecin nano crystal lyophilized powder for injection preparation of the present invention, it is undertaken by following step:
(1) being scattered in the distilled water the hydroxy camptothecin of 1～6 weight portion is molten, is 9～12 with the sodium hydrate regulator solution pH value;
(2) phospholipid of 2～12 weight portions is joined in the solution that step (1) obtains the water-bath ultra-sonic dispersion;
(3) poloxamer 188 of 0～10 weight portion or polyglycol distearate-15 are added in the solution that step (2) obtains to stirring and dissolving under 33～38 ℃ of water-baths;
(4) the hydroxy camptothecin crystallization is separated out in pH value to 4.0～6.0 of the solution that obtains with sour regulating step (3);
(5) suspension that step (4) is obtained is under the pressure of 3000～18000PSI, and even matter 2～20 times obtains the hydroxycamptothecin nano crystal suspension, and the hydroxy camptothecin crystallite size is 200～600nm.
(6) the lyophilizing auxiliary material excipient of 0.5～10 weight portion is added in the hydroxycamptothecin nano crystal suspension that step 5 obtains stirring and dissolving;
(7) the hydroxycamptothecin nano crystal suspension that step (6) is obtained carries out lyophilization, obtains hydroxycamptothecin nano crystal lyophilized powder for injection preparation.
In described step (2), the water-bath ultrasonic time is 1～10 minute, and temperature is 25～40 ℃.
In described step (4), separating out the hydroxy camptothecin crystallite size is 600～1500nm.
In described step (7), lyophilization is at-60～-70 ℃, carries out vacuum lyophilization under 0.5～0.1Pa condition.
Hydroxy camptothecin exists with the nanocrystal state in the hydroxycamptothecin nano crystal lyophilized powder for injection preparation of the present invention, see accompanying drawing 1, it is the closed loop state that this state can keep the lactone ring in the hydroxy camptothecin structure, make medicine composition hydroxy camptothecin stable, reduce the side reaction that produces owing to the lactone ring structural degradation, thereby improve curative effect.The heavy good dispersion of said preparation, stability is high.Behind the intravenous administration, liver and lung there is higher selectivity, and abundance is less in other organs, improve the therapeutic effect of hydroxy camptothecin thereby reach to hepatocarcinoma and pulmonary carcinoma, minimizing is to the influence of other normal tissue cells, the final compliance of realizing improving the antitumor drug treatment improves patient's life quality, prolongs the effect of life span.
The method for preparing hydroxycamptothecin nano crystal lyophilized powder for injection preparation provided by the invention, this method adopt the alkali dissolution medicine in preparation process, not with an organic solvent, avoided in environmental pollution and the preparation residual organic solvent to the influence of Drug therapy.This preparation method is simple, easily realizes, can not produce organic solvent residual, the medicament contg height.
Description of drawings
Fig. 1 is the hydroxycamptothecin nano crystal transmission electron microscope picture.
Fig. 2 is a hydroxycamptothecin nano crystal lyophilized powder for injection preparation preparation method flow chart.
The specific embodiment
Below in conjunction with embodiment the present invention is elaborated
Embodiment 1
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 1 weight portion,
Soybean lecithin 2 weight portions,
Surfactant poloxamer 1881 weight portions,
Mannitol 0.5 weight portion.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 1 weight portion, adding sodium hydroxide adjusting pH value is 9, after the glass rod stirring and dissolving, adds soybean lecithin 2 weight portions again, 25 ℃ of water-baths dissolving in ultrasonic 10 minutes; 35 ℃ of water-bath magnetic agitation add surfactant poloxamer 188 dissolvings of 1 weight portion; Regulating pH value with glacial acetic acid is 4.0; High pressure homogenization pressure is 3000PSI, and even matter 20 times adds Osmitrol to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Embodiment 2
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 2 weight portions,
Ovum Gallus domesticus Flavus lecithin 4 weight portions,
Surfactant polyethylene stearate-15 5 weight portion,
Mannitol 1 weight portion.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 2 weight portions, adding sodium hydroxide adjusting pH value is 12, after the glass rod stirring and dissolving, adds soybean lecithin 4 weight portions again, 40 ℃ of water-baths dissolving in ultrasonic 1 minute; 33 ℃ of water-bath magnetic agitation add surfactant poloxamer 188 dissolvings of 5 weight portions; Regulating pH value with glacial acetic acid is 6.0; High pressure homogenization pressure is 18000PSI, and even matter 2 times adds Osmitrol to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Embodiment 3
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 3 weight portions,
Soybean lecithin 6 weight portions,
Polyglycol distearate-15 6 weight portion,
