CN102512692B - Tumor targeting embolization therapeutic composition and preparation method thereof - Google Patents
Tumor targeting embolization therapeutic composition and preparation method thereof Download PDFInfo
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- 230000001225 therapeutic effect Effects 0.000 title abstract description 4
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a tumor targeting embolization therapeutic composition and a preparation method thereof. The composition comprises the following ingredients: 1) polymers and 2) anti-tumor targeting medicine, wherein the polymers are generated by monomers containing unsaturated double bonds and anionic groups through polymerization reaction, and the anti-tumor targeting medicine is combined onto the anionic groups of the polymers. The anti-tumor targeting medicine is combined onto polymer carriers, and the efficacies of the anti-tumor targeting medicine of realizing the tumor targeting, not damaging the peripheral normal tissues, inhabiting the compensatory circulation and preventing the tumor recurrence can be fully realized in the chemoembolization. Compared with a medicine solution filling method, the preparation method has the advantages that medicine combined into the polymer carriers can be slowly released, the medicine can be maintained for a longer time at higher concentration in the local tumor part, the toxic or side effect of the medicine on the whole body is reduced, and the curative effect of the chemoembolization is improved.
Description
Technical field
The invention belongs to interventional medicine field, relate to a kind of tumor-targeted medicament composition for embolotherapy and preparation method thereof.
Background technology
Interventional therapy is 21st century development one of subject the most rapidly.With medical treatment and surgical intervention, run neck and neck at present, become the third therapy system.
Embolotherapy is the important component part of interventional therapy, belongs to invasive treatment.Embolotherapy is under the guiding of medical imaging device, and suppository is introduced to human body by the accurate apparatus such as special conduit, seal wire, artificially occluding vascular and the topical therapeutic that carries out.Thromboembolism therapy all has good curative effect at aspects such as treatment malignant tumor, hysteromyoma, hemangioma, vascular malformation and hemostasis, has become the alternative medicine of part operative treatment.
For some malignant tumor, as hepatocarcinoma, renal carcinoma, pulmonary carcinoma etc., once symptom appears in patient, its course of disease has entered middle and advanced stage mostly, has lost the chance of operative treatment.Clinical research shows, intervention embolization has become the therapeutic regimen of this type of advanced malignant tumor.
Embolotherapy can also carry out Comprehensive Treatment in conjunction with other treatment method, and as treatments such as combination with radiotherapeutic, chemotherapy or thermotherapies, its curative effect is better than simple embolotherapy.Wherein thromboembolism is clinically the method for common Comprehensive Treatment tumor in conjunction with chemotherapy, be called Chemoembolization (TACE), the method is suppository and chemotherapeutics solution to be injected to the small artery of tumor feeding, the blood of not only having blocked tumor for and also make chemotherapeutics direct effect to tumor by local.
Yet there is certain defect in this method, first, the drug solution that is filled into lesions position spreads rapidly, drug level sharply reduces, and medicine is very short in the local holdup time, has limited the therapeutical effect of medicine; The second, medicine easily enters whole body from part through blood circulation, causes the toxic and side effects of whole body; Three, common antitumor drug also causes certain toxic and side effects to local normal structure; Four, after thromboembolism operation, vasculai endothelium growth factor (VEGF) up-regulated, produces new vessels and also forms collateral circulation, can cause tumor to recover blood confession, tumor recurrence.
Chinese patent CN101670095A has described a kind of pharmaceutical composition of embolotherapy, the macromolecular material that this pharmaceutical composition includes hydroxyl with contain unsaturated double-bond and anionic monomer, and the polymer that forms of optional polymerization of vinyl monomer; Because medicine is only combined with anionic group, so the composition beyond unsaturated double-bond and anionic monomer has limited medicine carrying speed and the drug loading of polymer in this technology.
Summary of the invention
The present invention is surprised to find that, if remove macromolecular material in aforementioned pharmaceutical compositions, can make polyreaction faster, and drug encapsulation rate improves, and slow release effect is better simultaneously.Therefore, the invention provides a kind of tumor-targeted medicament composition using for interventional medicine field embolotherapy, wherein by more tumor-targeting drug in conjunction with or be embedded in micro polymer ball-type suppository, and make the controllably slow sustained release of medicine to thromboembolism position, therefore can the prolong drug local action time and improve local drug concentration, reduce systemic drug concentration, reduce toxic and side effects; And compare with common antitumor drug, in thromboembolism local organization, tumor-targeting drug is more directly applied to tumor tissues, not perilesional normal structure; Tumor-targeting drug can also stop collateral circulation to form, prevent tumor recurrence by suppressing angiogenesis.
