CN101670095B - Pharmaceutical composition for treating embolism and preparation method thereof - Google Patents
Pharmaceutical composition for treating embolism and preparation method thereof Download PDFInfo
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- CN101670095B CN101670095B CN2009100818349A CN200910081834A CN101670095B CN 101670095 B CN101670095 B CN 101670095B CN 2009100818349 A CN2009100818349 A CN 2009100818349A CN 200910081834 A CN200910081834 A CN 200910081834A CN 101670095 B CN101670095 B CN 101670095B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 208000005189 Embolism Diseases 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 37
- 229920000642 polymer Polymers 0.000 claims abstract description 29
- 108700004675 bleomycetin Proteins 0.000 claims abstract description 26
- QYOAUOAXCQAEMW-UTXKDXHTSA-N bleomycin A5 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCNCCCCN)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QYOAUOAXCQAEMW-UTXKDXHTSA-N 0.000 claims abstract description 26
- 108010006654 Bleomycin Proteins 0.000 claims abstract description 21
- 229960001561 bleomycin Drugs 0.000 claims abstract description 21
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims abstract description 21
- 239000000178 monomer Substances 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 229920000249 biocompatible polymer Polymers 0.000 claims abstract description 8
- 239000002861 polymer material Substances 0.000 claims abstract description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 8
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- -1 acrylic ester Chemical class 0.000 claims description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 9
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 7
- 235000019394 potassium persulphate Nutrition 0.000 claims description 7
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- 206010006187 Breast cancer Diseases 0.000 claims description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 3
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- 239000004094 surface-active agent Substances 0.000 claims description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical group NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052684 Cerium Inorganic materials 0.000 claims description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002872 contrast media Substances 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
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- 239000000890 drug combination Substances 0.000 claims 1
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- 229940079593 drug Drugs 0.000 abstract description 11
- 238000011068 loading method Methods 0.000 abstract description 6
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- 230000003073 embolic effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006116 polymerization reaction Methods 0.000 abstract 2
- 239000003972 antineoplastic antibiotic Substances 0.000 abstract 1
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- 239000012531 culture fluid Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 5
- 208000001435 Thromboembolism Diseases 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 3
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- 206010003694 Atrophy Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
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- 230000000699 topical effect Effects 0.000 description 2
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- 230000001988 toxicity Effects 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010045168 Tumour embolism Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 229940057995 liquid paraffin Drugs 0.000 description 1
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- 230000001954 sterilising effect Effects 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Images
Abstract
The invention provides a pharmaceutical composition for treating embolism and a preparation method thereof, the pharmaceutical composition comprises a hydroxyl-contained biocompatible polymer material and a monomer containing unsaturated double bonds and anion groups, as well as a polymer generated by polymerization reaction of an optional vinyl monomer, wherein the polymerization is initiated through free radicles, and bleomycin or pingyangmycin is combined on the anion groups of the generated polymer. The preparation method combines the bleomycin or the pingyangmycin on a carrier of the polymer, thereby being capable of fully playing the dual effects of an anti-tumor antibiotic and a hardening agent owned by the bleomycin or the pingyangmycin during the embolism treatment. The anion part of the polymer can be properly combined with the bleomycin or the pingyangmycin which is rich in amino groups, thereby not only realizing the higher drug loading, but also leading the drug in an emboliaztion agent to be exchanged by cation in human body, and further realizing the slow release. In addition, the embolic carrier of the polymer has the advantages of simple prepration technology and low cost, thereby being applicable to large-scale industrial production.
Description
Technical field
The invention belongs to the interventional medicine field, relate to a kind of pharmaceutical composition that is used for the treatment of bolt base and preparation method thereof, be specifically related to a kind of pharmaceutical composition that comprises bleomycin or Bleomycin A5 that is used for embolotherapy and preparation method thereof.
Background technology
Intervention embolization is a kind of invasive Therapeutic Method that utilizes modern high tech method to carry out, and is meant under the guiding of medical imaging device, and suppository through accurate apparatuses such as special conduit, seal wires, is introduced human body and carried out topical therapeutic.The thromboembolism therapy all has better curative effect at aspects such as treatment hemangioma, hepatocarcinoma, hysteromyoma, malignant breast tumor, arteriovenous malformotion and hemostasis, has become the alternative medicine of part operative treatment.
