CN103239730B - Medical sodium alginate gel microsphere and preparation method and application thereof - Google Patents
Medical sodium alginate gel microsphere and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a medical sodium alginate gel microsphere and a preparation method and application of the medical sodium alginate gel microsphere. The medical sodium alginate gel microsphere consists of a composite medicine carrier and a water-insoluble medicine; the medicine is coated with the composite medicine carrier; and the composite medicine carrier is an ion crosslinking agent-sodium alginate-divalent metal ion, wherein the ion crosslinking agent is 4-aminomethylbenzoic acid or tranexamic acid. The preparation method comprises the following steps of: (1) mixing ion crosslinking agent aqueous solution with divalent metal ion solution in the same volume to obtain composite solidifying liquid; (2) dispersing medicine powder or an agent into sodium alginate aqueous solution; uniformly mixing; dropwise adding the mixture into the composite solidifying liquid obtained in step (1) through a high-voltage static droplet generating device or a syringe needle, so that the mixture drops are solidified into spheres; and (3) dehydrating gel microspheres which are washed with the distilled water; and drying at normal temperature. The medical sodium alginate gel microsphere can be used for treating tuberculosis, endocrine disease and tumor, and also can be used for treating local acute hemorrhage and chronic errhysis.
Description
Technical field
The present invention relates to a kind of medical sodium alginate gel microsphere and its preparation method and application.
Background technology
Since O ' Shea in 1986 etc. have made alginate-polylysine-Sargassum sodium (APA) microsphere (capsule), this microsphere becomes the most ripe medical microsphere (capsule) (O ' Shea GM of current development with its good biocompatibility, Sun AM.Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice.[J] .J Am Diabetes Assoc, 1986,35:943.).In recent years, people attempt to adopt other method and material development new medical microsphere (capsule), Microspheres Technique improves some biologys and the chemical characteristic of microsphere, so that can be controlled at the treatment of metabolic disease, medicament slow release, be used widely in body and the field such as cell in vitro cultivation.
Alginate is a kind of anionic polyelectrolyte polysaccharide, and alginic acid monovalent salt aqueous solution can form recessive physical gel by intermolecular interaction, and sodium alginate colloidal sol is splashed into divalent metal (Ca
2+, Sr
2+, Ba
2+deng) solution, can form and take chelation as main gel micro-ball.Bivalent metal ion (the Ca that this application is single
2+, Sr
2+, Ba
2+deng) crosslinked sodium alginate micro ball, enter in organism, be exposed in monovalent cation solution environmental, owing to there being ion exchange, the just corrosion fast of sodium alginate gel microsphere, causes burst drug release phenomenon to occur.Prominent release phenomenon and refer to that medicine is discharged at short notice in a large number, this phenomenon often appears at the initial period of drug release, may cause blood drug level in body suddenly raise and produce untoward reaction.And the burst drug release phenomenon of medicine carrying gel micro-ball preparation is insoluble problem always, wherein particularly evident with the burst drug release of medicine carrying sodium alginate micro ball preparation.For targeted sustained release microsphere, will cause the minimizing of target site active drug amount, finally weaken the targeting of microball preparation.Therefore, how effectively to reduce the burst drug release of sodium alginate micro ball, it is the direction that pharmaceutics worker makes great efforts research that the control that realizes medicine discharges always.