Another object of the present invention is: the preparation method of described compositions is provided, and technique is simple, and cost is further reduced.
A further object of the present invention is: the application of described compositions is provided.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The invention provides a kind of tumor-targeted medicament composition for embolotherapy, this pharmaceutical composition comprises following component:
1) polymer that the monomer that contains unsaturated double-bond and anionic group generates by polyreaction;
2) antineoplastic target medicine;
Wherein, antineoplastic target medicine is attached on the anionic group of polymer of generation.
This pharmaceutical composition does not comprise other macromolecular materials, as the macromolecular material that contains hydroxyl.
In pharmaceutical composition of the present invention, 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 phosphate radical anion, is preferably carboxylate anion or azochlorosulfonate acid anion.
The monomer that contains unsaturated double-bond and anionic group is selected from acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid, sodium allylsulfonate and their combination.Preferably acrylic acid or acrylates, the preferred sodium acrylate of acrylates, particularly preferably be acrylic acid, acrylates, with being combined with of 2-acrylamide-2-methylpro panesulfonic acid, sodium allylsulfonate.
In pharmaceutical composition of the present invention, antineoplastic target medicine can be selected from one or more in Sutent (Sunitinib), gefitinib (Gefitinib), BAY 43-9006 (Sorafenib), imatinib (imatinib), PTK787 (Vatalanib) and salt thereof, is preferably Sutent and Sorafenib.
In pharmaceutical composition of the present invention, the weight proportion of above component is: 1 part of the monomer that contains unsaturated double-bond and anionic group, 0～5 part of medicine.
In specific embodiment of the invention scheme, aforementioned pharmaceutical compositions comprises the polymer that polyreaction that acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid, sodium allylsulfonate cause by free radical generates, and antineoplastic target medicine is attached on the carboxylate anion and/or azochlorosulfonate acid anion group of polymer of generation.
The present invention also provides a kind of preparation method of aforementioned pharmaceutical compositions, and this preparation method comprises the following steps:
(1) adopt the polyreaction that monomer that via Inverse-Phase Suspension Polymerization makes to contain unsaturated double-bond and anionic group causes by free radical to generate polymer;
(2) polymer of generation is placed in to the solution containing tumor-targeting drug.
The preparation method of preferred this law invention comprises the following steps:
(1) adopt via Inverse-Phase Suspension Polymerization, in the oil phase that contains surfactant, pass into nitrogen, then the solution that is dissolved with the monomer that contains unsaturated double-bond and anionic group, cross-linking agent, initiator is added in the oil phase of 50～70 ℃, after fully mixing, add catalyst, react and isolate microsphere after 3～5 hours, clean, by size, sieve out different size, collect the microsphere of each particle size range;
(2) blot after microsphere surface moisture, be placed in the solution containing antineoplastic target medicine, after immersion, wash away the medicine of surperficial not exchange and get final product.
Particularly preferred preparation method is as follows:
(1) adopt via Inverse-Phase Suspension Polymerization to prepare microsphere, first in the oil phase that contains surfactant, pass into nitrogen, monomer, the N that contains unsaturated double-bond and anionic group will be dissolved with again, the solution of N '-methylene-bisacrylamide and potassium peroxydisulfate dropwise adds in the oil phase of 50～70 ℃, after fully mixing, add again tetramethylethylenediamine, stir lower reaction and isolate microsphere after 3～5 hours, clean, by size, sieve out different size, collect the microsphere of each particle size range;
(2) blot after microsphere surface moisture, be placed in the solution containing antineoplastic target medicine, after immersion, wash away the medicine of surperficial not exchange and get final product.