With embolotherapy and cancer therapy drug chemotherapy combined treatment tumor, accepted extensively by the interventional therapy field.Normally carry out therapeutic alliance with chemotherapeutics solution and suppository, chemotherapy and embolotherapy synergism can improve the curative effect to tumor.Bleomycin is a kind of AGPM class medicine, and Bleomycin A5 is a kind of single component A5 in the multiple composition of bleomycin, and they can use as sclerosing agent.Sclerosing agent can impel thrombosis, improves the curative effect of embolotherapy.Particularly when bleomycin or Bleomycin A5 were used to treat tumor, they can also make to form thrombosis in the tumor except the function of performance AGPM killing tumor cell, so make that the tumor body hardens, atrophy and disappearing, further improve curative effect.Yet because the drug solution of bleomycin or Bleomycin A5 is short in the partial holdup time of thromboembolism, the rapid diffusion that has limited its therapeutical effect to tumor and vascular malformation, particularly medicine also can produce the whole body toxic and side effects.In addition, the curative effect of vascular malformation is poorer faster to VPV, therefore the bigger focus of scope is needed multiple dosing, has increased patient's misery.
Summary of the invention
Therefore; The invention provides the pharmaceutical composition that uses in a kind of interventional medicine embolotherapy field; Wherein more chemotherapeutics bleomycin or Bleomycin A5 are combined or be embedded in the micro polymer ball-type suppository, and make medicine controllably slowly be discharged into tumor locus, therefore can prolong topical remedy's action time and improve local drug concentration; Reduce systemic drug concentration simultaneously, reduce toxic and side effects.The present invention combines the medicine in micro polymer ball-type suppository and the polymer microballoon, has the multi-efficiency of thromboembolism, sclerosis blood vessel and treatment tumor.
Be used to realize that the technical scheme of above-mentioned purpose of the present invention is following:
A kind of pharmaceutical composition that is used for embolotherapy; This pharmaceutical composition comprises biocompatible polymer material that contains hydroxyl and the monomer that contains unsaturated double-bond and anionic group; And the polymer that generates of the polyreaction that causes through free radical of optional vinyl monomer, bleomycin or Bleomycin A5 are attached on the anionic group of polymer of generation.
In aforementioned pharmaceutical compositions, the biocompatible polymer material that contains hydroxyl can be preferably polyvinyl alcohol for polyvinyl alcohol, alginic acid, chitosan, cellulose or amylose; Anionic group can be selected from one or more in carboxylate anion, azochlorosulfonate acid anion, sulfate anion, phosphonate radical anion, nitrate anion, carbonate anion and the phosphate radical anion, is preferably carboxylate anion; Preferably, the monomer that contains unsaturated double-bond and anionic group is acrylic acid and/or acrylates.Vinyl monomer can be acrylamide, acrylonitrile, acrylic ester and/or styrene.
In a specific embodiments of the present invention; Pharmaceutical composition comprises the polymer that polyreaction that polyvinyl alcohol and acrylic acid or acrylates cause through free radical generates, and bleomycin or Bleomycin A5 are attached on the carboxylate anion of polymer of generation.
Above-mentioned polyreaction can also add cross-linking agent, N ' for example, N '-methylene-bisacrylamide; Above-mentioned initiator of polyreaction can be selected from azo class, per-compound etc., and for example azodiisobutyronitrile, N-nitroso-group anilid, Ammonium persulfate., potassium peroxydisulfate, hydrogen peroxide and/or quadrivalent cerium are preferably potassium peroxydisulfate.
In aforementioned pharmaceutical compositions, the polymer of generation is a microsphere, is preferably the microsphere that particle size range is 40～1500 μ m.
Aforementioned pharmaceutical compositions can also comprise preparation, for example contrast agent.
The present invention also provides aforementioned pharmaceutical compositions in preparation treatment tumor, the for example purposes in the medicine of hemangioma, hepatocarcinoma, hysteromyoma or malignant breast tumor.
The present invention also provides the purposes of aforementioned pharmaceutical compositions in the medicine of preparation treatment vascular malformation.
