CN100586480C - A sodium alginate microsphere vascular embolizing agent containing water soluble drug, its preparation and application - Google Patents

A sodium alginate microsphere vascular embolizing agent containing water soluble drug, its preparation and application Download PDF

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CN100586480C
CN100586480C CN200610092123A CN200610092123A CN100586480C CN 100586480 C CN100586480 C CN 100586480C CN 200610092123 A CN200610092123 A CN 200610092123A CN 200610092123 A CN200610092123 A CN 200610092123A CN 100586480 C CN100586480 C CN 100586480C
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sodium alginate
water soluble
soluble drug
microsphere
human serum
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CN1879607A (en
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李小平
李新建
崔恒
魏丽惠
冯捷
郎景和
向阳
雷呈志
洪宏
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Beijing Shengyiyao Science & Technology Development Co Ltd
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Beijing Shengyiyao Science & Technology Development Co Ltd
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Abstract

The invention relates to a sodium alginate micro ball vessel suppository which contains soluble medicine, and relative preparation and application, wherein said agent can be divided into two kinds aswet ball and dry ball made from degradable biological material; said carrier comprises sodium alginate, blood serum albumin, chitose, or transparent sodium solution, via the static to be solidified with calcium ion, to be made into the micro ball at 20 mum-1000 mum. The inventive material has high mechanical strength, biological compatibility, biological degradability and stability. The inventioncan be used to cure the vessel suppository of variable cancers.

Description

A kind of sodium alginate micro ball vascular embolism agent and preparation and application that contains water soluble drug
Technical field
The present invention relates to vascular occlusive agent and preparation thereof and application, being particularly related to the degradable biomaterial microsphere vascular embolizing agent that contains water soluble drug is wet bulb and dry bulb two-form, its carrier comprises sodium alginate, human serum albumin, chitosan or sodium hyaluronate solution, under electrostatic effect, form curing with ionic calcium soln, under strongization of acetone, make the microsphere of 20 μ m--1000 μ m again, can be divided into the microsphere of the specification that differs in size as required.Can preserve by wet bulb, also available Refrigeration Technique will be with the medicine microsphere to make dry bulb and preserve.The microsphere that water soluble drug is manufactured does not also appear in the newspapers with the method for wet bulb preservation is at present domestic.The present invention is raw materials used to have good biocompatibility, and biological degradability through zoopery and clinical observation, is a kind of safe, effective, novel form that thromboembolism adds targeted chemotherapy.The solid tumor that is used for the treatment of the human or animal, as primary hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, bladder cancer, uterus carcinoma, ovarian cancer, the arterial thrombosis of various malignant tumor such as colorectal cancer and local targeting immunochemotherapy.
Background technology
Arsenic trioxide (Arsenic Trioxide, As 2O 3) be the effective constituent that mainly contains of Chinese medicine arsenicum, as existing more than the 2400 year history of medicinal application.Ancient Times in China just has utilization to contain the record that arsenic Chinese medicine carries out multiple disease treatment.Phase earlier 1970s, the scholar of Harbin Medical University is according to the cancer spirit I injection for treating leukemia of development among the people.Since in August, 1996 " science " magazine serve as that topic is introduced Chinese science man application As with " ancient medicine is emitted new brilliance " 2O 3Since the achievement in research of treatment acute promyelocytic leukemia (APL), arsenic preparation becomes one of focus of oncotherapy.The biological characteristics of arsenic preparation divides two aspects, is extremely toxic substance on the one hand, and cumulative action is arranged in vivo, can with the sulfydryl protein binding, influence the important enzyme system, thereby influence the cellular metabolism oxidizing process, bring out tumor simultaneously, but be not carcinogen; On the other hand, arsenic is the natural material that extensively is distributed in the environment, is present in the normal human as trace element, and total amount is about 14-21mg, is the necessary element of life, and an amount of arsenic can hemopoietic, promotes the cell growth.In antileukemie application, be clear superiority,, be difficult for bringing out DIC, do not cause severe infections and hemorrhage, can see through blood brain barrier etc. as no bone marrow depression.At solid tumor resisting such as anti-constitutional liver cancer, curative effect is obvious, and to the cancer cell selectivity height, toxic and side effects is little etc.
Studies show that both at home and abroad at present: As 2O 3To hepatocarcinoma, gastric cancer, cancer of pancreas, the esophageal carcinoma, colon cancer, pulmonary carcinoma, ehrlich ascites tumor, a large amount of solid tumors such as neuroblastoma, cervical cancer, ovarian cancer and breast carcinoma all have obvious inhibitory action.Domestic a plurality of in recent years report As of research unit 2O 3Safety and the effectiveness of treatment APL, the U.S. is carrying out the multicenter study of APL at present, further to determine As 2O 3Safety and the effectiveness of treatment APL.SDA approval As in 1999 2O 3Be national II kind new medicine, by the formal production and selling of Harbin Yida Pharmaceutical Co., Ltd., U.S. FDA is also ratified U.S. CellTherapeutic company in by the end of September, 2000 and is produced As in 2O 3Injection listing as recurrent APL second line treatment medicine, carrying out multiple myeloma, malignant lymphoma, the clinical trial of other malignant tumor such as MDS at present both at home and abroad.
Studies show that As 2O 3Mechanism of action be: 1, arsenical has certain cell toxicant (protoplasmic poison) effect, suppresses cell proliferation.Suppress the oncocyte nucleic acid metabolism, disturb the synthetic of DNA and RNA, Profilin is synthetic, and the mitosis of retardance cell is killed oncocyte thereby make; 2, cell death inducing, as by with contain sulfydryl (SH) material combines, influences mitochondrion transmembrane potential, downward modulation Bcl-2/Bax ratio, activates apoptosis effect molecule caspase3,8, Fas and Fas-L express aspects such as increase, Cytoplasmic Ca 2+ rising; 3, inducing cell differentiation in the leukemia research process, shows that it can induce the ripe differentiation of promyelocyte, but solid tumor cell report as yet; 4, the apoptosis of induction of vascular endothelial cell and inhibition angiogenesis.Analogy intelligence is brave to be waited arsenic trioxide to the apoptosis of human umbilical vein endothelial cell with suppress the angiogenesis research that experimentizes.The result shows As 2O 3Suppress HUVECs growth, cell death inducing, angiogenesis is had inhibitory action.