Described cross-linking agent, is selected from: N, and N '-methylene-bisacrylamide, N, one or more in N '-diallyl tartaric acid diamides and glyoxal-bis acrylamide etc., are preferably N, N '-methylene-bisacrylamide;
Described initiator, is selected from: one or more in azodiisobutyronitrile, N-nitroso-group anilid, Ammonium persulfate., potassium peroxydisulfate, hydrogen peroxide and quadrivalent cerium, are preferably potassium peroxydisulfate;
Described catalyst, is selected from: tetramethylethylenediamine.
Described surfactant, is selected from: one or more in the mixture of spans and spans and Tweens.
Described oil phase, is selected from: mineral oil, vegetable oil, silicone oil and with the immiscible organic solvent of water in one or more.
Above component is respectively with respect to the addition of unsaturated double-bond and anionic group monomer by weight ratio: 0.0005～0.1 part of cross-linking agent, 0.0002～0.05 part of initiator, 0.05～0.2 part of catalyst, 0.01～0.3 part, surfactant, 4～25 parts of oil phases.
In aforementioned pharmaceutical compositions, preferably, the polymer of generation is microsphere, and more preferably particle size range is the microsphere of 10～2000 μ m.
Aforementioned pharmaceutical compositions can also comprise preparation, contrast agent for example, and its addition with respect to the monomer of unsaturated double-bond and anionic group is: 0～5 part.
The present invention also provides aforementioned pharmaceutical compositions for example, in preparation treatment tumor, the purposes in the medicine of hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor.
Polymer microballoon of the present invention is only formed by the monomer polymerization that contains unsaturated double-bond and anionic group, and the anion base mass contg of not pbz polymer material, so polymer microballoon of the present invention is higher; And because medicine is only combined with anionic group, so the medicine carrying speed of polymer microballoon of the present invention is faster, drug loading is higher.
Below data further illustrate beneficial effect of the present invention by experiment:
The microsphere that contains other macromolecular materials (prior art) that the microsphere of preparing by the embodiment of the present invention 1 method and Chinese patent CN101670095A describe compares, and microsphere prepared by the microsphere of under the same conditions being prepared by prior art and the present invention carries out respectively the medicine carrying experiment of Sunitinib malate:
The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml, obtains following result after mensuration:
A. the comparison of drug loading: the maximum drug loading of microsphere prepared by the present invention is 49.1mg/ml, the maximum drug loading of microsphere prepared by prior art is 43.2mg/ml.Visible, the drug loading of microsphere prepared by the present invention is greater than the drug loading 13.6% of microsphere prepared by prior art.
B. relatively seeing the following form of medicine carrying speed:
Table 1 medicine carrying percent (%)
Visible, microsphere medicine carrying speed prepared by the present invention obviously improves, and is conducive to improve the work efficiency of thromboembolism operation.
In the present invention, also the monomer containing acrylic anionic group and the monomer copolymerization containing sulfonic acid anion group are made to microsphere, with only containing the monomer of acrylic anionic group or only compare containing the polymer microballoon of the monomer of sulfonic acid anion group, the drug releasing rate of copolymerization microsphere falls between, therefore, regulate the proportion of composing of two kinds of monomers can realize different drug releasing rates.
Below data further illustrate beneficial effect of the present invention by experiment:
The assay method discharging according to embodiment 8 Chinese medicines, measure respectively the drug release percent of microsphere in embodiment 8,10 and 11, acrylic anionic group monomer in embodiment 8,10 and 11 and the weight proportion of sulfonic acid anion group monomer are respectively 1: 0,0: 1 and 1: 1.5, and its drug release percent sees the following form:
Table 2 drug release percent (%)
Visible, the proportion of composing of two kinds of monomers is different, and drug releasing rate is different.
The present invention finds through research, there is down the polymer obtaining in the monomer of the monomer of acrylic anionic group and sulfonic acid anion group simultaneously, also there is better elasticity, in preparation pharmaceutical composition of the present invention, effect is more excellent, both proportions can be 1-5: 1-5, preferably 1-2: 1-2, most preferably is 1: 1.5.
Wherein being combined with of acrylic acid and 2-acrylamide-2-methylpro panesulfonic acid is useful especially.Both proportions can be 1-5: 1-5, and preferably 1-2: 1-2, most preferably is 1: 1.5.