The present invention also provides a kind of method for preparing of aforementioned pharmaceutical compositions, and this method for preparing may further comprise the steps:
(1) employing inverse suspension polymerization method makes biocompatible polymer material that contains hydroxyl and the monomer that contains unsaturated double-bond and anionic group, and optional vinyl monomer generates polymer through the polyreaction that free radical causes;
(2) polymer that generates is placed the solution that contains bleomycin or Bleomycin A5.
Particularly, above-mentioned method for preparing may further comprise the steps:
(1) adopts the inverse suspension polymerization method; In the oil phase that contains surfactant (the for example mixture of span or span and tween) (for example mineral oil and/or with the immiscible organic solvent of water), feed nitrogen; To be dissolved with polyvinyl alcohol, acrylic acid, N ' then, the solution of N '-methylene-bisacrylamide and potassium peroxydisulfate dropwise adds in 50～70 ℃ the oil phase, adds tetramethylethylenediamine again after fully mixing; Stir down and isolate microsphere after the reaction; Clean, sieve out different size, collect the microsphere of each particle size range by size;
(2) blot microsphere surface moisture after, be placed in the solution that contains bleomycin or Bleomycin A5, soak the medicine that flush away surface, back do not exchange and promptly get.
The present invention has following beneficial effect:
1, bleomycin or Bleomycin A5 are attached to the polymer support that is used for embolotherapy; Can in the tumor embolism treatment, give full play to AGPM and the sclerosing agent double effects that bleomycin or Bleomycin A5 have, can also in the vascular malformation treatment, play the hardened effect of thromboembolism.
2, the present invention is directed to the polymer support that uses in the multiple embolotherapy and carried out a large amount of screenings; The selection result shows: for other polymer support; The biocompatible polymer material and the monomer that contains unsaturated double-bond and anionic group that contains hydroxyl of the present invention; And the polymer that generates of the polyreaction that causes through free radical of optional vinyl monomer; Particularly the anionicsite of the polymer that generates of the polyreaction that causes through free radical of polyvinyl alcohol and acrylic acid or acrylates can suitably combine with the therapeutic agent bleomycin or the Bleomycin A5 that are rich in amino group; Both can realize higher drug loading (up to 104mg/ml), the medicine in the suppository is exchanged by intravital cation, thereby discharge lentamente.
3, polymer plug preparing carriers technology used in the present invention is simple, and cost is low, is fit to large-scale industrial production, helps the clinical application of product.
4, the present invention makes microsphere type embolic agent through the inverse suspension polymerization reaction, and the microspherulite diameter scope is 40～1500 μ m, is more suitable in clinical practice.
5, medicine-carrying method of the present invention is simple, and medicine carrying dosage can be regulated within the specific limits, more helps satisfying the needs of clinical treatment.
Description of drawings
Fig. 1 has shown that year Bleomycin A5 microsphere is respectively at water and phosphate buffer (pH=7.4, the cumulative release degree in 154mM);
Fig. 2 has shown the influence of blank microsphere 50%, 100% lixiviating solution, feminine gender and the relative rate of increase of positive control pair cell.
The specific embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment with form or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall in protection scope of the present invention the details of technical scheme of the present invention.
Embodiment 1: the preparation of microsphere
A. the preparation of blank microsphere
Adopt the inverse suspension polymerization method, in there-necked flask, add the liquid paraffin and an amount of Span80 of 50ml, logical nitrogen; To be dissolved with polyvinyl alcohol, acrylic acid, N ' then; N '-methylene-bisacrylamide (cross-linking agent), the solution 12.5ml of potassium peroxydisulfate (initiator) dropwise are added in 55 ℃ the oil phase, behind the precrosslink 10min; Add tetramethylethylenediamine (catalyst) again, the stirring of 500rpm is isolated microsphere after reacting 4h down; Clean, sieve out different size, collect the microsphere of each particle size range by size.
B. the preparation of medicine carrying microballoons
Get the wet microsphere of 0.10ml, blot surface moisture after, place the Bleomycin A5 solution of 12mg/ml, soak after 2 hours under 4 ℃ of conditions, the medicine that does not exchange with deionized water flush away surface promptly gets.