Huang Shouguo etc. are As relatively 2O 3With the comparative study of cisplatin to human oophoroma cell line 3AO effect, As 2O 3After the effect, S phase cell is by being obstructed, and morphological observation finds that cell is typical apoptotic cell feature.Compare As with cDDP 2O 3Ovarian cancer cell strain 3AO cell is had more effective growth inhibited effect and apoptosis-induced effect, and make the retardance of S phase cell.Research arsenic trioxide such as Wei state's celebrating and chemotherapeutics daunorubicin (DNR), cytosine arabinoside (Ara-C), harringtonine (H) and vincristine (VCR) are united the experimentation to acute non-promyelocytic leukemia vitro cytotoxicity.The result shows As 2O 3Do not have cross resistance with Ara-C, H and VCR, the part cross resistance is arranged with DNR; Can form new chemotherapy regimen with DNR, VCR etc., treatment is just controlled and refractory recurrence ANPL patient.Magnifying sunrise etc. is experimental subject with Proliferation of Human Ovarian Cell SKOV3, inquires into arsenic trioxide and unites the influence that radiation is killed tumor cell.Results suggest As 2O 3In the clinical practice dosage range, when uniting with conventional fractionated dose radiotherapy, being expected to has radiopotentiation preferably to tumor.
Zhu Hongli etc. inquire into VP16, As 2O 3And retinoic acid (ATRA) chemotherapeutics and cytokine IL2, IL6 and GMCSF are to mice T lymphoma cell effect of apoptosis, the result shows that chemotherapeutics and cytokine and time spent can lower the concentration of medicine trigger cell apoptosis, and the time that apoptosis is taken place shifts to an earlier date.Both have synergism in cell death inducing.The chemotherapeutics compatibility uses the treatment malignant lymphoma that certain experimental basis is provided.Employing arsenic trioxide such as Su Ying and interferon coupling are studied the effect of K562 and K562/ADM medicine-resistant cell line.As a result 2O 3Suppress K562, the proteic expression of K562/ADM cell Bcl-2, cell death inducing, and the metering time effect is arranged; IFN α-2b and As 2O 3Coupling can strengthen the effect to the K562 cell, and the K562/ADM cell is not seen obvious enhancement effect.Prompting As 2O 3Have K562, K562/ADM cell GST-π, the proteic expression of Bcl-2 and the cell death inducing effect of inhibition; The P-gp protein expression there is not obvious influence; IFN α-2b can strengthen its this effect to the K562 cell.Song Tiefang etc. adopt As 2O 3Unite the inhibiting research to the human hepatoma cell line HepG2 with tumor necrosis factor, the result shows As 2O 3Uniting with tumor necrosis factor has synergism, uses tumor necrosis factor or As more separately 2O 3Stronger apoptosis-induced effect is arranged.
At present the usage of arsenical mostly is parenteral administration as intravenous injection, intramuscular injection, local injection, intracavitary administration, Teat pipette administration and insertion administration.Zheng Mingyou etc. inquire into variable concentrations As 2O 3The inhibitory action of Arterial administration perfusion therapy liver transplantation tumor.Results suggest trans-hepatic artery perfusion As 2O 3Treatment rabbit Vx2 liver transplantation tumor has remarkable antitumor effect, and has dosage dependence characteristics.It induces apoptosis of tumor mainly to work by raising bax gene expression.Percutaneous transhepatic puncture intratumor injection arsenic trioxide cooperates hepatic arterial chemoembolization art treatment primary hepatocarcinoma under the super guiding such as Qi Xiaojun, results suggest primary hepatocarcinoma injection for curing associating arsenic trioxide curative effect is better than simple hepatic arterial chemoembolization art, is a kind of Therapeutic Method preferably.Zhu Anlong etc. study chemotherapy value and best medication thereof that arsenic trioxide carries out primary hepatocarcinoma.17 examples are not suitable for the hepatocarcinoma patient of operative treatment and do through thigh or axillary artery puncture, the position and the scope of the clear and definite tumor in hepatic arteriography (DSA) back, respectively on a liver left side, the liver right side, proper hepatic artery keep somewhere subcutaneous embedded device for casting (Micropump), then Micropump is connected with micro-injection pump, gives As 2O 3Continuum chemotherapy (20mg/ days, continuous 5 days).After 4 courses of treatment, 6 routine gross tumor volumes dwindle more than 50% as a result, do not have new focus and (PR=35.2%) occur; 8 examples are dwindled 10%～49% (obvious effective rate 41.1%), 1 routine no change, and 2 routine gross tumor volumes increase more than 25%, non-evident effect.As is used in prompting 2O 3The continuum chemotherapy has certain therapeutic value to solid tumor, and it is low to have a toxicity, the advantage of determined curative effect.
Common adverse effect: digestive tract reactions such as xerostomia, bitter taste, abdominal distention, skin pruritus, dermoreactions such as erythra, urinary system reactions such as face lower limbs edema, leukopenia etc., but rare clotting mechanism etc. appear in minority.Relevant its best dosage, the compatibility and the course of treatment require study.Outside the APL, which entity tumor is still to As 2O 3Responsive effectively whether safety such as acute and chronic arseniasis can cause the secondary tumor, whether can produce drug resistance, with uniting of other drug etc.
Tumor arterial thrombosis therapy is to inject embolization material in the arteriole of domination cancerous tissue, makes this place's arteriole generation mechanical type thromboembolism, reaches a kind of new therapy that suppresses the tumor growth purpose.Kato at first proposed the chemoembolization method in 1981, and chemotherapeutics and embolization material are effectively organically combined, and some inoperable malignant tumor are proposed new method.Domestic and international application chemoembolization therapy can be used for treatments such as hepatocarcinoma, renal carcinoma, tumor of pelvic cavity and tumor of head and neck clinically in recent years, receive curative effect preferably, but relapse rate is higher behind the thromboembolism.
