CN1326528C - Process for preparing arsenic magnetized nanometer glutin minipill - Google Patents
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- CN1326528C CN1326528C CNB2004100413674A CN200410041367A CN1326528C CN 1326528 C CN1326528 C CN 1326528C CN B2004100413674 A CNB2004100413674 A CN B2004100413674A CN 200410041367 A CN200410041367 A CN 200410041367A CN 1326528 C CN1326528 C CN 1326528C
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Abstract
The present invention relates to a medicine for treating tumors, and particularly relates to a technology for preparing arsenic magnetized nanometer gelatin microspheres. Gelatin and composite ferrite evenly mixed by a certain mass ratio, added with As2O3 alkaline auqeous solution (1M) of 1 mg/ml, and double distilled water by a certain mass/volume ratio, and processed through pH value regulation and ultrasonic emulsification to be made into solution A; 200 to 250 ml liquid paraffin containing 1% of span 85 is used as solution B; in a water bath of 55 DEG C to 60 DEG C, the solution A is slowly dripped into the solution B at a certain stirring speed to be processed through ultrasonic emulsification, the temperature of the water bath is lowered to 0 to 4 DEG C, agitation is carried out for an hour, glutaraldehyde is dripped, and agitation is continued; isopropyl alcohol is added, agitation is carried out once more, standing is carried out for 2 to 4 hours, and centrifugation of 2000 to 3000 r/min is carried out for 10 to 15 minutes; arsenic magnetized nanometer gelatin microspheres are obtained by that microspheres are separated, washed with absolute ether, and processed through vacuum drying.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of tumor, relate in particular to a kind of preparation technology of arsenicum magnetic Nano gelatine microsphere.
Background technology
Pharmaceutical dosage form can be divided into following several generations substantially: the red ball of cream diffusing (first generation), tablet and injection and capsule and aerosol (second filial generation), slow release and controlled release form (third generation).And desire to make medicine to concentrate in target site, improve curative effect and reduce the whole body toxic and side effects, be the 4th generation targeting drug delivery system, as novel forms such as the liposome of development in recent years, nanoparticles, but these particulate carriers can only be brought into play the effect of passive target, easily are difficult to give full play to drug effect by the macrophage phagocytic of MPS.The seventies in 20th century, Widder etc. proposed the notion of magnetic control target to drug delivery system, and at first carried out the research of drug loaded magnetic microsphere, result of study shows: drug loaded magnetic microsphere pharmaceutical dosage form more in the past has the characteristics of unrivaled efficient, low toxicity, high anelasticity.In recent years, along with the progress of nanotechnology, development nano-magnetic microsphere carrier and medicine have caused people's extensive attention again on nanometer level.At present, the 4th generation targeting drug delivery system become one of most active fields in the novel pharmaceutical formulation research.
Chinese medicine arsenicum and arsenic preparation are hot research in recent years to tumor treatment, particularly leukemic treatment are paid close attention to by people.At present, to the oncocyte of some solid carcinomaes, all there is experiment in vitro to confirm inhibition growth and the apoptosis-induced effect of arsenic to them.The systemic reaction of arsenic preparation intravenously administrable still exists, as symptom of digestive tract, and xerosis cutis and pigmentation, peripheral neuritis, hepatorenal damage, even serious side effects such as ascites pleural fluid appear.Has the important clinical meaning so change administering mode and pharmaceutical dosage form.
Magnetic microsphere preparation generally has two kinds of methods: the method that is heating and curing and add the cross-linking agent solidification method.The stability of the albumin microsphere that the employing method that is heating and curing prepares when external and storage is poor slightly, the medicine amount of inlaying is few, antitumor drug easy heated denaturalization (100-160 ℃ of the temperature that is heating and curing) in being heating and curing reduces its anti-tumor activity, and cost of manufacture is higher, is difficult for applying.Adding the cross-linking agent solidification method can be in the low-temperature setting balling-up, the good stability when external and storage, and the medicine amount of inlaying increases.This type of medicine magnetic carrier of development can reach nanometer level at present, but the magnetic medicinal microglobule that carries behind the medicine belongs to micrometer level more.
Technology contents
The invention provides a kind of preparation technology that can keep the arsenicum magnetic Nano gelatine microsphere of gained medicine anti-tumor activity and good stability.
The present invention adopts following technical scheme:
A kind of preparation technology of the arsenicum magnetic Nano gelatine microsphere as the medicine for treating tumor thing, it is characterized in that gelatin and complex ferrite by 1: the quality of 0.375-0.400 is than mix homogeneously, again by 275-300: 1 mass/volume is than to the As that wherein adds 1mg/ml
2O
3Alkaline aqueous solution (1M) and distilled water, the adjusting pH value is 8-9,55 ℃-60 ℃ ultrasonic emulsification 10-15 minute, make A liquid, the liquid paraffin that contains 1% sorbester p37 with 200-250ml is a B liquid, in 55 ℃ of-60 ℃ of water-baths, under the mixing speed of 2000-3000r/min, slowly (50-60 drips/min) splashes in the B liquid, and ultrasonic emulsification is 10-15 minute simultaneously, and cooling changes 0-4 ℃ of ice-water bath into A liquid, stirred 1 hour, drip glutaraldehyde, dripping quantity is 30-50ml, continues to stir 50-60 minute, add isopropyl alcohol, dripping quantity is 50-60ml, restir 10-15 minute, leaves standstill 2-4 hour, under 2000-3000r/min centrifugal 10-15 minute, separate microsphere, with absolute ether washing 5-10 time, vacuum drying promptly gets arsenicum magnetic Nano gelatine microsphere.