Glucose for injection 5 weight portions.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 3 weight portions, adding sodium hydroxide adjusting pH value is 10, after the glass rod stirring and dissolving, adds soybean lecithin 6 weight portions again, 30 ℃ of water-baths dissolving in ultrasonic 5 minutes; 34 ℃ of water-bath magnetic agitation add surfactant poloxamer 188 dissolvings of 6 weight portions; Regulating pH value with glacial acetic acid is 5.0; High pressure homogenization pressure is 6000PSI, and even matter 10 times adds the glucose for injection aqueous solution to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Embodiment 4
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 6 weight portions,
Soybean lecithin 12 weight portions,
Surfactant poloxamer 188 10 weight portions,
Glucose for injection 10 weight portions.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 6 weight portions, adding sodium hydroxide adjusting pH value is 11, after the glass rod stirring and dissolving, adds soybean lecithin 12 weight portions again, 35 ℃ of water-baths dissolving in ultrasonic 8 minutes; 36 ℃ of water-bath magnetic agitation add surfactant poloxamer 188 dissolvings of 10 weight portions; Regulating pH value with glacial acetic acid is 5.5; High pressure homogenization pressure is 10000PSI, and even matter 15 times adds the glucose for injection aqueous solution to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Embodiment 5
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 5.5 weight portions,
Soybean lecithin 11 weight portions,
Glucose for injection 1.5 weight portions.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 5.5 weight portions, adding sodium hydroxide adjusting pH value is 11, after the glass rod stirring and dissolving, adds soybean lecithin 12 weight portions again, 37 ℃ of water-baths dissolving in ultrasonic 8 minutes; Regulating pH value with glacial acetic acid is 5.5; High pressure homogenization pressure is 12000PSI, and even matter 12 times adds the glucose for injection aqueous solution to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Embodiment 6
(1) primary raw material of preparation hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
Hydroxy camptothecin 4 weight portions,
Ovum Gallus domesticus Flavus lecithin 10 weight portions,
Polyglycol distearate-15 8 weight portion,
Injection lactose 8 weight portions.
(2) prepare the method for hydroxycamptothecin nano crystal lyophilized powder for injection preparation:
With the molten 100ml container obtained aqueous solution 90ml that places of the hydroxy camptothecin of 6 weight portions, adding sodium hydroxide adjusting pH value is 11, after the glass rod stirring and dissolving, adds soybean lecithin 12 weight portions again, 35 ℃ of water-baths dissolving in ultrasonic 8 minutes; 38 ℃ of water-bath magnetic agitation add surfactant poloxamer 188 dissolvings of 10 weight portions; Regulating pH value with glacial acetic acid is 5.5; High pressure homogenization pressure is 8000PSI, and even matter 15 times adds the injection lactose aqueous solution to 100ml, be sub-packed in the cillin bottle, and every bottle of 2ml, lyophilizing obtains finished product.
Medicine to above-mentioned prepared is done quality testing:
The mensuration of hydroxycamptothecin nano crystallite size, PDI and zeta current potential: sample thief adds the suitable dilution of water or is distributed to lyophilized powder in the water again, adopt nano particle size and zeta potential measurement instrument to measure hydroxycamptothecin nano crystallite size, PDI and zeta current potential, the results are shown in Table 1～3.
Table 1 hydroxycamptothecin nano crystallite size (nm)
The crystalline PDI of table 2 hydroxycamptothecin nano
The crystalline zeta current potential of table 3 hydroxycamptothecin nano (mV)
Assay: get the hydroxycamptothecin nano crystal lyophilized powder, with mobile phase (acetonitrile: 0.1% triethylamine-phosphate buffer=75: 25) dissolve and be settled to 100ml, the degassing, sample introduction 20 μ 1, the record chromatogram as external standard, is pressed external standard method with reference substance solution, with calculated by peak area, the content that gets hydroxy camptothecin in the sample is 98.7%, 97.6%, 99.2%, 98.2%, 99.3% and 98.5% of labelled amount.
External pharmacodynamic experiment:
The hydroxycamptothecin nano crystal lyophilized powder is to hepatocarcinoma and the inhibiting research of stomach cancer cell
Hepatoma carcinoma cell SMMC-7721 and stomach cancer cell SGC-7901 cell grow in the RPMI-1640 culture fluid that contains 10% calf serum.Cell culture condition is: 37 ℃, and 5%CO
2, saturated humidity, every 2-3 days go down to posterity with 0.25% trypsinization.Get cell confession experiment exponential phase of growth.With 0.5 * 10
5/ ml cell inoculation is in 96 well culture plates, every hole 100 μ L, and at 37 ℃, 5%CO
2Cultivate under the condition.Dilute hydroxycamptothecin nano crystal lyophilized powder and alkyl camptothecine injection respectively to testing desired concn with the RPMI-1640 culture fluid, behind cell inoculation 24h, add 96 orifice plates, every hole 100 μ l.Zeroing group and matched group add the culture fluid of respective volume, establish 4 parallel holes for every group.After cultivating 72h, every hole adds 5mg/mL MTT 20 μ L (except the zeroing group), cultivates 4h again, and the culture fluid that inclines adds DMSO 150mL/ hole, treats that precipitation fully after the dissolving, reads absorbance (A) with microplate reader after wavelength 490nm place returns to zero.Tumor cell group with not dosing is contrast, calculates IC
50Value.
