CN1068199C - Anti-cancer microballs and manufacture thereof - Google Patents
Anti-cancer microballs and manufacture thereof Download PDFInfo
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- CN1068199C CN1068199C CN96118931A CN96118931A CN1068199C CN 1068199 C CN1068199 C CN 1068199C CN 96118931 A CN96118931 A CN 96118931A CN 96118931 A CN96118931 A CN 96118931A CN 1068199 C CN1068199 C CN 1068199C
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Abstract
The present invention relates to a microballoon containing medicines for treating cancers and a preparation thereof. The microballoon is prepared by coating anticancer medicines and magnetic materials in a high molecular material CAP by using the CAP as substrate, the grain diameter of the microballoon is from 30 to 300 mum, the medicine content is from 4 to 6%, and the magnetic material content is from 0 to 56%; the microballoon is prepared with a solvent volatilization method at a preparation temperature of lower than 38 DEG C without adding crosslinking agents and water. The microballoon is mainly used as the embolism chemotherapeutant of the feeding arteries of tumors, can be used for treating liver cancer, lung cancer, renal carcinoma, breast cancer, tumors of pelvis, head and neck neoplasm, etc., and can be used to treat all malignant tumors caused by the embolisms of feeding arteries.
Description
The present invention relates to a kind of pastille microsphere and manufacture method thereof for the treatment of malignant tumor.
Cancer is a kind of serious threat human life's a malignant tumor, hepatocarcinoma for example, not only sickness rate height, and dangerous refractory, mortality rate height.General conventional therapy: excision, systemic chemotherapy, radiotherapy, Chinese medicine, laser, thermotherapy etc., curative effect is very poor, can not obviously prolong survival time of patients.
The discovery and the application of supply artery of the tumor embolism chemical therapeutic art make the treatment of hepatocarcinoma produce once big leap as hepatic artery embolism (HAE).This kind method is that cancer therapy drug, iodized oil, gelfoam etc. are injected from Hepatic artery, and the blood supply of blocking-up tumor makes the death of cancerous cell ischemia, excision of secondary operation then or the existence of band tumor.This kind method proves by a large amount of clinical practices, is the first-selected therapy for the treatment of hepatocarcinoma at present.But up to now, clinically adopt iodized oils, gelfoam particle, stainless steel coil, micro glass pearl more, from body sludged blood etc. as suppository.And iodized oil enters pulmonary circulation by sinus hepaticus easily, causes acute pulmonary embolism, so the consumption of iodized oil is subjected to strict restriction, this just causes the iodized oil thromboembolism incomplete, thereby causes tumor recurrence.Gelfoam and stainless steel coil can only the thicker blood vessels of thromboembolism, thereby cause huge strong thromboembolism syndrome, and bead in vivo can not degraded and absorbed, can not carry medicine, and is too short from the body sludged blood thromboembolism time, makes revascularization easily, tumor recurrence.Therefore, seek the key point that a kind of comparatively ideal suppository has become the treatment cancerous protuberance.
Purpose of the present invention promptly is to provide a kind of pastille microsphere and manufacture method thereof that can be used for the function admirable of cancerous protuberance feeding artery embolism chemical therapeutic.
As suppository, two crucial difficult problems of cancerous protuberance feeding artery Interruption and intra arterial chemotherapy art have successfully been solved with the pastille microsphere.Simple hepatic arterial blockage art can only cause the incomplete necrosis of tumor, the very fast foundation of its collateral circulation, and simple hepatic arterial infusion chemotherapy medicine is difficult to keep for a long time the high concentration of cancer therapy drug at target site again.The pastille microsphere then has above the two dual-use function simultaneously, wide field (Japanese cancer therapeutics meeting will, 1988 the 3rd phases) do with the pastille microsphere that the annual rate of depositing that the embolism chemical therapeutic agent makes hepatocarcinoma patient reaches 63% (mostly being end-stage patients) and the annual rate of depositing of hepatocarcinoma patient of early operation excision only is 28% (Ministry of Public Health publication " pharmaceutical information forum " newspaper, 1993 years report).