Compared with prior art, the present invention has following advantage:
The arsenicum magnetic Nano microsphere that adopts technology manufacturing of the present invention is the yellowish-brown powder, the about 190nm size of microspherulite diameter, and sphere or oval evenly, have the higher magnetic material core of an electron density, good dispersion; Contain arsenicum As in the arsenicum magnetic Nano microsphere
2O
30.65989 ± 0.42 μ g/mg, magnetic material 69.57027 ± 0.36 μ g/mg.Dynamically delivery system proves that it has slow-releasing preferably, be placed on 4 ℃, 25 ℃, 37 ℃ three months, arsenicum and amount of magnetic material no change (P＞0.05) prove that it has good stability.This preparation technology orthogonal design gelatin concentration (10%, 15%, 20%), the amount of manganese-zinc ferrite (100mg, 150mg, 200mg) and the amount of arsenicum (2mg, 6mg, 10mg) optimization gelatin concentration 10% wherein, manganese-zinc ferrite 150mg and arsenicum 2mg be the best.Gelatin concentration is too big, and the manganese-zinc ferrite bulk concentration is too high, and then 4 ℃ have bulk deposition when solidifying, even high-speed stirred is not good yet, the transmission electron microscope observing balling-up is bad.Emulsifying agent span85 is dissolved in the 500ml liquid paraffin dispersant with 1% concentration, prolong the ultrasonic homogenize time, the more preceding scholar of mixing speed brings up to 2000r/min, and firming agent is used to be glutaraldehyde, for well, prepared arsenicum magnetic Nano microsphere is the yellowish-brown powder to its effect than formaldehyde.Gelatin has excellent biological compatibility, once be used as blood plasma substitute, its abundant water and after, dark exhibition is for fibrous, stirring under the condition such as freezing, gelatin molecule begins to curl, and become microgranule by a plurality of coheres, under the effect of firming agent (formaldehyde or glutaraldehyde), gelatin molecule forms three-dimensional network structure, this structure makes having good stability of microsphere, certain affinity is arranged between drug molecule and the gelatin molecule, thereby make medicine adsorbed, and be wrapped in the microsphere by gelatin, forming a kind of oil bag solid type Emulsion, is brown powder after drying.The XRD instrument is levied spectrum analysis, and the result shows: the kurtosis of existing manganese-zinc ferrite has As again in its spectrogram
2O
3Kurtosis, searching database proves manganese-zinc ferrite and As
2O
3Use the Electronic Speculum energy spectrum analysis, beat on single microsphere, can get to the manganese-zinc ferrite composition in its power spectrum and can get to As again with probe
2O
3Composition, the two illustrates that all microsphere prepares successfully.Adopting thermogravimetry to record Curie temperature is 105.407 ℃ Mn
0.4Zn
0.6Fe
2O
4Magnetic nano-particle is that temperature was elevated to 100 ℃ rapidly on the board-like coil of high-frequency magnetic induction heater of 300 A in short several seconds at output current, just can be near its Curie temperature in 1 minute; With its be dissolved in be made into the magnetic fluid that concentration is 8mg/ml, 10mg/ml, 12mg/ml in 0.9% normal saline after, at output current is that the board-like coil of high-frequency magnetic induction heater of 300A can reach 43 ℃, 45 ℃, 47 ℃ respectively last 30 minute, and maintenance constant temperature, realized the temperature control and the constant temperature of tumor thermotherapy.
Description of drawings
Fig. 1 is the As203 magnetic Nano microsphere that is made by the present invention.
Fig. 2 is As
2O
3The magnetic Nano microsphere transmission electron microscope can spectrogram.
Fig. 3 is the external intensification experimental result picture of Mn0.4Zn0.6Fe204 magnetic Nano material, and output current is 300A, and magnetic fluid concentration is 8mg/ml, 10mg/ml, 12mg/ml.