Affect a lot of because have of sodium alginate micro ball Chinese medicine rate of release, comprise the character of polymer, the character of medicine, the preparation method of drug loading and microsphere etc.But after all, these factors are all to change microsphere surface pattern and medicine decides the release performance of medicine in the distribution situation of microsphere by chemical crosslinking.The universal method that solves at present burst drug release is to introduce polycationic polymer in sodium alginate micro ball, as chitosan and polyamino acid (poly ornithine or polylysine).Polycationic polymer can form compound polyelectrolyte film on sodium alginate micro ball surface by electrostatic interaction, both stability and the drug loading of microsphere can have been improved, again can regulating drug release, and the pH dependency of strengthening alginate, can weaken the sodium alginate gel microsphere corrosion that ion exchange causes simultaneously.Its medicament slow release principle is: when drug release, microsphere outermost layer is that the chitosan or the polyamino acid that are settled out are outer, does not generally contain encapsulated medicine; Middle level is dispersed the have chitin-sodium alginate of encapsulated medicine or the composite membrane of polyamino acid-sodium alginate; Inner core is the dispersed alginate core material that has encapsulated medicine.(Murata，Y.，Tsumoto，K.，Kofuji，K.，Kawashima，S.，2002.Effect?of?natural?polysaccharide?addition?on?drug?release?from?calcium-induced?alginate?gel?beads.Chem.Pharm.Bull.，2002，51：218-220.)。Yet above-mentioned compound polyelectrolyte membrane permeability is higher, the scope of application is narrower, can not control small-molecule drug and discharge, and only limits to coated cell, vaccine and polymer drug.Prepare the polylysine material price that compound polyelectrolyte film more often adopts very expensive, be difficult to be applied in large-scale industrial production.
In addition, sodium alginate gel microsphere is also used for hemostasis and chemotherapy of tumors as vascular occlusive agent.The sodium alginate gel microsphere vascular suppository (KMG) of Discussion on Chinese Listed there is no dry glue type granular preparation at present, can only be stored in bivalent cation solution with the glue type gel micro-ball form that wets, before using, must wash through normal saline, to remove bivalent cation unnecessary in sodium alginate gel microsphere.But during clinical practice, easily there is germ contamination in washing sodium alginate gel microsphere, brings inconvenience and medical safety hidden danger to user.
Summary of the invention
One of object of the present invention is to provide a kind of medical sodium alginate gel microsphere, this gel micro-ball is to combine the medicine carrying sodium alginate gel microsphere that uses amphion cross-linking agent and bivalent metal ion to prepare, can effectively control small-molecule drug slow release, medical usage is extensive.
Another object of the present invention is to provide a kind of preparation method of described medical sodium alginate gel microsphere, adopt new ionomer technique, the problems that exist at aspects such as production, packing and application to solve the crosslinked sodium alginate gel microsphere of bivalent cation.
Another object of the present invention is to provide the application in the medicine for the preparation of the local acute hemorrhage for the treatment of and chronic oozing of blood as slow release or controlled release form of a kind of described medical sodium alginate gel microsphere.
A further object of the present invention is to provide the application in the medicine for the preparation for the treatment of tuberculosis, tumor and endocrinopathy as injectable sustained-release or controlled release drug of a kind of medical sodium alginate gel microsphere.
For achieving the above object, the present invention is by the following technical solutions:
A kind of medical sodium alginate gel microsphere, comprise combination drug carrier and water-insoluble drug, wherein said combination drug carrier bag carries described water-insoluble drug, described combination drug carrier is ion crosslinking agent-sodium alginate-bivalent metal ion, and ion crosslinking agent is wherein Aminomethylbenzoic Acid or to aminomethyl naphthenic acid.Aminomethylbenzoic Acid and to aminomethyl naphthenic acid medically generally as hemorrhage.
Described bivalent metal ion is Ca
2+, Ba
2+and Sr
2+in one or more.
Described medical sodium alginate gel microsphere intermediate ion cross-linking agent Aminomethylbenzoic Acid or the mass fraction 14.0～68.0wt% to the mass fraction 1.0～5.0wt% of aminomethyl naphthenic acid, sodium alginate, mass fraction 20.0～the 65.0wt% of water-insoluble drug, the mass fraction 4.0～16.0wt% of water.
Described water-insoluble drug comprises rifamycin drug (as rifapentine and Mycobutin), antitumor drug (as paclitaxel), steroid hormone (as estradiol, hydrocortisone and testosterone) and diosmin.