The manufacture method of pastille microsphere is a lot, as the method that is heating and curing, cross-linking agent solidification method, waves the molten coal polymerization of loosing, irradiation polymerization or the like (list of references 1.Chem Pharm Bull 1979; 27 (1): 204 2. medical industries 1987; 18 (12): 542 3. medical science ぁ ゅ body 1987; 141 (8): 495-496 4.J Pharm Pharmacol 1984; 36:803-807)
The weak point of above-mentioned manufacturing pastille micro-sphere method is: the method that is heating and curing easily causes the cancer therapy drug degeneration, and many cancer therapy drugs are understood decomposition and lost effect after temperature surpasses 100 ℃; The cross-linking agent solidification method must add cross-linking agent (as glutaraldehyde etc.), and many cancer therapy drugs are to the cross-linking agent sensitivity, as the medicine methotrexate that has an amido can be lost active anticancer with the glutaraldehyde reaction; The irradiation polymerization will be used expensive gamma-ray machine etc., and irradiation dose also is difficult for accurately grasping.And the general solvent polymerization of loosing of waving will be made oil-in-water (o/w) type emulsion earlier, medicine is leaked ooze in water, and loss is serious.
The manufacture method of pastille anti-cancer microballs of the present invention has overcome above-mentioned defective.It is characterized in that:
1, macromolecular scaffold (substrate) material selection can be in human body slow cellulose acetate-phthalate (the Cellulose Acetate Phthalate of degraded and absorbed.Abbreviation CAP) approval number: Shanghai Q/WS-1-918-80.
2, anticarcinogen is selected cisplatin, carboplatin, mitomycin, amycin, fluorouracil or the like for use, everyly in principle all can not select for use with the cancer therapy drug of substrate CAP and magnetic material, mixed solvent, dispersant, petroleum ether generation chemical reaction, content of dispersion is from 4% up to 60%, and adjustable extent is big.
3, magnetic material is selected Fe for use
3O
4, r-Fe
2O
3, FeCo alloy, reduced iron powder.The magnetic anti-cancer microballs that contains magnetic material can concentrate on the tumor target site rapidly under the guiding of external magnetic field, help treatment for cancer more.
4, the cancer therapy drug that is wrapped up in the microsphere can be a kind of, also can be two kinds or three kinds, if chemically reactive not between the medicine, as cisplatin microsphere, cisplatin-amycin microsphere, cisplatin-amycin-mitomycin microsphere etc.
5, in the process of whole manufacturing anti-cancer microballs, temperature is no more than 38 ℃, need not shine by any high-energy ray, does not add cross-linking agent, does not also add any distilled water or deionized water, also needn't make oil-in-water or water-in-oil emulsion.
6, dispersant is selected the liquid Paraffin that contains with 2% (V/V) surfactant sorbester p17 for use, and consumption is 4-6 a times of macromolecule glue, and the liquid Paraffin physicochemical property is reliable and stable, is difficult for and the anti-biochemical reaction of medicine.
7, solvent is selected the mixed solvent of acetone, dehydrated alcohol and butyl acetate for use, and its volume ratio is 4: 2: 1.
8, the content of macromolecular scaffold material C AP is 35～96% (W/W) in the microsphere, and the content of anticarcinogen is 4～60% (W/W), and the content of magnetic material is 0～56% (W/W), makes nonmagneticly when containing the medicine microsphere, and magnetic material can.
The manufacturing process of pastille microsphere of the present invention is as follows:
1, macromolecular material CAP is dissolved in the mixed solvent, room temperature was placed 24～48 hours under air-tight state, made macromolecular material fully be dissolved into the transparent glue of molecule state.Solvent is selected the above guaranteed reagent of analytical pure for use, and at aseptic in-house operation, is strictly on guard against that dust and foreign material fall into glue, and gelatin concentration is 6～8% (W/V), in promptly every 100ml glue, and pbz polymer material 6～8 grams.