Embodiment 2: the sign of microsphere
A. the form of microsphere and water-absorption characteristics
With the form of observation by light microscope microsphere and carry out grain diameter measurement,, investigate the water absorption rate and the swelling ratio of microsphere then with the microsphere lyophilization.The water absorption rate of microsphere is meant the ratio of absorb water the of poor quality of front and back and the preceding microspheres quality of suction, and swelling ratio is the particle diameter difference of swelling front and back and the ratio of the preceding microspherulite diameter of swelling.Computing formula is following:
Microspheres quality before water absorption rate=(microspheres quality before suction back microspheres quality-suction)/suction
Microspherulite diameter before swelling ratio=(the preceding microspherulite diameter of microspherulite diameter-swelling after the swelling)/swelling
Result: the microsphere outward appearance rounding that reaction makes.The water absorption rate of microsphere is 20.8g/g, and swelling ratio is 64.1%.
B. the mensuration of drug loading and envelop rate
Adopt the obtained the maximum absorption of determined by ultraviolet spectrophotometry Bleomycin A5 solution, set up standard curve equation C=0.0102A-0.0038 at the 291nm place.Before and after " preparation of medicine carrying microballoons " experiment, measure the absorption value of Bleomycin A5 in the solution respectively, calculate the content of Bleomycin A5 in the solution, calculate the drug loading and the envelop rate of microsphere by following formula.
Drug loading=(solution content of dispersion behind the preceding solution content of dispersion-medicine carrying of medicine carrying)/wet bulb volume
Solution content of dispersion * 100% before envelop rate=(solution content of dispersion behind the preceding solution content of dispersion-medicine carrying of medicine carrying)/medicine carrying
The result: the microsphere drug loading is 104mg/ml, envelop rate 86.7%.
C. the outer release of microsphere is measured
Adopt the in-vitro simulated microsphere dispose procedure of vibration dialysis.Get the microsphere 12mg that carries Bleomycin A5; Go in the bag filter with 1.0ml release medium solution (being respectively distilled water, phosphate buffer (PBS)) flushing, tighten at two ends, places the 20ml medium solution; In 37 ± 0.5 ℃, 100rpm constant temperature oscillator; Respectively 0.25,0.5,0.75,1,2,4,8,12, the 24h 1ml that takes a sample, replenish the medium of 1ml simultaneously rapidly, with the medium that takes out in 291nm place the mensuration ultraviolet absorption value.
Discharge with the PBS simulation, medicine is slow release from microsphere, and 24h cumulative release rate is 88.3%, t
50Be 2.19h.And in distilled water, medicine does not discharge basically, and is as shown in Figure 1.Respectively to the release dynamics of medicine carrying microballoons in PBS according to zero level, one-level and Higuchi equation model, the result shows that first _ order kinetics equation can well describe the release characteristic of microsphere, the release dynamics equation is ln (y
∞-y)=-0.2987t+4.5919 (R
2=0.9978).
D. the cell compatibility of blank microsphere
With 10% hyclone that contains two anti-DMEM HighGlucose as culture fluid, in 37 ℃, 5%CO
2Cultivate L929 cell line in the incubator.
The microsphere of will sterilizing is soaked in the culture fluid, and the volume ratio of microsphere and culture fluid is 1: 5,37 ℃ leave standstill 24h after, draw the sample of lixiviating solution as 100% concentration, half is diluted to the sample of 50% concentration with culture fluid with it.With the negative contrast of culture fluid, 0.64% the positive contrast of phenol culture fluid solution.
Took out culture plate respectively at the 1st day, the 3rd day, the 5th day behind the application of sample, absorb the sample lixiviating solution, add 10% trichloroacetic acid solution, in culture plate, back oven dry culture plate washes, dyes with cell fixation.Add Tris solution concussion dissolved cell, on immune ELIASA, survey absorption value with the 540nm wavelength.(Relative growth rate, RGR), the result is as shown in Figure 2 to calculate the relative rate of increase by following formula.