A preparation method for described medical sodium alginate gel microsphere, is characterized in that, comprises the following steps:
(1) Aminomethylbenzoic Acid that is 0.5～3.0wt% by concentration or the divalent metal saline solution equal-volume that is 2.0～6.0wt% with concentration to the aqueous solution of aminomethyl naphthenic acid mix, and obtain composite solidification liquid;
(2 wish bag medicine carrying powder or medicament are distributed in the sodium alginate aqueous solution of 1～4wt% in the ratio of mass fraction 0.1%～8.0wt%, after mix homogeneously, by high-pressure electrostatic drop generating device and syringe needle, splash in the composite solidification liquid of step (1) gained, drop is solidified into rapidly gel micro-ball;
(3) gel micro-ball is detained after 1～24h in composite solidification liquid, and gel micro-ball is filtered, and proceeds in the divalent metal saline solution of 2～6wt%, continues to solidify 0.5～4h;
(4) collect gel micro-ball, through distilled water wash 1～3 time, dehydration, dry, obtains described medical sodium alginate gel microsphere, and particle size range is 80 μ m～1000 μ m.
The present invention using hemorrhage Aminomethylbenzoic Acid or to aminomethyl naphthenic acid as novel ion crosslinking agent, for large-scale production sodium alginate gel microsphere technique.Aminomethylbenzoic Acid and the special acid that is synthetic to aminomethyl naphthenic acid, its Molecular Geometries is extremely similar to lysine residue (monomer) in polylysine macromole, for ampholyte, can in sodium alginate micro ball, form compound polyelectrolyte by stronger electrostatic interaction, greatly degree has improved molecule crosslinked effect in sodium alginate micro ball.In addition, because Aminomethylbenzoic Acid and aminomethyl naphthenic acid is introduced to phenyl ring or 6 carbocyclic rings between the amino of amino acid structure and carboxyl, can effectively overcome amino acid derivativges because of the participation of contiguous amino with carboxyl, and under weakly acidic condition the shortcoming of facile hydrolysis, improve this aminoacid cross-linking agent chemical stability.Therefore, adopt it as ion crosslinking agent, can obviously improve pliability and the chemical stability of sodium alginate gel microsphere.
The present invention also provides the application in the medicine for the preparation of topical therapeutic acute hemorrhage and chronic oozing of blood as slow release or controlled release form of described medical sodium alginate gel microsphere.Sodium alginate gel microsphere of the present invention is specially adapted to treat arterial hemorrhage, has hemostasis fast, eutherapeutic feature.Aminomethylbenzoic Acid-sodium alginate cross-linking microsphere of preparing by the present invention is effectively better than common suppository-sodium alginate embolism microball at viscoelasticity, tack, swelling ratio and thromboembolism aspect the time.After Aminomethylbenzoic Acid/enter in body to aminomethyl naphthenic acid-sodium alginate cross-linking medicine carrying microballoons, abnormal bleeding to when operation, the various diseases such as department of obstetrics and gynecology and postpartum hemorrhage and hemoptysis of pulmonary tuberculosis or sputum mixed with blood, hematuria, prostate hyperplasia are hemorrhage, upper gastrointestinal hemorrhage cause hemorrhagely also will have good auxiliary therapeutic action.
In addition, the present invention also provides the application in the medicine for the preparation for the treatment of tuberculosis, tumor and endocrinopathy as injectable sustained-release or controlled release drug of described medical sodium alginate gel microsphere.
The invention has the advantages that:
The present invention combines and uses cheap, avirulent hemorrhage (Aminomethylbenzoic Acid or to aminomethyl naphthenic acid) and two kinds of cross-linking agent of bivalent metal ion to prepare medicine carrying sodium alginate gel microsphere, can effectively control small-molecule drug slow release, avoid univalent cation for being cross-linked separately with bivalent metal ion the quick corrosion that sodium alginate causes.Medicine carrying sodium alginate gel microsphere of the present invention is implanted experimental rat intraperitoneal, within 4 months, degrades gradually later and disappears, having no inflammatory reaction.