2, anticarcinogen and the abundant microgranule of magnetic material are changed into granule below the 1 μ m; if anticarcinogen can dissolve in mixed solvent; then needn't micronize, but must be noted that medicine can not with macromolecular material, magnetic material and mixed solvent, dispersant and petroleum ether generation chemical reaction.
3, medicine after the micronize and magnetic material are joined in the macromolecule glue, air-tight state stirred 1 hour down, made it become the pastille glue of mix homogeneously, and room temperature is no more than 25 ℃ during operation, and avoids strong illumination as far as possible.
4, the dispersant-liquid Paraffin that contains 2% (V/V) surfactant sorbester p17, join in the circular band neck vial, neck finish diameter should be able to be inserted blade mixer and be advisable.Can not contain moisture content in the dispersant liquid Paraffin, otherwise dried in advance.
5, under stirring, slowly join in the dispersant macromolecule glue of pastille, mixing speed is controlled at 500～1000 rev/mins, speed can make microspherulite diameter diminish soon, speed can make microspherulite diameter become big slowly, require microspherulite diameter to be controlled at 30～300 μ m, after the microsphere molding, stop to stir.
6, isolate microsphere with centrifuging, dispersant inclines and back repetition reuse.Isolated microsphere with petroleum ether flushing 5 times, is put into drying baker, was warming up to 37 ℃ of dryings 6 hours, the pastille microsphere of favorable dispersibility.
Further specify content of the present invention below by embodiment:
Embodiment 1:
Get high-molecular bone frame material cellulose acetate-phthalate (CAP) 1500mg, be dissolved in the 20ml mixed solvent, in airtight glass container, placed 48 hours, CAP is fully dissolved, make concentration and be 7.5% glue.Get cisplatin 1000mg, be processed into the micropowder of particle diameter below 1 μ m, join in the CAP glue, under air-tight state, stirred 1 hour, make it become the pastille glue of content of dispersion 40% (W/W).Get dispersant liquid Paraffin 125ml, add sorbester p17 2.5ml, the liquid Paraffin that contains surfactant is injected in the circle band neck open bottles that capacity is 200ml again, bottleneck diameter is answered＞5.5cm.Insert and fixing agitator, connect the agitator motor power supply, rotational speed regulation to 600 rev/min, slowly add the pastille glue, and increasing rotating speed to 850 rev/min gradually, sampling 0.2ml examines under a microscope every about 5 minutes, if microspherulite diameter is excessive, suitably increase rotating speed, if microspherulite diameter is too small, suitably reduce rotating speed, require microspherulite diameter to be controlled in 75～300 mu m ranges, after treating microsphere hardening molding, stop to stir.The dispersion liquid that contains the molding microsphere moved on to carry out middling speed in the centrifuge centrifugal, incline and the liquid Paraffin on upper strata, microsphere after separating with petroleum ether flushing 5 times, is put into vacuum drying oven, be evacuated down to 0.01kPa, be warming up to 37 ℃, keep taking out after 6 hours, promptly get finely disseminated pastille microsphere, be divided into A level microsphere with sub-sieve: particle diameter 75～150 μ m, B level microsphere: 151～300 μ m, cisplatin content is 40% in the microsphere.
Embodiment 2:
Get CAP2000mg, dissolve in the 33.3ml mixed solvent, fully be dissolved into concentration and be 6% glue.Get each 1000mg of amycin, cisplatin and reduced iron powder, be processed into the following microgranule of particle diameter 1 μ m earlier, join in the glue mix homogeneously.Get the liquid Paraffin 160ml that contains 2% (V/V) sorbester p17, be injected in the circle band neck open bottles of 250ml, agitator speed is adjusted to 550 rev/mins, slowly inject and contain the glue of amycin, cisplatin and reduced iron powder, and increase rotating speed to 900 rev/min gradually, the control microspherulite diameter is within 30～150 mu m ranges, up to microsphere hardening molding, isolate microsphere with centrifuging,, insert with petroleum ether flushing 5 times
In the vacuum drying oven, be evacuated down to 0.01kPa, be warming up to 37 ℃, keep taking out after 6 hours, promptly get finely disseminated magnetic pastille microsphere.Be divided into A level microsphere with sub-sieve: particle diameter 30～75 μ m, B level microsphere: 76～150 μ m.Contain in the microsphere amycin, cisplatin, magnetic material each 20%.