Measure of the inhibition of hydroxycamptothecin nano crystal lyophilized powder with mtt assay to SMMC-7721 and two kinds of growth of tumour cell of SGC-7901.The hydroxycamptothecin nano crystal lyophilized powder has obvious suppression and lethal effect to SMMC-7721 and SGC-7901 growth of tumour cell.Along with increasing of hydroxycamptothecin nano crystal lyophilized powder amount, its inhibition degree strengthens, and compares with the control formulation alkyl camptothecine injection, and significant difference (p＜0.001) is arranged.The hydroxycamptothecin nano crystal lyophilized powder acts on the IC of SMMC-7721 and two kinds of tumor cells of SGC-7901
50Be worth forr a short time 7.61 and 6.73 times than alkyl camptothecine injection respectively, the results are shown in Table 4.The result shows that the hydroxycamptothecin nano crystal lyophilized powder obviously is better than alkyl camptothecine injection to the inhibitory action of SMMC-7721 and two kinds of tumor cells of SGC-7901.
Table 4 hydroxycamptothecin nano crystal lyophilized powder and injection are to the IC of two kinds of tumor cells
50Value (ng/ml)
Claims (5)
1. the preparation method of a hydroxycamptothecin nano crystal lyophilized powder for injection preparation, it is characterized in that: it is undertaken by following step:
(1) being scattered in the distilled water the hydroxy camptothecin of 1～6 weight portion is molten, is 9～12 with the sodium hydrate regulator solution pH value;
(2) phospholipid of 2～12 weight portions is joined in the solution that step (1) obtains the water-bath ultra-sonic dispersion;
(3) poloxamer 188 of 0～10 weight portion or polyglycol distearate-15 are added in the solution that step (2) obtains to stirring and dissolving under 33～38 ℃ of water-baths;
(4) the hydroxy camptothecin crystallization is separated out in pH value to 4.0～6.0 of the solution that obtains with sour regulating step (3);
(5) suspension that step (4) is obtained is under the pressure of 3000～18000PSI, and even matter 2～20 times obtains the hydroxycamptothecin nano crystal suspension, and the hydroxy camptothecin crystallite size is 200～600nm.
(6) the lyophilizing auxiliary material excipient of 0.5～10 weight portion is added in the hydroxycamptothecin nano crystal suspension that step 5 obtains stirring and dissolving;
(7) the hydroxycamptothecin nano crystal suspension that step (6) is obtained carries out lyophilization, obtains hydroxycamptothecin nano crystal lyophilized powder for injection preparation.
2. the method for preparing hydroxycamptothecin nano crystal lyophilized powder for injection preparation according to claim 1 is characterized in that: in described step 2, the water-bath ultrasonic time is 1～10 minute, and temperature is 25～40 ℃.
3. the method for preparing hydroxycamptothecin nano crystal lyophilized powder for injection preparation as claimed in claim 1 or 2 is characterized in that: in described step (4), separating out the hydroxy camptothecin crystallite size is 600～1500nm.
4. according to the preparation method of the described hydroxycamptothecin nano crystal lyophilized powder for injection preparation of claim 2, it is characterized in that: in described step (7), lyophilization is at-60～-70 ℃, carries out vacuum lyophilization under 0.5～0.1Pa condition.
5. according to the preparation method of the described hydroxycamptothecin nano crystal lyophilized powder for injection preparation of claim 3, it is characterized in that: in described step (7), lyophilization is at-60～-70 ℃, carries out vacuum lyophilization under 0.5～0.1Pa condition.
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| CN105748413B (en) * | 2016-03-10 | 2018-06-29 | 华南理工大学 | Hydroxycamptothecin nano crystal load microballoon and preparation method thereof |
| CN106466296B (en) * | 2016-04-01 | 2019-09-24 | 中国医学科学院药用植物研究所 | A kind of camptothecine it is nanocrystalline and preparation method thereof |
| CN108653236A (en) * | 2017-03-31 | 2018-10-16 | 复旦大学 | A kind of biomembrane contains the preparation method and its usage of medicament nano crystal |
| CN110759928B (en) * | 2018-07-27 | 2022-04-01 | 四川大学 | Preparation of camptothecin drug nanocrystals by reversible decomposition method |
| CN113423388A (en) * | 2018-10-30 | 2021-09-21 | 托马斯拔佳大学 | Method for preparing nanocrystals with improved bioavailability and formulation of such nanocrystal formulations for anticancer therapy |
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| CN1568994A (en) * | 2004-05-13 | 2005-01-26 | 黄石李时珍药业集团武汉李时珍药业有限公司 | Targeting hydroxycamptothecin bean phospholipid nano freeze-dried powder injection preparation, preparation method and application |
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| CN1568994A (en) * | 2004-05-13 | 2005-01-26 | 黄石李时珍药业集团武汉李时珍药业有限公司 | Targeting hydroxycamptothecin bean phospholipid nano freeze-dried powder injection preparation, preparation method and application |
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