Aminomethylbenzoic Acid or to aminomethyl naphthenic acid as new a kind of sodium alginate cross-linking agent, compare with chitosan and polylysine, not only cross-linking effect is good, and the gel micro-ball surface of formation is brighter and cleaner, and can obviously reduce sodium alginate micro ball and produce and packing cost.Sodium alginate gel microspheres product can natural drying becomes ball, it is safer, more convenient to use.
Compare with the crosslinked medicine carrying microballoons of sodium alginate-divalent metal, sodium alginate gel microsphere of the present invention has outstanding advantage at aspects such as microsphere toughness, roundness, swelling ratio, entrapment efficiency and drug release rates.Product of the present invention, as vascular occlusive agent, can demonstrate fabulous curative effect aspect topical therapeutic acute hemorrhage and chronic oozing of blood, has expanded the medical application scope of sodium alginate gel microsphere.
Accompanying drawing explanation
Fig. 1 is the micro-image of microsphere in embodiment 1, the micro-image that wherein a is Mycobutin-calcium alginate microsphere; B is Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere micro-image.
Fig. 2 is the swelling ratio in two kinds of medicine carrying microballoons normal saline and gel micro-ball corrosion comparison schematic diagram in embodiment 1, the swelling ratio change curve that wherein A is Mycobutin-calcium alginate microsphere; B is the swelling ratio change curve of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere.
Fig. 3 is the drug release curve of two kinds of medicine carrying microballoonss in embodiment 1, the drug release curve that wherein A is Mycobutin-calcium alginate microsphere, and B is the drug release curve of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere.
The specific embodiment
Below by embodiment, the invention will be further described, but do not mean that limiting the scope of the invention.
Embodiment 1
1, bag carries the preparation of Mycobutin-calcium alginate-aminomethyl phenyl formic acid gel micro-ball, and preparation method comprises the following steps:
(1) Mycobutin medicated powder is crossed after 160 mesh sieves, taken 4g standby.
(2) take 1.5g sodium alginate and be dissolved in 100mL distilled water, obtain the sodium alginate soln that concentration is 1.5wt%.
(3) take Aminomethylbenzoic Acid 2g, join in 200mL distilled water, under room temperature, stir, obtain concentration and be 1% Aminomethylbenzoic Acid solution.
(4) take anhydrous calcium chloride 8g, join in 400mL distilled water, under room temperature, stir, obtain concentration and be 2% calcium chloride solution.
(5) Aminomethylbenzoic Acid solution 200mL step (3) being obtained mixes with the calcium chloride solution equal-volume that 200mL step (4) obtains, and under room temperature, stirs, and obtains composite solidification liquid.
(6) step (1) gained 4g Mycobutin medicated powder is distributed in the sodium alginate soln of step (2), splashes in the composite solidification liquid of step (5) by high-pressure electrostatic drop generating device, gel drop is solidified into ball.
(7) after gel micro-ball cured 4h, microsphere is filtered, and immerse in the calcium chloride solution of 200mL step (4), continue to solidify 0.5h.With distilled water wash 2 times, with buchner funnel, filter, collect gel micro-ball, drying at room temperature 3 days, obtains 6.3g bag and carries Mycobutin-calcium alginate-aminomethyl phenyl formic acid xerogel microsphere.Under optical microscope, observe 50 xerogel microspheres, microsphere is compared with rounding, and surface is slightly aobvious coarse, and particle size range is 153 μ m～207 μ m.Compare with common Mycobutin sodium alginate xerogel microsphere, aspect microsphere roundness and any surface finish, be significantly improved, as shown in Figure 1.
2, bag carries Mycobutin sodium alginate gel microsphere equilibrium swelling experiments
From common Mycobutin-calcium alginate microsphere and Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere sample, precision weighing 50mg dry microspheres is poured into respectively in 2 100mL conical flasks respectively, add 50mL normal saline, be transferred to rapidly in constant-temperature shaking incubator, at 20 ℃, 150rmin
-1condition under vibrate.When 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, sample, under stereomicroscope, observe microsphere diameter, microsphere breakage rate, record the quality of total microsphere of this moment, by following formula, calculate microsphere swelling ratio.