RGR=(A
Experiment-A
Blank)/(A
Contrast-A
Blank) * 100%
Morphological observation result shows that the equal indifference of cellular morphology of negative control group and two concentration experimental grouies is fusiformis or sealene triangle; Do not see cytopathy, atrophy or necrosis; From the 1st day to the 5th day, cell continued growing multiplication, and the area that covers culture plate is increasing.And the cell of positive controls is fragmented, no had significant proliferation, and cell density is no change almost.
The relative rate of increase of cell is converted into toxicity grading, the equal I level of the toxicity grading result of each concentration experimental group (RGR 75-99%), illustrative material has good biocompatibility.
Claims (17)
1. pharmaceutical composition that is used for embolotherapy; This pharmaceutical composition comprises biocompatible polymer material that contains hydroxyl and the monomer that contains unsaturated double-bond and anionic group; And the polymer that generates of the polyreaction that causes through free radical of optional vinyl monomer; Bleomycin or Bleomycin A5 are attached on the anionic group of polymer of generation
The said biocompatible polymer material that contains hydroxyl is a polyvinyl alcohol; The said monomer that contains unsaturated double-bond and anionic group is acrylic acid and/or acrylates.
2. pharmaceutical composition according to claim 1 is characterized in that, said vinyl monomer is acrylamide, acrylonitrile, acrylic ester and/or styrene.
3. pharmaceutical composition according to claim 1; It is characterized in that; Said pharmaceutical composition comprises the polymer that polyreaction that polyvinyl alcohol and acrylic acid cause through free radical generates, and bleomycin or Bleomycin A5 are attached on the carboxylate anion of polymer of generation.
4. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that said polyreaction adds cross-linking agent.
5. pharmaceutical composition according to claim 4 is characterized in that, said cross-linking agent is N ', N '-methylene-bisacrylamide.
6. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that said initiator is selected from azo class, per-compound.
7. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that said initiator is azodiisobutyronitrile, N-nitroso-group anilid, persulfuric acid by, potassium peroxydisulfate, hydrogen peroxide and/or quadrivalent cerium.
8. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that said initiator is a potassium peroxydisulfate.
9. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that the polymer of said generation is a microsphere.
10. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that the polymer of said generation is that particle size range is the microsphere of 40-1500 μ m.
11., it is characterized in that said pharmaceutical composition also comprises preparation according to each described pharmaceutical composition in the claim 1 to 3.
12. pharmaceutical composition according to claim 11 is characterized in that, said preparation is a contrast agent.
13. according to the purposes of each described pharmaceutical composition in the claim 1 to 12 in the medicine of preparation treatment tumor and vascular malformation.
14. purposes according to claim 13 is characterized in that, said tumor is hemangioma, hepatocarcinoma, hysteromyoma or malignant breast tumor.
15. according to each described preparation of drug combination method in the claim 1 to 12, this method for preparing may further comprise the steps:
(1) employing inverse suspension polymerization method makes biocompatible polymer material that contains hydroxyl and the monomer that contains unsaturated double-bond and anionic group, and optional vinyl monomer generates polymer through the polyreaction that free radical causes;
(2) polymer that generates is placed the solution that contains bleomycin or Bleomycin A5.
16. method for preparing according to claim 15 is characterized in that, said method for preparing may further comprise the steps:
(1) adopts the inverse suspension polymerization method, in the oil phase that contains surfactant, feed nitrogen, will be dissolved with polyvinyl alcohol, acrylic acid, N ' then; The solution of N '-methylene-bisacrylamide and potassium peroxydisulfate dropwise adds in 50-70 ℃ the oil phase; Add tetramethylethylenediamine again after fully mixing, stir down and isolate microsphere after the reaction, clean; Sieve out different size by size, collect the microsphere of each particle size range;
(2) blot microsphere surface moisture after, be placed in the solution that contains bleomycin or Bleomycin A5, soak the medicine that flush away surface, back do not exchange and promptly get.
17. method for preparing according to claim 16 is characterized in that, said surfactant is the mixture of span or span and tween; Said oil phase be mineral oil and/or with the immiscible organic solvent of water.
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| AT511671A1 (en) * | 2011-07-13 | 2013-01-15 | Bischof Georg Dr | COMPOSITION FOR GENERATING TEMPORARY OCCLUSION OF THE IMMUNE OF AN IMAGE AGENT |
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