The anti-cancer microballs that the present invention makes, compare with related documents (on the market not yet commodity selling) and to have the following advantages:
1, the microballoon forming temperature is low, without the high-energy ray irradiation, does not add crosslinking agent and solidifies, no Add water, oil-in-water not processed or water-in-oil emulsion do not damage the effective ingredient of cancer therapy drug, not yet Medicine is decomposed, to all suitable delivery of most anticarcinogens.
2, there is not the adding of water in the microballoon forming process, so drug loss is few, stable performance, Yield is also high.
3, macromolecular scaffold (matrix) material selection can be in human body the adjacent benzene that absorbs of slow degradation Dioctyl phthalate cellulose acetate (CAP). Making the host material of microballoon in the general document selects Maximum is gelatin, human albumin, ethyl cellulose etc., but gelatine microsphere is inhaled in human body Receive comparatively fast, the time of keeping reliable embolism is shorter, makes easily revascularization, so embolism need be many Inferior carrying out, and gelatin is easy and some anticarcinogen generation chemical reaction, (clinically should such as cis-platinum With broad-spectrum anti-cancer drug very widely), can make cis-platinum lose active anticancer. Human albumin is not Only the source is difficult for, and must solidify by high temperature (about 130 ℃), and anticarcinogen is decomposed. Second The absorption of can not degrading in vivo of base cellulose is a kind of " foreign matter " to human body. The present invention selects CAP be typically used as the dressing material of tablet, the present invention makes matrix with CAP, in blood vessel Can slowly absorb, can keep the reliable embolism of long period, can slowly discharge anticarcinogen again. And chemical reaction does not take place with most anticarcinogens in the CAP stable performance, and human body is not had Toxicity. It is the pharmaceutic adjuvant that the official approval of China hygiene department is produced.
4, dose and the magnetic material amount of microballoon delivery are moderate, content of dispersion and contain magnetic material amount adjusting range Can adapt to clinically different demands greatly.
5, microspherulite diameter is 30～300 μ m, divides and elects three grades as, A level microballoon: grain Footpath 30～75 μ m, B level microballoon: particle diameter 76～150 μ m, C level microballoon: Particle diameter 151～300 μ m. Can be respectively applied to the occlusion of bone tumors feeding artery far-end, in End, near-end are to clinical very practical.
Anti-cancer microballs of the present invention is not only applicable to liver cancer, is applicable to lung bronchogenic carcinoma, kidney yet Cancer, breast cancer, spleen tumor, tumor of pelvis, head and neck neoplasm, superficial tumor etc., in principle Every suitable malignant tumour of carrying out the supply artery of the tumor embolism all can be used of the present invention anti-The cancer microballoon.
When specifically using clinically, can be anti-cancer microballs of the present invention and lipiodol (as tracer With carry agent), the anticarcinogen of other conventional usefulness makes heterogeneous emulsion jointly. As with of the present invention Anti-cancer microballs 400mg, it is even to join in 5～8ml lipiodol suspendible, gets general anticarcinogen again Such as mitomycin 14mg, be dissolved in 15～25ml physiological saline, and add the tween type surface-active Agent 0.3ml dissolving is mixed and made into heterogeneous emulsion with the lipiodol microballoon, then from supply artery of the tumor Inject, have good embolism chemical therapeutic effect. If the use magnetic microsphere, can body surface corresponding to The magnet that tumor locus is placed 5000～8000GS guides, and makes microballoon rapidly accurate True target site, the better efficacy of concentrating on.