As seen from Figure 2, Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere in normal saline after approximately 60 hours swelling ratio reach 19, now gel micro-ball is complete.Mycobutin-calcium alginate microsphere has reached 20 at 12 hours swelling ratios, has half gel micro-ball to break.Corrosion is immediately broken.Whole gel micro-ball corrosions or break at 24 hours.This shows that Mycobutin-calcium alginate-aminomethyl phenyl formic acid micro-sphere structure is stable, to Na in normal saline
+corrosion microsphere has opposing more by force, so gel micro-ball good toughness.And Mycobutin-calcium alginate microsphere microsphere toughness in normal saline is poor, Ca wherein
2+easily by the Na in normal saline
+cement out rapidly, cause its quick corrosion, spheroid easily breaks.
3, drug release in vitro performance
Release in vitro is measured Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere drug stripping curve with turning basket method.Concrete operations: take a certain amount of medicine carrying microballoons (particle diameter is more than 500 microns) in turning basket, 37 ± 0.5 ℃ of water-baths, rotating speed 50rmin
-1.Dissolution medium is simulated intestinal fluid.In different time sections, sample respectively 1mL, and add the dissolution medium of the same race of same volume simultaneously, be settled to 50.0mL, in 334nm place working sample ultraviolet absorptivity, by standard curve, calculate accumulative total stripping percentage rate.Mycobutin-calcium alginate-aminomethyl phenyl formic acid gel micro-ball drug-eluting curve is shown in Fig. 3.
As shown in Figure 3, in simulated intestinal fluid first 20 hours of medicine carrying microballoons, Mycobutin-calcium alginate microsphere has obvious burst drug release phenomenon, and the drug release rate of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere will be considerably slower than common Mycobutin-calcium alginate medicine carrying microballoons.The drug release rate of Mycobutin-calcium alginate microsphere has the trend progressively tending towards stability subsequently, and after 40 hours, most microspheres break, and now preparation approximately 70%.The drug release rate of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere is comparatively mild all the time, reaches release balance, drug accumulation release rate approximately 75% after about 120 hours.
4, bag carries experiment in Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere
Dog experiment: respectively the 0.2g Mycobutin-calcium alginate microsphere of preparation and Mycobutin-calcium alginate-aminomethyl phenyl formic acid each 0.2g of microsphere and 18mL normal saline are sneaked in 20mL syringe before experiment, every part can be for 4 animals.By 8 beasle dogs, divide two groups of A, B.A group gives Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere, and B group gives Mycobutin-calcium alginate microsphere.Dog general anesthesia, through branchofiberoscope guiding, slowly injects 2 kinds of medicine carrying gel micro-ball suspensions in dog right lung bronchus respectively every dog 4mL respectively.Every 12 hours afterwards, use branchofiberoscope to observe beasle dog bronchus medicine-feeding part microsphere quantity and bag year Mycobutin medicine change color.Dog bronchus administration experimental result is in Table 1.
Table 1 Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere dog bronchus administration experimental result
Bag carries Mycobutin gel micro-ball and from dark red, becomes completely transparently in dog bronchus, and in meaning gel micro-ball, Mycobutin discharges completely.The minimizing of dog bronchus inner gel microsphere content mostly is gel micro-ball corrosion, and minority is by the outside expectoration of bronchus.Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere holdup time in beasle dog bronchus reaches more than 12 days, and medicament slow release is 10 days; And Mycobutin-calcium alginate microsphere only has respectively 8 days and 4 days aspect holdup time and medicament slow release in bronchus, be equivalent to half that Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere characterizes.This shows that sodium alginate gel microsphere sustained drug release effect in lung is better.
Embodiment 2
Bag carries the preparation of paclitaxel sodium alginate gel microsphere, and preparation method comprises the following steps:
(1) by paclitaxel medicated powder after 160 mesh sieves, take 2g.
