CN101670095A - Pharmaceutical composition for treating embolism and preparation method thereof - Google Patents

Pharmaceutical composition for treating embolism and preparation method thereof Download PDF

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CN101670095A
CN101670095A CN200910081834A CN200910081834A CN101670095A CN 101670095 A CN101670095 A CN 101670095A CN 200910081834 A CN200910081834 A CN 200910081834A CN 200910081834 A CN200910081834 A CN 200910081834A CN 101670095 A CN101670095 A CN 101670095A
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pharmaceutical composition
bleomycin
polymer
anion
preparation
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CN101670095B (en
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范田园
袁惠燕
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Hygea Medical Technology Co Ltd
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Peking University
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Abstract

The invention provides a pharmaceutical composition for treating embolism and a preparation method thereof, the pharmaceutical composition comprises a hydroxyl-contained biocompatible polymer materialand 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 partof 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 andlow cost, thereby being applicable to large-scale industrial production.

Description

A kind of pharmaceutical composition that is used for embolotherapy and preparation method thereof
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 by 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 antitumor antibiotics 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 for the treatment of tumor, they can also make to form thrombosis in the tumor except the function of performance antitumor antibiotics 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 blood flow rate, 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 with more chemotherapeutics bleomycin or Bleomycin A5 in conjunction with 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 as follows:
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 by 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, acrylate 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 by 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, 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 preparation method of aforementioned pharmaceutical compositions, and this preparation method 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 by the polyreaction that free radical causes;
(2) polymer that generates is placed the solution that contains bleomycin or Bleomycin A5.
Particularly, above-mentioned preparation method may further comprise the steps:
(1) adopts the inverse suspension polymerization method, in the oil phase that contains surfactant (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, 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 medicine that flush away surface, back do not exchange promptly.
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 antitumor antibiotics 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 by free radical of optional vinyl monomer, particularly the anionicsite of the polymer that generates of the polyreaction that causes by 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), 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 by 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=7.4,154mM) the cumulative release degree in;
Fig. 2 has shown the influence of blank microsphere 50%, 100% lixiviating solution, negative 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 or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall within the scope of protection of the present invention the details of technical solution of the present invention and form.
Embodiment 1: the preparation of microsphere
A. the preparation of blank microsphere
Adopt the inverse suspension polymerization method, the liquid paraffin and an amount of Span80 that in there-necked flask, add 50ml, logical nitrogen, to be dissolved with polyvinyl alcohol then, acrylic acid, N ', 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, cleans, sieve out different size by size, collect the microsphere of each particle size range.
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 under 4 ℃ of conditions after 2 hours, the medicine that does not exchange with deionized water flush away surface is promptly.
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 as follows:
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 as follows.
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, place 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 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 substantially, 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 microplate reader, survey absorption value with the 540nm wavelength.(Relative growth rate, RGR), the result 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 the fragment shape, 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 (12)

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 by free radical of optional vinyl monomer, bleomycin or Bleomycin A5 are attached on the anionic group of polymer of generation.
2. pharmaceutical composition according to claim 1 is characterized in that, the described biocompatible polymer material that contains hydroxyl is polyvinyl alcohol, alginic acid, chitosan, cellulose or amylose, is preferably polyvinyl alcohol; Described anionic group is 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.
3. pharmaceutical composition according to claim 1 and 2 is characterized in that, the described monomer that contains unsaturated double-bond and anionic group is acrylic acid and/or acrylates.
4. according to each described pharmaceutical composition in the claim 1 to 3, it is characterized in that described vinyl monomer is acrylamide, acrylonitrile, acrylate and/or styrene.
5. according to each described pharmaceutical composition in the claim 1 to 4, it is characterized in that, described pharmaceutical composition comprises the polymer that polyreaction that polyvinyl alcohol and acrylic acid cause by free radical generates, and bleomycin or Bleomycin A5 are attached on the carboxylate anion of polymer of generation.
6. according to each described pharmaceutical composition in the claim 1 to 5, it is characterized in that described polyreaction adds cross-linking agent, N ' for example, N '-methylene-bisacrylamide.
7. according to each described pharmaceutical composition in the claim 1 to 6; it is characterized in that; described initiator is 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.
8. according to each described pharmaceutical composition in the claim 1 to 7, it is characterized in that the polymer of described generation is a microsphere, be preferably the microsphere that particle size range is 40~1500 μ m.
9. according to each described pharmaceutical composition in the claim 1 to 8, it is characterized in that described pharmaceutical composition also comprises preparation, for example contrast agent.
According to each described pharmaceutical composition in the claim 1 to 9 in preparation treatment tumor, for example hemangioma, hepatocarcinoma, hysteromyoma or malignant breast tumor, and the purposes in the medicine of vascular malformation.
11. according to each described preparation of drug combination method in the claim 1 to 9, this preparation method 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 by the polyreaction that free radical causes;
(2) polymer that generates is placed the solution that contains bleomycin or Bleomycin A5.
12. preparation method according to claim 11 is characterized in that, described preparation method may further comprise the steps:
(1) adopts the inverse suspension polymerization method, in the oil phase that contains surfactant (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, 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 medicine that flush away surface, back do not exchange promptly.
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CN102250277A (en) * 2011-05-17 2011-11-23 郑隆泗 Macromolecular polymer capable of carrying medicine and used for embolism
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CN102784112B (en) * 2011-05-19 2014-08-06 东华理工大学 Preparation method for porous slow-release microsphere of chitosan graft copolymer
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