Claims (8)
1, a kind of anti-cancer microballs, polymer-based material by 35～96% and 4～60% anticarcinogen and 0～56% magnetic material are formed, it is characterized in that selecting for use cellulose acetate-phthalate to make host material, it is the anti-cancer microballs of 30～300 μ m that parcel anticarcinogen and magnetic material constitute particle diameter.
2, anti-cancer microballs according to claim 1, it is characterized in that anticarcinogen contained in the microsphere selects cisplatin or amycin, mitomycin, fluorouracil for use, everyly all can not select for use with the anticarcinogen of cellulose acetate-phthalate and magnetic material, mixed solvent, dispersant, petroleum ether generation chemical reaction.
3, anti-cancer microballs according to claim 1, the anticarcinogen that it is characterized in that in the microsphere being wrapped up can be a kind of, also can be two kinds or three kinds.
4, anti-cancer microballs according to claim 1, the magnetic material that it is characterized in that in the microsphere being wrapped up is selected Fe for use
3O
4Or r-Fe
2O
3, FeCo alloy, reduced iron powder.
5, a kind of method of making anti-cancer microballs as claimed in claim 1; it is characterized in that earlier cellulose acetate-phthalate being dissolved in the mixed solvent; be mixed with concentration and be 6～8% glue; in glue, add micronized anticarcinogen and magnetic material then; be mixed with mixed uniformly pastille glue; again the pastille glue is joined in the dispersant, make the anti-cancer microballs that particle diameter is 30～300 μ m by the control mixing speed.
6, the method for manufacturing anti-cancer microballs according to claim 5 is characterized in that in whole manufacture processes that temperature remains on below 38 ℃, and mixing speed is 500～1000 rev/mins.
7, the method for manufacturing anti-cancer microballs according to claim 5 is characterized in that described mixed solvent selects acetone, dehydrated alcohol and butyl acetate for use, and three's volume ratio is 4: 2: 1.
8, the method for manufacturing anti-cancer microballs according to claim 5 is characterized in that described dispersant selects liquid paraffin for use, wherein is added with the surfactant span of 2% (V/V)
80
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96118931A CN1068199C (en) | 1996-12-26 | 1996-12-26 | Anti-cancer microballs and manufacture thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96118931A CN1068199C (en) | 1996-12-26 | 1996-12-26 | Anti-cancer microballs and manufacture thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1185945A CN1185945A (en) | 1998-07-01 |
| CN1068199C true CN1068199C (en) | 2001-07-11 |
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| CN96118931A Expired - Fee Related CN1068199C (en) | 1996-12-26 | 1996-12-26 | Anti-cancer microballs and manufacture thereof |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100344277C (en) * | 2005-03-30 | 2007-10-24 | 深圳市人民医院 | Nano-magnetic medicinal microglobule, its preparation method and application |
| CN100355418C (en) * | 2005-10-14 | 2007-12-19 | 中山大学 | Magnetic nano-balls carried with cisplatin and its prepn. method |
| CN100428957C (en) * | 2006-08-07 | 2008-10-29 | 中国科学院广州化学研究所 | A fibroid magnetic medicament and preparation method thereof |
| CN101274985B (en) * | 2008-05-12 | 2011-04-20 | 武汉大学 | Magnetic cellulose microsphere, preparation thereof and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5824516A (en) * | 1981-08-06 | 1983-02-14 | Masao Sako | Microcapsule containing ferromagnetic material and its preparation |
| CN1124135A (en) * | 1993-12-30 | 1996-06-12 | 湖南医科大学附属第二医院 | Producing method for vascular embolism porcelain powder |
-
1996
- 1996-12-26 CN CN96118931A patent/CN1068199C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5824516A (en) * | 1981-08-06 | 1983-02-14 | Masao Sako | Microcapsule containing ferromagnetic material and its preparation |
| CN1124135A (en) * | 1993-12-30 | 1996-06-12 | 湖南医科大学附属第二医院 | Producing method for vascular embolism porcelain powder |
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| CN1185945A (en) | 1998-07-01 |
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