Microball preparation be medicine with the suitable adjuvant grain by miniature technique for packing system through being 20-1000 μ m microsphere.Factors such as the curative effect of embolism microball and its particle diameter, skeleton degradation rate, medicine carrying and drug release rate thereof have much relations.Stop up the arteriole of domination cancerous tissue with the microball preparation that contains medicine, the thromboembolism position can continuous directed cancer target area release anti-cancer medicine, kill and wound cancerous cell, make medicine have targeting and controlled-release function, and having changed medicine distributes and kinetics in vivo, improve bioavailability of medicament, therapeutic effect is remarkable, and toxic and side effects reduces.
The microsphere class preparation that tumor arterial thrombosis therapy is selected for use should have following character: thromboembolism power is strong, and enough mechanical strengths and physical and chemical stability are arranged; Medicine discharges slowly and lastingly from carrier, can keep treatment concentration in the target area; Carrier can be lost gradually by body separates disappearance, has biocompatibility; No antigen, it is harmless etc. to body to be stranded in the target area for a long time.
Therefore, how to utilize the characteristic of degradable biomaterial, preparation Bao Zaicheng antineoplastic arsenic trioxide microsphere vascular embolizing agent; How to use it for the topochemistry treatment of tumor; The arsenic trioxide that the degradable biomaterial bag is carried; How to solve water soluble drug microsphere wet bulb and preserve the problem that does not leak outside; Just become this area and be badly in need of the problem of research.
Microball preparation is a medicine and the suitable adjuvant microsphere by miniature technique for packing system, medicine with the microspheres form administration after, can make medicine have targeting and controlled-release function, can change pharmaceutical in vivo dynamics simultaneously, improve its bioavailability, the reduction toxic and side effects.Microsphere chemotherapy blood vessel embolism is to make to contain near medicine microsphere aggregation arteries tumor to the kill mechanism of tumor cell, block the tumor tissues blood supply on the one hand, on the other hand, continue to discharge chemotherapeutics at tumor by local, bring out cancer cell-apoptosis effectively, finally cause the cancerous cell ischemia, anoxia necrosis and apoptosis.At present used clinically is arsenic trioxide injection, the very fast rising of blood plasma arsenic concentration behind the intravenously administrable, and rapid disperse is to surrounding tissue, can make the patient symptom of digestive tract occur, peripheral neuritis, xerosis cutis and pigmentation, even renal function injury or hydrothorax, untoward reaction such as ascites appear.The present invention is prepared into novel form with water soluble drug and some special carrier by certain chemistry, physical method---the water soluble drug sodium alginate micro ball vascular embolism agent.By zone or intervention approach solid tumor is treated, reduce dosage to reach, alleviate untoward reaction and improve the purpose of curative effect.
Summary of the invention
One of the object of the invention provides a kind of sodium alginate micro ball vascular embolism agent that contains water soluble drug.
Two of the object of the invention provides the preparation method of the sodium alginate micro ball vascular embolism agent that contains water soluble drug.
It is that wet bulb is preserved and dry bulb is preserved two kinds of dosage forms that three of the object of the invention provides the sodium alginate micro ball vascular embolism agent that contains water soluble drug.
Four of the object of the invention provides the sodium alginate micro ball vascular embolism agent that contains water soluble drug is used for the treatment of the human or animal in preparation solid tumor, as primary hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, bladder cancer, uterus carcinoma, ovarian cancer, colon cancer, the application in the medicine of the arterial thrombosis of various malignant tumor such as rectal cancer and local targeting immunochemotherapy.
Technical scheme of the present invention reaches by following technological means:
A kind of sodium alginate micro ball vascular embolism agent that contains water soluble drug is characterized in that: comprise combination drug carrier and water soluble drug, described combination drug carrier wraps up described water soluble drug.
A kind of optimal technical scheme is characterized in that: the scope of the weight ratio of described combination drug carrier and described water soluble drug is 3: 1～30: 1.
A kind of optimal technical scheme is characterized in that: described water soluble drug is arsenic trioxide, amycin, daunorubicin, mitomycin, fluorouracil, cisplatin, cyclophosphamide, vinblastine, vincristine, camptothecine.
A kind of optimal technical scheme, it is characterized in that: described combination drug carrier comprises the mixed liquor of sodium alginate, human serum albumin and chitosan or the mixture of sodium alginate, human serum albumin and hyaluronate sodium, wherein sodium alginate: the human serum albumin: the scope of the weight ratio between chitosan or the hyaluronate sodium is 1: 1: 0.1～1: 10: 0.9.
A kind of optimal technical scheme is characterized in that: the described sodium alginate micro ball vascular embolism agent that contains water soluble drug is to be stored in the central circle of divalent metal consolidation liquid or the micro gel bead or the microsphere of similar round.
A kind of optimal technical scheme is characterized in that: described divalent metal consolidation liquid is calcium chloride or barium chloride consolidation liquid.
A kind of optimal technical scheme is characterized in that: the particle size range of described micro gel bead or microsphere is at 20～1000 μ m.
A kind of optimal technical scheme is characterized in that: the described sodium alginate micro ball vascular embolism agent that contains water soluble drug is a powdery particles.
A kind of optimal technical scheme is characterized in that: the particle size range of described powdery particles is at 10～800 μ m.