(2) take 2g sodium alginate and be dissolved in 100mL distilled water, obtain the sodium alginate soln that concentration is 2.0wt%.
(3) take 1g4-aminomethyl phenyl formic acid, join in 200mL distilled water, under room temperature, stir, obtain concentration and be 0.5% Aminomethylbenzoic Acid solution.
(4) take 6g anhydrous calcium chloride, join in 400mL distilled water, under room temperature, stir, obtain concentration and be 1.5% calcium chloride solution.
(5) the calcium chloride solution 200mL equal-volume that Aminomethylbenzoic Acid solution 200mL step (3) being obtained obtains with step (4) mixes, and under room temperature, stirs, and obtains composite solidification liquid.
(6) step (1) gained 2g paclitaxel medicated powder is distributed in step (2) gained solution, pack in 50mL syringe, by high-pressure electrostatic drop generating device, splash in the composite solidification liquid of step (5) gained, gel drop is solidified into ball.
(7) after gel micro-ball cured 4h, microsphere is filtered, and immerse in the calcium chloride solution of 200mL step (4) gained, continue to solidify 0.5h.Distilled water wash 2 times, buchner funnel filters, and collects gel micro-ball, and drying at room temperature 3 days obtains the sodium alginate xerogel microsphere that 5.5g bag carries paclitaxel.Under optical microscope, observe 50 xerogel microspheres, microsphere is compared with rounding, and particle size range is 166 μ m～234 μ m.
Embodiment 3
Bag carries the preparation of 17 beta estradiol sodium alginate gel microspheres, and preparation method comprises the following steps:
(1) by 17 beta estradiol medicated powder after 160 mesh sieves, take 1g.
(2) take 2g sodium alginate and be dissolved in 100mL distilled water, obtain the sodium alginate soln that concentration is 2.0wt%.
(3) take 1g4-aminomethyl phenyl formic acid, join in 200mL distilled water, under room temperature, stir, obtain concentration and be 0.5% Aminomethylbenzoic Acid solution.
(4) take 8g anhydrous calcium chloride, join in 400mL distilled water, under room temperature, stir, obtain concentration and be 2% calcium chloride solution.
(5) 200mL step (3) gained Aminomethylbenzoic Acid solution is mixed with the calcium chloride solution equal-volume of 200mL step (4) gained, under room temperature, stir, obtain composite solidification liquid.
(6) step (1) gained 1g17 beta estradiol medicated powder is distributed in step (2) gained solution, pack in 50mL syringe, by high-pressure electrostatic drop generating device, splash in the composite solidification liquid of step (5) gained, gel drop is solidified into ball.
(7) after gel micro-ball cured 4h, microsphere is filtered, and immerse in the calcium chloride solution of 200mL step (4) gained, continue to solidify 0.5h.Distilled water wash 2 times, buchner funnel filters, and collects gel micro-ball, and drying at room temperature 3 days obtains calcium alginate-aminomethyl phenyl formic acid xerogel microsphere that 4.8g bag carries 17 beta estradiols.Under optical microscope, observe 50 xerogel microspheres, microsphere is compared with rounding, and particle size range is 156 μ m～204 μ m.
Embodiment 4
Bag carries the preparation of diosmin sodium alginate gel microsphere, and preparation method comprises the following steps:
(1) by diosmin medicated powder after 160 mesh sieves, take 3g.
(2) take 1.5g sodium alginate and be dissolved in 100mL distilled water, obtain the sodium alginate soln that concentration is 1.5wt%.
(3) take 4g to aminomethyl naphthenic acid, join in 200mL distilled water, under room temperature, stir, obtain concentration and be 2.0wt% to aminomethyl naphthenic acid solution.
(4) take 8g anhydrous calcium chloride, join in 400mL distilled water, under room temperature, stir, obtain the calcium chloride solution that concentration is 2.0wt%.