Therefore, the present invention has following beneficial effect:
1, neoplasm targeted therapy
The present invention is attached to the polymer support for embolotherapy by tumor-targeting drug, can in embolotherapy, give full play to the tumor-targeting that tumor-targeting drug has.Compare with using common antitumor drug in prior art, tumor-targeted medicament composition of the present invention has the molecular targeted therapy effect for tumor, does not damage tumor normal structure around.
2, prevent tumor recurrence
Tumor-targeted medicament composition of the present invention, can suppress side Zhi Xunhuan and form.Compare with using common antitumor drug in prior art, the present invention more effectively prevents tumor recurrence.
3, slow release effect improves
The present invention is directed to the polymer support using in multiple embolotherapy and carried out a large amount of screenings, the selection result shows: the polymer that the polyreaction that the monomer that contains unsaturated double-bond and anionic group causes by free radical generates, the anionicsite of the polymer that the polyreaction particularly causing by free radical with the monomer that contains sulfonic acid anion group containing the monomer of acrylic anionic group generates can be suitably combined with Sutent, BAY 43-9006 etc., has improved slow release effect.
4, the raising of medicine carrying speed and drug loading
Compared with prior art, the present invention has improved the content of the anionic group relevant to drug loading in polymer, thereby can realize higher medicine carrying speed and drug loading.
5, the present invention is by regulating the proportion of composing of different anions group monomer can realize different drug releasing rates.
6, polymer plug carrier preparation technology used in the present invention is simple, and cost is low, is applicable to large-scale industrial production, is conducive to the clinical application of product.
7, medicine-carrying method of the present invention is simple, and medicine carrying dosage can regulate within the specific limits, is more conducive to meet the needs of clinical treatment.
Accompanying drawing explanation
Fig. 1 has shown the release profiles of Sutent in the embodiment of the present invention 11 microspheres;
Fig. 2 has shown the release profiles of BAY 43-9006 in the embodiment of the present invention 13 microspheres;
The specific embodiment
Below in conjunction with specific embodiment, further describe the present invention, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
Embodiment 1: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, in there-necked flask, add 10 parts of liquid paraffin and appropriate Span80, logical nitrogen, then will be dissolved with 1 part of acrylic acid, 0.02 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.02 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 55 ℃, after precrosslink 10min, add again 0.14 part of tetramethylethylenediamine (catalyst), under the stirring of 500rpm, react after 4h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 2: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, in there-necked flask, add 12 parts of liquid paraffin and appropriate Span85, logical nitrogen, then will be dissolved with 1 part of acrylic acid, 0.04 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.04 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 65 ℃, after precrosslink 10min, add again 0.14 part of tetramethylethylenediamine (catalyst), under the stirring of 400rpm, react after 4h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 3: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span85 that in there-necked flask, add 10 parts, logical nitrogen, then will be dissolved with 1 part of 2-acrylamide-2-methylpro panesulfonic acid, 0.02 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.02 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 55 ℃, after precrosslink 10min, add again 0.14 part of tetramethylethylenediamine (catalyst), under the stirring of 500rpm, react after 4h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 4: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span85 that in there-necked flask, add 15 parts, logical nitrogen, then will be dissolved with 1 part of acrylic acid and 1.5 parts of 2-acrylamide-2-methylpro panesulfonic acids, 0.01 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.01 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 55 ℃, after precrosslink 10min, add again 0.09 part of tetramethylethylenediamine (catalyst), under the stirring of 500rpm, react after 5h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 5: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span80 that in there-necked flask, add 18 parts, logical nitrogen, then will be dissolved with 1.5 parts of acrylic acid and 1 part of 2-acrylamide-2-methylpro panesulfonic acid, 0.02 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.02 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 60 ℃, after precrosslink 10min, add again 0.15 part of tetramethylethylenediamine (catalyst), under the stirring of 600rpm, react after 3h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 6: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span80 that in there-necked flask, add 12 parts, logical nitrogen, then will be dissolved with 3 parts of acrylic acid, 1 part of sodium allylsulfonate, 0.01 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.02 part of Ammonium persulfate. (initiator) is dropwise added in the oil phase of 65 ℃, after precrosslink 10min, add again 0.1 part of tetramethylethylenediamine (catalyst), under the stirring of 400rpm, react after 4h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 7: the preparation of microsphere
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span80 that in there-necked flask, add 10 parts, logical nitrogen, then will be dissolved with 2 parts of acrylic acid, 1 part of sodium allylsulfonate, 0.006 part of N, N '-methylene-bisacrylamide (cross-linking agent), the solution of 0.04 part of potassium peroxydisulfate (initiator) is dropwise added in the oil phase of 60 ℃, after precrosslink 10min, add again 0.08 part of tetramethylethylenediamine (catalyst), under the stirring of 500rpm, react after 4h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of the particle size range such as 350～560 μ m and 560～710 μ m.