A kind of preparation method that contains the sodium alginate micro ball vascular embolism agent of water soluble drug, its step is as follows:
(1) water soluble drug is weighed according to the above ratio, use dissolution with solvents; Get water soluble drug solution;
(2) sodium alginate, human serum albumin, chitosan or hyaluronate sodium were weighed by 1: 1: 0.1～1: 10: 0.9, use water dissolution, get sodium alginate, human serum albumin, chitosan or sodium hyaluronate solution respectively;
(3) with calcium chloride or barium chloride, water is mixed with the solution of 1～20% concentration, gets consolidation liquid;
(4) elder generation is with the water soluble drug solution of step (1) gained, and the human serum albumin solution of step (2) gained mixes, add sodium alginate soln and chitosan solution or sodium hyaluronate solution more successively, the gained mixed liquor is splashed into microsphere or the micro gel bead that forms circle or similar round in the described consolidation liquid by high-pressure electrostatic microsphere drop generating device at last;
(5) microsphere or the consolidation liquid decant in the micro gel bead of the circle that forms in step (4) the gained consolidation liquid or similar round are removed, must be contained the sodium alginate micro gel bead or the microsphere of water soluble drug;
(6) be 1: 0.5～100 mixed by acetone and step (3) gained consolidation liquid with volume ratio, the consolidation liquid that strengthened is poured in the sodium alginate micro gel bead or microsphere that contain water soluble drug of step (5) gained, keeps three minutes to 30 minutes;
(7) decant is removed the reinforcement consolidation liquid in the step (6), washs secondary at least with step (3) gained consolidation liquid; Pour an amount of liquid paraffin or the iodized oil storage liquid as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, water soluble drug sodium alginate micro gel bead or microsphere suspension.
A kind of optimal technical scheme, it is characterized in that: used high-pressure electrostatic microsphere drop generating device comprises in described (5) step: an electrostatic generator, on the described electrostatic generator positive and negative polarities are arranged, positive pole links to each other with the syringe needle of microinjection apparatus, negative pole is connected with stainless steel coil in being immersed in described consolidation liquid, water soluble drug, sodium alginate, human serum albumin, chitosan or hyaluronate sodium mixed solution are housed in the injection device, splash in the described consolidation liquid and form microsphere.
A kind of optimal technical scheme, it is characterized in that: the water soluble drug sodium alginate micro gel bead or the microsphere suspension 1-5 part of getting step (7) gained, water 1-3 part, 5-25% mannitol solution 10-30 part is mixed, put in the cryogenic refrigerator freezingly more than 2 hours, put then in the freezer dryer and promptly to get powdery particles in lyophilization 15-48 hour.
A kind of sodium alginate micro ball vascular embolism agent that contains water soluble drug is used for the treatment of primary hepatocarcinoma in preparation, pulmonary carcinoma, renal carcinoma, uterus carcinoma, ovarian cancer, and gastric cancer, bladder cancer, colon cancer, the application in the medicine of the arterial thrombosis of rectal cancer and local targeting immunochemotherapy.
Clinical practice: adopt intervention radiation or get involved ultransonic method, conduit is inserted the target organ feeding artery, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
If containing the sodium alginate micro ball vascular embolism agent of water soluble drug is powdery granule, to be kept at earlier then that dry bulb is dissolved in swelling in normal saline (wet bulb) in the hermetic container, add the contrast agent mix homogeneously (microsphere fully is suspended in the contrast agent) after an amount of or the dilution again, again under image documentation equipment monitors by the blood vessel of conduit super-selective thromboembolism at diseased region in slowly or slowly repeatedly injection (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
Sodium alginate pharmaceutical carrier of the present invention is a natural extract, be that β-D-mannitol and the α-L-gulose that extracts from the natural plants Brown algae mixes the polysaccharide sodium salt of forming, it is a kind of linear macromolecule, molecular weight 50,000-200,000 dalton, Hydration Force is strong, the water-soluble thickness colloid that forms is producing crosslinking curing between macromolecular chain under the calcium ion effect, can be processed into the wet microsphere or the solid-state-microspherical of different size specification circles or similar round according to clinical needs.This kind microsphere has excellent biological compatibility, and in living organism, calcium ion is separated out gradually, and microsphere takes off form nontoxic degraded in 3-6 month of chain with molecule.Do not produce chip during degraded, and can cause the permanent thromboembolism (when suppository reaches 2 months in blood vessel, the thrombosis in the patient's blood vessel and reach the purpose of permanent thromboembolism) of target organ blood vessel, and reach the purpose of treatment.
In the practical operation, stop up tumor or therapentic part small artery blood vessel on every side with this " biological multi-functional microsphere " embolism materials by physics, cause corresponding vascular occlusion, the blood that cuts off this position tissue supplies and nutrition, causes it because of hypoxic-ischemic atrophy and necrosis.Simultaneously also can be by reducing the blood confession of target organ, for operative treatment creates favorable conditions.This kind microsphere as the carrier that adds the oncotherapy medication, regularly, the location, directionally local lesion tissue is slowly discharged, thereby is improved curative effect greatly, reduce the toxic and side effects of medicine, have thromboembolism and medicament dual therapeutical effect.
The present invention is according to the antitumaous effect mechanism and the clinical practice situation of water soluble drug uniqueness, half interpenetrating network structure and degradable principle according to the biodegradation material microsphere, actual in conjunction with biodegradation material microsphere embolization agent application in the past, from safety, nontoxic, non-immunogenicity, hereditary-less toxicity, no genotoxicity, aspects such as non-carcinogenesis are considered.Select for use biodegradation material to add antineoplastic target medicine as carrier, regularly, fixed point, directed, regular part discharge the target medicine, killing tumor cell reaches therapeutic purposes.
The inventor is by discovering, earlier water soluble drug solution and human serum albumin solution are mixed, water soluble drug is adsorbed by the human serum albumin earlier, add sodium alginate soln and chitosan solution or sodium hyaluronate solution more successively, form mixed liquor, the gained mixed liquor is splashed into microsphere or the micro gel bead that forms circle or similar round in the consolidation liquid by high-pressure electrostatic microsphere drop generating device at last.Mix the network structure density that can make pharmaceutical carrier with sodium alginate and chitosan or hyaluronate sodium and increase, improve the difficulty of drug release; Solve a difficult problem that does not live with single carrier coated water-soluble pharmaceutical pack merely.