(5) 200mL step (3) gained is mixed with the calcium chloride solution equal-volume of 200mL step (4) gained aminomethyl naphthenic acid solution, under room temperature, stir, obtain composite solidification liquid.
(6) step (1) gained 2g diosmin profit medicated powder is distributed in step (2) gained solution, pack in 50mL syringe, by high-pressure electrostatic drop generating device, splash in the composite solidification liquid of step (5) gained, gel drop is solidified into ball.
(7) after gel micro-ball cured 4h, microsphere is filtered, and immerse in the calcium chloride solution of 200mL step (4) gained, continue to solidify 0.5h.Distilled water wash 2 times, buchner funnel filters, and collects gel micro-ball, and drying at room temperature 3 days obtains 5.3g bag and carries a Mycobutin-calcium alginate-to aminomethyl naphthenic acid xerogel microsphere.Under optical microscope, observe xerogel microsphere, microsphere is compared with rounding, and surface is more smooth, and particle size range is 153 μ m～207 μ m.
Embodiment 5
1, the preparation of Aminomethylbenzoic Acid sodium alginate gel microsphere, preparation method comprises the following steps:
(1) take 1.8g sodium alginate and be dissolved in 100mL distilled water, obtain 1.8% sodium alginate soln.
(2) take 6g4-aminomethyl phenyl formic acid, join in 200mL distilled water, under room temperature, stir, obtaining concentration is the Aminomethylbenzoic Acid solution of 3.0wt%.
(3) take 8g anhydrous calcium chloride, join in 400mL distilled water, under room temperature, stir, obtain concentration and be 2% calcium chloride solution.
(4) step (2) gained 200mL4-aminomethyl phenyl formic acid solution is mixed with the calcium chloride solution equal-volume of step (4) gained 200mL2.0%, under room temperature, stir, obtain composite solidification liquid.
(5) step (1) gained 1.8% sodium alginate soln is packed in 50mL syringe, by high-pressure electrostatic drop generating device, splash in the composite solidification liquid of step (4) gained, gel drop is solidified into ball.
(6) after gel micro-ball cured 4h, microsphere is filtered, and immerse in the calcium chloride solution of 200mL step (3) gained, continue to solidify 0.5h.Distilled water wash 2 times, buchner funnel filters, and collects gel micro-ball, and drying at room temperature 3 days, obtains 2.6g calcium alginate-aminomethyl phenyl formic acid xerogel microsphere.Under optical microscope, observe, microsphere rounding, surface is more smooth, and particle size range is 185 μ m～206 μ m.
2, arterial thrombosis experiment
First get 20mg sterilizing calcium alginate-aminomethyl phenyl formic acid xerogel microsphere, immerse in appropriate normal saline.Anaesthetize 13 bitches, femoral artery puncture, is inserted into dog mid-uterine artery by 4F conduit.With syringe, draw 2mL calcium alginate-aminomethyl phenyl formic acid gel micro-ball suspension, through 4F conduit by gel micro-ball thromboembolism in dog mid-uterine artery.Separately get commercially available KMG sodium alginate micro ball vascular embolism agent 1.0g, add appropriate normal saline, stand-by after washing 2 times.Anaesthetize 14 bitches, through same method by KMG sodium alginate micro ball thromboembolism dog mid-uterine artery tremulous pulse.Regularly adopt DSA to detect bitch mid-uterine artery thromboembolism state, experimental result is in Table 2.
Two kinds of gel micro-ball thromboembolism dog mid-uterine artery experimental results of table 2
Claims (5)
1. a medical sodium alginate gel microsphere, it is characterized in that, comprise combination drug carrier and water-insoluble drug, wherein said combination drug carrier bag carries described water-insoluble drug, described combination drug carrier is ion crosslinking agent-sodium alginate-bivalent metal ion, and ion crosslinking agent is wherein Aminomethylbenzoic Acid or to aminomethyl naphthenic acid; Described bivalent metal ion is Ca
2+, Ba
2+and Sr
2+in one or more; Described medical sodium alginate gel microsphere intermediate ion cross-linking agent Aminomethylbenzoic Acid or be 1.0～5.0wt% to the mass fraction of aminomethyl naphthenic acid, the mass fraction of sodium alginate is 14.0～68.0wt%, the mass fraction of water-insoluble drug is 20～65.0wt%, and the mass fraction of water is 4.0～16.0wt%.