The specific embodiment
The preparation technology of a kind of arsenicum magnetic Nano gelatine microsphere as the medicine for treating tumor thing of embodiment, with gelatin and complex ferrite by 1: the quality of 0.375-0.400 compares mix homogeneously, mass ratio can be 1: 0.375,1: 0.385,1: 0.390,1: 0.400, press 275-300 again: 1 mass/volume is than (being 275: 1,285: 1,295: 1,300: 1) to the As that wherein adds 1mg/ml
2O
3Alkaline aqueous solution (1M) and distilled water, the adjusting pH value is 8-9,55 ℃-60 ℃ (can be 57 ℃) ultrasonic emulsification 10-15 minute, can be 11 minutes in the present embodiment, 13 minutes, 14 minutes, make A liquid, the liquid paraffin that contains 1% sorbester p37 with 200-250ml is a B liquid, in the present embodiment, desirable 225ml, in 55 ℃ of-60 ℃ of water-baths, under the mixing speed of 2000-3000r/min, can be taken as 2500r/min in the present embodiment, slowly (50-60 drips/min) splashes in the B liquid with A liquid, ultrasonic emulsification is 10-15 minute simultaneously, can be taken as 13 minutes in the present embodiment, and cooling changes 0-4 ℃ of ice-water bath into, stirred 1 hour, drip glutaraldehyde, dripping quantity is 30-50ml, is taken as 40ml in the present embodiment, continue to stir 50-60 minute, can be taken as 55 minutes in the present embodiment, add isopropyl alcohol, dripping quantity is 50-60ml, can be taken as 55ml in the present embodiment, restir 10-15 minute, can be taken as 13 minutes in the present embodiment, left standstill 2-4 hour, can be taken as 3 hours in the present embodiment, under 2000-3000r/min centrifugal 10-15 minute, the present embodiment medium speed can be 2500r/min, and the time can be taken as 13min, separate microsphere, with absolute ether washing 5-10 time, can be taken as in the present embodiment 8 times, vacuum drying promptly gets arsenicum magnetic Nano gelatine microsphere.
Claims (1)
1, a kind of preparation technology of the arsenicum magnetic Nano gelatine microsphere as the medicine for treating tumor thing, it is characterized in that with concentration be 10%, 15% or 20% gelatin and complex ferrite by 1: the quality of 0.375-0.400 is than mix homogeneously, again by 275-300: 1 mass/volume is than to the As that wherein adds 1mg/ml
2O
3Alkaline aqueous solution 1M and distilled water, the adjusting pH value is 8-9,55 ℃-60 ℃ ultrasonic emulsification 10-15 minute, make A liquid, the liquid paraffin that contains 1% sorbester p37 with 200～250ml is a B liquid, in 55 ℃ of-60 ℃ of water-baths, under the mixing speed of 2000-3000r/min, the slow 50-60 of A liquid is dripped/min splashes in the B liquid, and ultrasonic emulsification is 10-15 minute simultaneously, and cooling changes 0-4 ℃ of ice-water bath into, stirred 1 hour, drip glutaraldehyde, dripping quantity is 30-50ml, continues to stir 50-60 minute, add isopropyl alcohol, dripping quantity is 50-60ml, restir 10-15 minute, leaves standstill 2-4 hour, under 2000-3000r/min centrifugal 10-15 minute, separate microsphere, with absolute ether washing 5-10 time, vacuum drying promptly gets arsenicum magnetic Nano gelatine microsphere.
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| CNB2004100413674A CN1326528C (en) | 2004-07-13 | 2004-07-13 | Process for preparing arsenic magnetized nanometer glutin minipill |
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| CNB2004100413674A CN1326528C (en) | 2004-07-13 | 2004-07-13 | Process for preparing arsenic magnetized nanometer glutin minipill |
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| CN1326528C true CN1326528C (en) | 2007-07-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10111836B2 (en) | 2015-02-01 | 2018-10-30 | Orsenix Holdings Bv | High surface-area lyophilized compositions comprising arsenic for oral administration in patients |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5147699B2 (en) * | 2005-12-20 | 2013-02-20 | 富士フイルム株式会社 | Protein nanoparticles and uses thereof |
| CN102151556B (en) * | 2011-01-29 | 2013-01-23 | 陕西科技大学 | Method for preparing magnetic gelatin microspheres and method for removing anionic dye by using same |
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2004
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Non-Patent Citations (3)
| Title |
|---|
| 砒霜磁性纳米微球的研制及表征 张东生，贾秀鹏，樊祥山，金立强，万美玲，李群慧，郑杰，顾宁，电子显微学报，第21卷第5期 2002 * |
| 纳米药物的研究进展 王子妤，张东生，东南大学学报（医学版），第23卷第2期 2004 * |
| 纳米药物的研究进展 王子妤，张东生，东南大学学报（医学版），第23卷第2期 2004;砒霜磁性纳米微球的研制及表征 张东生，贾秀鹏，樊祥山，金立强，万美玲，李群慧，郑杰，顾宁，电子显微学报，第21卷第5期 2002 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10111836B2 (en) | 2015-02-01 | 2018-10-30 | Orsenix Holdings Bv | High surface-area lyophilized compositions comprising arsenic for oral administration in patients |
| US10272045B2 (en) | 2015-02-01 | 2019-04-30 | Orsenix Holdings Bv | High surface-area lyophilized compositions comprising arsenic for oral administration in patients |
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| CN1593459A (en) | 2005-03-16 |
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