After water soluble drug solution and sodium alginate, human serum albumin, chitosan or water soluble drug solution and sodium alginate, human serum albumin and sodium hyaluronate solution mixing, the gained mixed liquor is splashed into microsphere or the micro gel bead that forms circle or similar round in the described consolidation liquid by high-pressure electrostatic microsphere drop generating device again; Wherein water soluble drug is preferentially adsorbed by the human serum albumin.
It is soluble in water to have finished water soluble drug in research biodegradation material coated water-soluble medicine microspheres target slow-release vascular occlusive agent process, entrapped water soluble drug microdroplet does not precipitate, can not form microsphere, step such as easily separate out, do the reinforcement consolidation liquid through adding special mix reagent-organic solvent-acetone, further solidify wet micro gel bead or wet microsphere, after adjusting concentration, frequency and speed, seal very goodly, microsphere is even, slyness, dispersion of medicine.Medicine is after microsphere carries, and the active group of protection medicine is kept intravital stability in interior environment, avoid water soluble drug to spill too quickly too early in body, reaches to meet the clinical practice needs.
The present invention contains the biodegradation material microsphere vascular embolizing agent of water soluble drug, and it is big to have a medicine microspheres drug loading, in vivo the holdup time long, have the narrow spectrum advantage of targeting again, become the most promising at present targeting drug release system.The microsphere particle surface that makes of biodegradation material has certain negative charge, repel each other between its granule, in use, should look the focus situation and select dosage, can select the method for intubate in intervention radiation or the operation for use, conduit is inserted target vessel, with syringe medicine microspheres and contrast agent are mixed behind the radiography, slowly inject, in conduit, do not condense not plugging.
The invention will be further described below by embodiment, but do not mean that limiting the scope of the invention.
The specific embodiment:
Embodiment 1:
The preparation of the sodium alginate micro ball of trioxygen-containingization two arsenic, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of arsenic trioxide and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available arsenic trioxide, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get arsenic trioxide and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned arsenic trioxide and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that get trioxygen-containingization two arsenic sink to below the container; The particle size range of microsphere is between 100～300 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere of trioxygen-containingization two arsenic of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, arsenic trioxide sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained arsenic trioxide sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 2 hours, put then that lyophilization promptly got the powdered microgranule in 15 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 75～150 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 2:
Contain the preparation of the sodium alginate micro ball of amycin, human serum albumin, hyaluronate sodium
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of amycin and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available amycin, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With water for injection dissolving human serum albumin 10 grams, get amycin and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 10 grams, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% barium chloride solution;
5. with water for injection dissolving 1 gram hyaluronate sodium, the sodium hyaluronate solution of preparation 0.2wt%;
6. mixed solution, sodium hyaluronate solution and the sodium alginate soln with above-mentioned amycin and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned barium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain amycin sink to below the container; The particle size range of microsphere is between 150～450 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 100 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain amycin of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of iodized oil as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid iodized oil with micro gel bead or microsphere, packing is preserved, amycin sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 5 parts of the sodium alginate micro ball suspensions of gained amycin of above-mentioned steps, 3 parts in water, 30 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 12 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 100～250 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 3:
Contain the preparation of the sodium alginate micro ball of daunorubicin, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of daunorubicin and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available daunorubicins, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get daunorubicin and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned daunorubicin and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain daunorubicin sink to below the container; The particle size range of microsphere is between 300～500 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 10 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain daunorubicin of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, daunorubicin sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained daunorubicin sodium alginate micro ball suspension of above-mentioned steps, 3 parts in water, 20 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 12 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 150～350 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 4:
Contain the preparation of the sodium alginate micro ball of mitomycin, human serum albumin, hyaluronate sodium
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of mitomycin and human serum albumin's mixed solution:
Take by weighing 70 milligrams of commercially available mitomycins, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With water for injection dissolving human serum albumin 1 gram, get mitomycin and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% barium chloride solution;
5. with 100 milligrams of hyaluronate sodiums of water for injection dissolving, the sodium hyaluronate solution of preparation 0.2wt%;
6. mixed solution, sodium hyaluronate solution and the sodium alginate soln with above-mentioned mitomycin and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned barium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain mitomycin sink to below the container; The particle size range of microsphere is between 20～50 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 100 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain mitomycin of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of iodized oil as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid iodized oil with micro gel bead or microsphere, packing is preserved, mitomycin sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 5 parts of the sodium alginate micro ball suspensions of gained mitomycin of above-mentioned steps, 3 parts in water, 30 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 12 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 10～35 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 5:
Contain the preparation of the sodium alginate micro ball of fluorouracil, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of fluorouracil and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available fluorouracil, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get fluorouracil and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned fluorouracil and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain fluorouracil sink to below the container; The particle size range of microsphere is between 500～700 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain fluorouracil of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, fluorouracil sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained fluorouracil sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 2 hours, put then that lyophilization promptly got the powdered microgranule in 25 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 350～500 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 5:
Contain the preparation of the sodium alginate micro ball of cisplatin, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of cisplatin and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available cisplatin, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get cisplatin and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned cisplatin and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain cisplatin sink to below the container; The particle size range of microsphere is between 700～900 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain cisplatin of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, cisplatin sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained cisplatin sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 10 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 500～700 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 5:
Contain the preparation of the sodium alginate micro ball of cyclophosphamide, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of cyclophosphamide and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available cyclophosphamide, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get cyclophosphamide and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned cyclophosphamide and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain cyclophosphamide sink to below the container; The particle size range of microsphere is between 800～1000 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain cyclophosphamide of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, cyclophosphamide sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained cyclophosphamide sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 10 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 600～750 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 5:
Contain the preparation of the sodium alginate micro ball of vinblastine, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of vinblastine and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available vinblastine, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get vinblastine and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned vinblastine and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain vinblastine sink to below the container; The particle size range of microsphere is between 300～500 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain vinblastine of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, vinblastine sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained vinblastine sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 10 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 150～250 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 6:
Contain the preparation of the sodium alginate micro ball of vincristine, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of vincristine and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available vincristine, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get vincristine and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned vincristine and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain vincristine sink to below the container; The particle size range of microsphere is between 300～500 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain vincristine of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, vincristine sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained vincristine sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 10 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 150～250 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Embodiment 7:
Contain the preparation of the sodium alginate micro ball of camptothecine, human serum albumin, chitosan
1, the preparation before the parcel:
1. the processing of glass drying oven:
With the glass drying oven airing that cleans up, be placed in the high temperature baking box in 300 degrees centigrade of bakings 3 hours down (degerming reduce phlegm and internal heat source);
2. the preparation of camptothecine and human serum albumin's mixed solution:
Take by weighing 700 milligrams of commercially available camptothecines, place in the above-mentioned glass drying oven, drip the water for injection dissolving; With 1000 milligrams of water for injection dissolving human serum albumins, get camptothecine and human serum albumin's mixed solution;
3. the preparation of sodium alginate soln:
Take by weighing the commercially available sodium alginate of 1 gram, place in the glass drying oven, stir on one side, add normal saline on one side, all dissolve until sodium alginate, get sodium alginate soln;
4. prepare 7% calcium chloride solution;
5. with 100 milligrams of chitosans of water for injection dissolving, the chitosan solution of preparation 0.2wt%;
6. mixed solution, chitosan solution and the sodium alginate soln with above-mentioned camptothecine and human serum albumin mixes, and gets mixed liquor;
7. draw step mixed liquor 6. with disposable sterilized injector, splash in the above-mentioned calcium chloride solution by high-pressure electrostatic microsphere drop generating device, the sodium alginate micro gel bead or the microsphere that must contain camptothecine sink to below the container; The particle size range of microsphere is between 300～500 μ m.
8. by acetone and step 4. the gained consolidation liquid be 1: 0.5 mixed with volume ratio, the consolidation liquid that strengthened is poured into step 7. in the sodium alginate micro gel bead or microsphere that contain camptothecine of gained, keeps three minutes to 30 minutes;
9. decant is removed the reinforcement consolidation liquid of step in 8., with step 4. the gained consolidation liquid wash secondary at least; Pour the storage liquid of an amount of liquid paraffin as micro gel bead or microsphere again into, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, camptothecine sodium alginate micro gel bead or microsphere suspension.
10. the freeze drying process of microsphere: get 9. 1 part of gained camptothecine sodium alginate micro ball suspension of above-mentioned steps, 1 part in water, 10 parts of mixing of mannitol solution were put in the cryogenic refrigerator freezing 10 hours, put then that lyophilization promptly got the powdered microgranule in 48 hours in the freezer dryer.
(11) with the upper solution decant of said vesse, following micro gel bead is put into oven drying, airtight preservation, the particle size range of gained powdered microgranule is between 150～250 μ m.Soak a few minutes with normal saline before using and be reduced into wet bulb.
After also can upper solution decant with said vesse, water flushing twice, the instant use.
Experimental example 1:
The application of the sodium alginate micro ball vascular embolism agent of trioxygen-containingization two arsenic
1. modelling of Hepar Leporis seu Oryctolagi cancer and application: purebred, cleaning 50 of new zealand white rabbits (providing), male and female inequality, 3～4 monthly ages, body constitution amount 2～3kg by Beijing Experimental Animal Center.
(2): experiment material: subcutaneous Vx2 transplanted tumor kind rabbit is provided by Beijing Medical University's ultrasound biological Graduate School of Engineering.Bcl2, bax immunohistochemical staining test kit are available from doctor's moral company, and VEGF immunohistochemical staining test kit is available from NeoMarker company.DAB colour reagent box, bonding die agent are available from new company advanced in years.Hepatic artery catheterization is available from BD company.
(3) experimental technique one: will be cut into 1～2mm3 tumor piece near the vigorous flesh of fish sample tissue of Vx2 transplanted tumor kind rabbit lump marginal growth, tumor mass is implanted in the left front leaf of liver.Form the tumor of the about 1cm infiltrative growth of a diameter after two weeks on the liver.The 2nd weekend of liver transplantation tumor postoperative is at Hepatic artery root puncture and intubation and fixing.The digital watch method is divided into laboratory animal 5 groups (every group of 10 animals) at random: negative control group (normal saline), positive controls (cisplatin 1.28mgkg-1d-1), experimental group 1 (As 2O 30.6mgkg-1d-1), experimental group 2 (As 2O 31.2mgkg-1d-1), experimental group 3 (As 2O 31.96mgkg-1d-1).Arterial administration perfusion every day embodiment 1 gained experimental drug is treated 7d continuously.The 5th week of liver transplantation tumor postoperative is last, cuts contiguous (1-5cm) tumor same area normal liver tissue and whole liver cancer tissue.Claim tumor heavy, get each 1 part of tumor and hepatic tissue light microscopic, electron microscope specimen.
(4) experimental technique two: purebred, cleaning 30 of new zealand white rabbits (providing) by Beijing Experimental Animal Center, and the male and female inequality, at 3～4 monthly ages, body constitution amount 2～3kg is divided into 3 groups at random, 10 every group.Make the Hepar Leporis seu Oryctolagi tumor model after two weeks, all through the right common femoral artery intubate to Hepatic artery, to the supply artery of the tumor administration:
(a) matched group: trans-hepatic artery injects normal saline 10ml; (b) blank microsphere embolization group: inject sodium alginate micro ball 5mg/kg; (C) arsenic trioxide sodium alginate micro ball embolization group: inject arsenic trioxide sodium alginate micro ball 5mg/kg.The 21st day liver spiral CT dynamic scan put to death animal, takes out liver, 10% formalin fixed.Multiple spot cuts tumor tissues, paraffin embedding, and pathological section, HE dyeing, microscope inspection calculates gross tumor volume.