Embodiment 8: the microsphere that carries Sunitinib malate
Method according to embodiment 1 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml.
A. drug loading is measured:
(1) foundation of standard curve: Sunitinib malate storing solution is diluted to respectively to the sample solution of 3,6,9,12,15 and 18 μ g/ml, place measures its absorbance in 427nm absorption maximum.With drug level (C), absorbance (A) is made to linear regression, gained standard curve equation is: A=0.047C-0.017, R
2=0.9999.
(2) after medicine carrying, timing sampling 50 μ l dilute after suitable multiple, measure absorbance, by absorbance substitution standard curve calculation sample contained drug concentration at 427nm place.
(3) drug loading calculates: drug loading=(dose of the dose-sample time adding before medicine carrying in solution)/microsphere volume
B. the mensuration of drug release:
Adopt vibration dialysis, 1ml medicine carrying microballoons is placed in to bag filter, add 1ml pH7.4 phosphate buffer (PBS), sealing.Bag filter is put into 37 ℃, the PBS of 100ml, and hunting speed is 100 times per minute.Respectively 0,30,60,120,240,360,480min and 24,48,72,96,120,144h draw 5mL and discharge liquid, after suitable dilution, in 427nm place mensuration absorbance, and adds immediately the PBS of 5ml isothermal; By the absorbance substitution standard curve equation recording.
Calculate drug release percent, drug release percent=(cumulative release amount/drug loading) * 100%.
In the present embodiment, the maximum drug loading of microsphere is 49.1mg/ml, and 6 days discharge percent is 15.6%.
Embodiment 9: the microsphere that carries Sunitinib malate
Method according to embodiment 1 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 15mg/ml.
According to the method for embodiment 8, measure drug loading and the drug release percent of microsphere.
In the present embodiment, the maximum drug loading of microsphere is 73.6mg/ml, and 6 days discharge percent is 9.3%.
Embodiment 10: the microsphere that carries Sunitinib malate
Method according to embodiment 3 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml.
According to the method for embodiment 8, measure drug loading and the drug release percent of microsphere.
In the present embodiment, the maximum drug loading of microsphere is 45.8mg/ml, and 6 days discharge percent is 7.8%.
Embodiment 11: the microsphere that carries Sunitinib malate
Method according to embodiment 4 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml.
According to the method for embodiment 8, measure drug loading and the drug release percent of microsphere.
In the present embodiment, the maximum drug loading of microsphere is 47.3mg/ml, and 6 days discharge percent is 13.1%.
Embodiment 12: the microsphere that carries Sunitinib malate
Method according to embodiment 7 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml.
According to the method for embodiment 8, measure drug loading and the drug release percent of microsphere.
In the present embodiment, the maximum drug loading of microsphere is 49.0mg/ml, and 6 days discharge percent is 14.8%.
Embodiment 13: the microsphere that carries toluenesulfonic acid BAY 43-9006
Method according to embodiment 1 is prepared microsphere.The microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the toluenesulfonic acid BAY 43-9006 solution 5ml of 4mg/ml.
A. drug loading is measured:
(1) foundation of standard curve: toluenesulfonic acid BAY 43-9006 storing solution is diluted to respectively to the sample solution of 1,2,4,6,8 and 10 μ g/ml, place measures its absorbance in 265nm absorption maximum.With drug level (C), absorbance (A) is made to linear regression, gained standard curve equation is: A=0.0768C+0.0051, R
2=0.9999.
(2) after medicine carrying, timing sampling 50 μ l dilute after suitable multiple, measure absorbance, by absorbance substitution standard curve calculation sample contained drug concentration at 265nm place.