2. medical sodium alginate gel microsphere according to claim 1, is characterized in that, described water-insoluble drug is rifamycin drug, antitumor drug, steroid hormone or diosmin.
3. a preparation method for medical sodium alginate gel microsphere described in claim 1, is characterized in that, comprises the following steps:
(1) Aminomethylbenzoic Acid that is 0.5～3.0wt% by concentration or the divalent metal saline solution equal-volume that is 2.0～6.0wt% with concentration to the aqueous solution of aminomethyl naphthenic acid mix, and obtain composite solidification liquid;
(2 wish bag medicine carrying agent are distributed in the sodium alginate aqueous solution of 1.0～4.0wt% in the ratio of mass fraction 0.1%～8.0wt%, after mix homogeneously, by high-pressure electrostatic drop generating device and syringe needle, splash in the composite solidification liquid of step (1) gained, drop is solidified into rapidly gel micro-ball;
(3) gel micro-ball is detained after 1～24h in composite solidification liquid, and gel micro-ball is filtered, and proceeds in the divalent metal saline solution of 2.0～6.0wt%, continues to solidify 0.5～4h;
(4) collect gel micro-ball, through distilled water wash 1～3 time, dehydration, dry, obtains described medical sodium alginate gel microsphere, and particle size range is 80 μ m～1000 μ m.
4. medical sodium alginate gel microsphere claimed in claim 2 application in the medicine for the preparation of the local acute hemorrhage for the treatment of and chronic oozing of blood as slow release or controlled release form.
5. medical sodium alginate gel microsphere claimed in claim 2 application in the medicine for the preparation for the treatment of tuberculosis, tumor and endocrinopathy as injectable sustained-release or controlled release drug.
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| CN107467672B (en) * | 2017-06-27 | 2020-11-13 | 福格森（武汉）生物科技股份有限公司 | Preparation method of ferrous composite gel microspheres |
| CN109464700B (en) * | 2018-11-22 | 2021-09-21 | 深圳先进技术研究院 | Paste for 3D printing, 3D structure and preparation method and application thereof |
| CN110478247B (en) * | 2019-08-27 | 2021-07-06 | 哈尔滨工业大学 | Micro-nano motor capsule and preparation method thereof |
| CN110734745B (en) * | 2019-11-28 | 2021-08-17 | 浙江海洋大学 | Cold chain coolant for tuna and preparation method thereof |
| CN111773428A (en) * | 2020-08-05 | 2020-10-16 | 华中科技大学 | Medicine sustained-release alginic acid embolism microsphere and preparation method thereof |
| CN112972664B (en) * | 2021-02-08 | 2022-07-05 | 武汉大学 | Device and method for preparing gel droplet monocyte vaccine from blood based on microfluidic chip |
| CN112956473B (en) * | 2021-03-10 | 2023-05-26 | 中科强参(吉林)科技有限公司 | Artificial transparent belt and preparation method thereof |
| CN114306724B (en) * | 2021-12-30 | 2022-11-11 | 上海汇禾医疗科技有限公司 | Embolism microsphere capable of slowly releasing medicine and preparation method thereof |
| CN115054724B (en) * | 2022-04-28 | 2024-01-12 | 浙江理工大学 | Hollow embolism microsphere, preparation method, pharmaceutical composition and application thereof |
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| EP1587424A4 (en) * | 2002-12-31 | 2012-01-25 | Marinepolymer Tech Inc | Hemostatic compositions and uses therefor |
| CN1330389C (en) * | 2003-03-05 | 2007-08-08 | 朱晓明 | Hematostatic gel |
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