(5) observation index:
The tumor weight of positive controls, experimental group and the heavy suppression ratio of average tumor thereof:
The heavy suppression ratio of average tumor=(the average tumor of the average tumor overabundant yin matched group of 1-administration group is heavy) * 100%.Transmission electron microscope observing: oncocyte, hepatocellular cell volume, nuclear morphology and nuclear chromatin change.Detect bcl2bax gene expression and vegf expression: wherein coloration result criterion bcl2bax gene expression: with endochylema or and the painted positive cell of brown xanchromatic oncocyte that is of after birth.Positive cell number＜5% is (-), and 5%～15% is (+), and 15%～50% is (++),＞50% be (+++).Vegf expression is new capillary vessel endotheliocyte and part tumor cell endochylema and or after birth is painted is brown positive cell.The obvious person that dyes is the VEGF positive, dyes weak or do not dye to be the VEGF feminine gender.
(6) statistical method: experimental data is represented with x ± s, with the capable q check of SAS8.1 statistical software, Fisher ' s Precision Test.The immunochemotherapy microsphere carries out the treatment of lotus human cervical carcinoma's nude mice through arterial thrombosis.
Experimental example 2:
Mice U14 cervical cancer transplanted tumor model
1. the U14 cervical cancer cell is diluted to 7 * 106/ml, after 34 mice right fores of the NIH mice axillary fossa district sterilization with average weight 18-22g, the above-mentioned tumor cell suspension 0.1ml/ of subcutaneous injection is (7 * 105/of cell number) only.3-4 is after week in growth, and transplantation tumor is taken off, and is cut into the tumor piece of 1mm * 1mm * 1mm size, is inoculated in once more under the leftlobe of liver tunicle of mice.
2. the treatment of lotus human cervical carcinoma's nude mice
Tumor piece injection inoculation is got former otch after 10 days once more, surveys plantation nodular maximum warp of tumor and minimum warp under operating microscope, parallel hepatic artery catheterization injection.Wherein animal is divided at random: A normal saline group; B IL-2 group; C IL-2 liposome group; The simple chemotherapy group of D; E IL-2+ chemotherapy group; F IL-2 liposome group+chemotherapy group.
Get 6 for every group after 2 weeks, measure plantation nodular maximum warp of tumor and minimum warp once more, calculate gross tumor volume, the comparison of tumor rate of growth.(wherein gross tumor volume rate of growth for treatment back volume divided by the treatment front volume), row HE dyeing observe the neoplasm necrosis degree (light: 0-30%, in: 30-70%, heavy: 71-100%) and the lymphocytic infiltration situation, the treatment back tumor-bearing rat nature time-to-live.
The rat liver cancer arterial thrombosis
3, rat implantation tumor liver cancer model is set up
Get inoculation Walker-256 oncocyte Wistar rat cancer ascites 0.5-1ml after 3-5 days, do not have that to be injected to healthy rat under the equal condition subcutaneous, 7-10 days can the about 1-2cm tumor of long diameter, cuts fresh fish sarcoid tissue and is cut into 1m 3Piece of tissue is inoculated into rats'liver left side siphonal lobe, is copied into the liver cancer model that diameter is 0.5-1cm after 1 week.Get 30 of liver cancer model rats.Under operating microscope, inject suppository with the PE-50 pipe, carry out hepatic artery embolism, temporary interruption common hepatic artery and ramus dexter arteriae hepaticae propriae in the time of injection through the retrograde proper hepatic artery that inserts of gastroduodenal artery.Injection finishes the back and finishes back stomach 12 intestinal arteries, closes abdomen, returns cage to raise.
Experimental example 2-7: carry out same test with the prepared sodium alginate micro ball vascular embolism agent that contains amycin, daunorubicin, mitomycin, fluorouracil, cisplatin, cyclophosphamide, vinblastine, vincristine, camptothecine of embodiment 2-7 respectively.
Clinical practice:
1, adopts intervention radiation or get involved ultransonic method, suffer from the patient of primary hepatocarcinoma with the sodium alginate micro ball vascular embolism agent treatment of trioxygen-containingization two arsenic of embodiment 1, conduit is inserted the target organ feeding artery, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
2, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from pulmonary carcinoma, conduit is inserted the target organ feeding artery with the sodium alginate micro ball vascular embolism agent that contains amycin of embodiment 2, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor three times with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
3, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from renal carcinoma, conduit is inserted the target organ feeding artery with the sodium alginate micro ball vascular embolism agent that contains daunorubicin of embodiment 3, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
4, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from uterus carcinoma, conduit is inserted the target organ feeding artery, action arteries and veins radiography with the sodium alginate micro ball vascular embolism agent of trioxygen-containingization two arsenic of embodiment 1, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
5, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from ovarian cancer, conduit is inserted the target organ feeding artery, action arteries and veins radiography with the sodium alginate micro ball vascular embolism agent of trioxygen-containingization two arsenic of embodiment 1, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
6, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from gastric cancer, conduit is inserted the target organ feeding artery, action arteries and veins radiography with the sodium alginate micro ball vascular embolism agent of trioxygen-containingization two arsenic of embodiment 1, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
7, adopt intervention radiation or get involved ultransonic method, for the patient who suffers from bladder cancer, conduit is inserted the target organ feeding artery with the sodium alginate micro ball vascular embolism agent that contains mitomycin of embodiment 4, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.
8, adopt intervention radiation or get involved ultransonic method, the sodium alginate micro ball vascular embolism agent that contains mitomycin of embodiment 4 is for suffering from colon cancer, the patient of rectal cancer, conduit is inserted the target organ feeding artery, action arteries and veins radiography, according to the radiography finding, the diameter of embolism microball is selected in decision for use.Use microtubular to surpass as far as possible and select thromboembolism, want the sterile working during use.Bottle cap is broken a seal, after staticly settling, Precerving liquid in the bottle (being consolidation liquid) is taken out the normal saline flushing microsphere three times that adds equivalent or Precerving liquid in the bottle (being consolidation liquid) taken out with syringe and add the equivalent normal saline, pour in the aseptic bowl together with normal saline and microsphere, discard flushing liquor one time with 50～60ml normal saline flushing microsphere, add contrast agent after an amount of or the dilution be mixed (microsphere fully is suspended in the contrast agent) again, perspective is looked concrete condition through conduit down and slowly or is slowly repeatedly injected (must guard against excessive thromboembolism), when the contrast agent flow velocity obviously slows down, promptly finish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.