(3) drug loading calculates: drug loading=(dose of the dose-sample time adding before medicine carrying in solution)/microsphere volume
B. the mensuration of drug release:
Adopt vibration dialysis, 1ml medicine carrying microballoons is placed in to bag filter, add in the mixed liquor of 1ml pH7.4 phosphate buffer (PBS) and isopropyl alcohol (v/v=70/30) sealing.Bag filter is put into 37 ℃, the mixed liquor of 100ml, and hunting speed is 100 times per minute.Respectively 0,30,60,120,240,360,480min and 24,48,72,96,120,144,168,192,216h draw 5mL mixed liquor, after suitable dilution, in 265nm place mensuration absorbance, and adds immediately the mixed liquor of 5ml isothermal; By its standard curve equation of the absorbance substitution recording.
Calculate drug release percent, drug release percent=(cumulative release amount/drug loading) * 100%.
In the present embodiment, the maximum drug loading of microsphere is 15.7mg/ml, and 6 days discharge percent is 13.4%.
Claims (2)
1. for a tumor-targeted medicament composition for embolotherapy, this pharmaceutical composition comprises following component:
1) polymer that the monomer that contains unsaturated double-bond and anionic group generates by polyreaction;
2) antineoplastic target medicine;
This pharmaceutical composition does not comprise the macromolecular material that contains hydroxyl;
Wherein, antineoplastic target medicine is attached on the anionic group of polymer of generation;
Wherein, the monomer that contains unsaturated double-bond and anionic group described in is selected from acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid, sodium allylsulfonate; Described antineoplastic target medicine is selected from one or more in Sutent, gefitinib, BAY 43-9006, imatinib, PTK787 or its salt;
Its preparation method comprises the following steps:
(1) adopt via Inverse-Phase Suspension Polymerization, in the oil phase that contains surfactant, pass into nitrogen, then the solution that is dissolved with the monomer that contains unsaturated double-bond and anionic group, cross-linking agent, initiator is added in the oil phase of 50～70 ℃, after fully mixing, add catalyst, react and isolate microsphere after 3～5 hours, clean, by size, sieve out different size, collect the microsphere of each particle size range;
(2) blot after microsphere surface moisture, be placed in the solution containing antineoplastic target medicine, after immersion, wash away the medicine of surperficial not exchange and get final product;
In preparation method, described cross-linking agent is selected from: N, N '-methylene-bisacrylamide, N, one or more in N '-diallyl tartaric acid diamides and glyoxal-bis acrylamide;
Described initiator is selected from: one or more in azodiisobutyronitrile, N-nitroso-group anilid, Ammonium persulfate., potassium peroxydisulfate, hydrogen peroxide and quadrivalent cerium;
Described catalyst is selected from: tetramethylethylenediamine;
Described surfactant is selected from: one or more in the mixture of spans and spans and Tweens;
Described oil phase is selected from: mineral oil, vegetable oil, silicone oil;
Above component is respectively with respect to the addition of unsaturated double-bond and anionic group monomer by weight ratio: 0.0005～0.1 part of cross-linking agent, 0.0002～0.05 part of initiator, 0.05～0.2 part of catalyst, 0.01～0.3 part, surfactant, 4～25 parts of oil phases;
The particle size range of microsphere is 10～2000 μ m.
2. the preparation method of pharmaceutical composition claimed in claim 1, is characterized in that, step is as follows:
Adopt via Inverse-Phase Suspension Polymerization, the liquid paraffin and the appropriate Span85 that in there-necked flask, add 15 parts, logical nitrogen, then will be dissolved with 1 part of acrylic acid and 1.5 parts of 2-acrylamide-2-methylpro panesulfonic acids, 0.01 part of N, N '-methylene-bisacrylamide, the solution of 0.01 part of potassium peroxydisulfate is dropwise added in the oil phase of 55 ℃, after precrosslink 10min, add again 0.09 part of tetramethylethylenediamine, under the stirring of 500rpm, react after 5h, isolate microsphere, clean, by size, sieve out different size, collect 150～350 μ m, the microsphere of 350～560 μ m and 560～710 μ m particle size range, the microsphere 1ml that gets 150～350 μ m, puts into 10ml cillin bottle, adds the Sunitinib malate solution 5ml of 10mg/ml, washes away the medicine of surperficial not exchange and get final product after immersion.
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