Claims (12)

1, a kind of sodium alginate micro ball vascular embolism agent that contains water soluble drug, it is characterized in that: comprise combination drug carrier and water soluble drug, described combination drug carrier wraps up described water soluble drug, described water soluble drug is arsenic trioxide, amycin, daunorubicin, vinblastine or vincristine, described combination drug carrier is the mixed liquor of sodium alginate, human serum albumin and chitosan, or the mixture of sodium alginate, human serum albumin and hyaluronate sodium.
2, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 1, it is characterized in that: the weight ratio of described combination drug carrier and described water soluble drug is 3: 1～30: 1.
3, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 2, it is characterized in that: the weight ratio between described sodium alginate and the human serum albumin is 1: 1, described human serum albumin and chitosan, or the weight ratio between human serum albumin and the hyaluronate sodium is 1: 0.1.
4, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 3, it is characterized in that: the described sodium alginate micro ball vascular embolism agent that contains water soluble drug is to be stored in the central circle of divalent metal consolidation liquid or the micro gel bead or the microsphere of similar round.
5, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 4, it is characterized in that: described divalent metal consolidation liquid is calcium chloride consolidation liquid or barium chloride consolidation liquid.
6, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 5, it is characterized in that: the particle size range of described micro gel bead or microsphere is at 20～1000 μ m.
7, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 3, it is characterized in that: the described sodium alginate micro ball vascular embolism agent that contains water soluble drug is a powdery particles.
8, by the described sodium alginate micro ball vascular embolism agent that contains water soluble drug of claim 7, it is characterized in that: the particle size range of described powdery particles is at 10～800 μ m.
9, according to each described preparation method that contains the sodium alginate micro ball vascular embolism agent of water soluble drug among the claim 1-8, its step is as follows:
(1) described water soluble drug is weighed, use dissolution with solvents, get drug solution;
(2) take by weighing sodium alginate, human serum albumin, chitosan or hyaluronate sodium respectively; Weight ratio between wherein said sodium alginate and the described human serum albumin is 1: 1, weight ratio between described human serum albumin and described chitosan or the hyaluronate sodium is 1: 0.1, use water dissolution, get sodium alginate soln, human serum albumin solution, chitosan solution or sodium hyaluronate solution respectively;
(3) with calcium chloride or barium chloride, water is mixed with the solution of 1～20% concentration, gets consolidation liquid;
(4) elder generation is with the drug solution of step (1) gained, and the human serum albumin solution of step (2) gained mixes, add the sodium alginate soln of step (2) gained and the sodium alginate soln and the sodium hyaluronate solution of chitosan solution or step (2) gained more successively respectively, the gained mixed liquor is splashed into microsphere or the micro gel bead that forms circle or similar round in the described consolidation liquid by high-pressure electrostatic microsphere drop generating device at last;
(5) microsphere or the consolidation liquid decant in the micro gel bead of the circle that forms in step (4) the gained consolidation liquid or similar round are removed, must be contained the sodium alginate micro gel bead of water soluble drug or contain the sodium alginate micro ball of water soluble drug;
(6) by acetone and step (3) gained consolidation liquid be 1: 0.5～100 mixed with volume ratio, consolidation liquid is strengthened, be poured into the sodium alginate micro gel bead that contains water soluble drug of step (5) gained or contain in the sodium alginate micro ball of water soluble drug, kept three minutes to 30 minutes;
(7) decant is removed the reinforcement consolidation liquid in the step (6), washs secondary at least with step (3) gained consolidation liquid; Pour an amount of liquid paraffin or iodized oil storage liquid again into as micro gel bead or microsphere, be as the criterion in the middle of being fully immersed in the storage liquid liquid paraffin with micro gel bead or microsphere, packing is preserved, and gets water soluble drug sodium alginate micro gel bead suspension or water soluble drug sodium alginate micro ball suspension.
10, by the described preparation method that contains the sodium alginate micro ball vascular embolism agent of water soluble drug of claim 9, it is characterized in that: used high-pressure electrostatic microsphere drop generating device comprises in described (5) step: an electrostatic generator, on the described electrostatic generator positive and negative polarities are arranged, positive pole links to each other with the syringe needle of microinjection apparatus, negative pole is connected with stainless steel coil in being immersed in described consolidation liquid, water soluble drug is housed in the injection device, sodium alginate, the mixed solution of human serum albumin and chitosan, or water soluble drug is housed, sodium alginate, the mixed solution of human serum albumin and hyaluronate sodium splashes in the described consolidation liquid and forms microsphere.
11, by claim 9 or the 10 described preparation methoies that contain the sodium alginate micro ball vascular embolism agent of water soluble drug, it is characterized in that: the water soluble drug sodium alginate micro gel bead suspension or the water soluble drug sodium alginate micro ball suspension 1-5 part of getting step (7) gained, water 1-3 part, 5-25% mannitol solution 10-30 part is mixed, put in the cryogenic refrigerator freezingly more than 2 hours, put then in the freezer dryer and promptly to get powdery particles in lyophilization 15-48 hour.
12, be used for the treatment of primary hepatocarcinoma as each described sodium alginate micro ball vascular embolism agent that contains water soluble drug among the claim 1-8 in preparation, pulmonary carcinoma, renal carcinoma, uterus carcinoma, ovarian cancer, gastric cancer, bladder cancer, the application in the medicine of the arterial thrombosis of colon cancer or rectal cancer and local targeting immunochemotherapy.
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