CN103239730A - 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 sodium alginate-poly-D-lysine-Sargassum sodium (APA) microsphere (capsule), this microsphere becomes the most ripe medical microsphere (the capsule) (O ' Shea GM of present development with its excellent biological compatibility, 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), improve some biologys and the chemical characteristic of microsphere so that the microsphere technology can be in the treatment of metabolic disease, medicament slow release control, body and field such as cell in vitro cultivation be used widely.
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 the gel micro-ball based on chelation.Bivalent metal ion (the Ca that this application is single
2+, Sr
2+, Ba
2+Deng) crosslinked sodium alginate micro ball, enter in the organism, be exposed in the monovalent cation solution environmental, owing to there is ion exchange, the just corrosion fast of sodium alginate gel microsphere causes the prominent phenomenon of releasing of medicine to take place.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 in the body blood drug level suddenly to raise and produces untoward reaction.To release phenomenon be insoluble problem always and the medicine of medicine carrying gel micro-ball preparation is prominent, wherein with the medicine of medicine carrying sodium alginate micro ball preparation prominent release particularly evident.For targeted sustained release microsphere, will cause the minimizing of target site active drug amount, finally weaken the targeting of microball preparation.Therefore, how to reduce prominent the releasing of medicine of sodium alginate micro ball effectively, realize that it is the direction that the pharmaceutics worker makes great efforts to study that controlled delivery of pharmaceutical agents discharges always.
The factor that influences sodium alginate micro ball Chinese medicine rate of release has a lot, comprises the character of polymer, the character of medicine, the preparation method of drug loading and microsphere etc.But after all, these factors all are to decide the release performance of medicine in the distribution situation of microsphere by chemical crosslinking change microsphere surface pattern and medicine.Solving the prominent universal method of releasing of medicine at present is to introduce polycationic polymer in sodium alginate micro ball, as chitosan and polyamino acid (poly ornithine or polylysine).Polycationic polymer can form the compound polyelectrolyte film on the sodium alginate micro ball surface by electrostatic interaction, stability and the drug loading of microsphere both can have been improved, can regulate drug release rate again, 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, the microsphere outermost layer is chitosan or the polyamino acid skin that is settled out, and does not generally contain encapsulated medicine; The middle level is evenly to be dispersed with the chitin-sodium alginate of encapsulated medicine or the composite membrane of polyamino acid-sodium alginate; Inner core is the alginate core material that evenly is dispersed with 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, and the scope of application is narrower, can not control small-molecule drug and discharge, and only limits to coated cell, vaccine and polymer drug.The polylysine material price that preparation compound polyelectrolyte film more often adopts is very expensive, is difficult to be applied in the large-scale industrial production.
In addition, the sodium alginate gel microsphere also is used for hemostasis and chemotherapy of tumors as vascular occlusive agent.The sodium alginate gel microsphere vascular suppository (KMG) of China's listing does not at present still have dried glue type granular preparation, can only be stored in the bivalent cation solution with wet glue type gel micro-ball form, must wash through normal saline before using, to remove bivalent cation unnecessary in the sodium alginate gel microsphere.But during clinical practice, germ contamination takes place in washing sodium alginate gel microsphere easily, brings inconvenience and medical safety hidden danger to user.
Summary of the invention
One of purpose of the present invention is to provide a kind of medical sodium alginate gel microsphere, this gel micro-ball is to unite the medicine carrying sodium alginate gel microsphere that uses amphion cross-linking agent and bivalent metal ion preparation, can effectively control the 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 technology, to solve the problems that the crosslinked sodium alginate gel microsphere of bivalent cation exists at aspects such as production, packing and application.
Another purpose of the present invention be to provide a kind of described medical sodium alginate gel microsphere as slow release or controlled release form for the preparation of the application in the medicine of the local acute hemorrhage for the treatment of and chronic oozing of blood.
A further object of the present invention be to provide a kind of medical sodium alginate gel microsphere as injectable sustained-release or controlled release drug for the preparation of the application in the medicine for the treatment of tuberculosis, tumor and endocrinopathy.
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 wherein is 4-aminomethyl phenyl formic acid or to the aminomethyl naphthenic acid.4-aminomethyl phenyl formic acid and to the 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 4-aminomethyl phenyl formic acid or to the mass fraction 1.0～5.0wt% of aminomethyl naphthenic acid, the mass fraction 14.0～68.0wt% of 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 kind of preparation method of described medical sodium alginate gel microsphere is characterized in that, may further comprise the steps:
(1) is the 4-aminomethyl phenyl formic acid of 0.5～3.0wt% with concentration or is that the divalent metal saline solution equal-volume of 2.0～6.0wt% mixes to the aqueous solution of aminomethyl naphthenic acid and concentration, obtain composite solidification liquid;
(2 desire 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%, behind the 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 gel micro-ball rapidly;
(3) after gel micro-ball is detained 1～24h in composite solidification liquid, gel micro-ball is filtered, change in the divalent metal saline solution of 2～6wt%, continue to solidify 0.5～4h;
(4) collect gel micro-ball, through distilled water wash 1～3 time, dehydration, drying obtain described medical sodium alginate gel microsphere, and particle size range is 80 μ m～1000 μ m.
The present invention is used for large-scale production sodium alginate gel microsphere technology with hemorrhage 4-aminomethyl phenyl formic acid or to the ion crosslinking agent of aminomethyl naphthenic acid as novelty.4-aminomethyl phenyl formic acid and be the special acid of synthetic to the aminomethyl naphthenic acid, lysine residue (monomer) is extremely similar in its Molecular Geometries and the polylysine macromole, be ampholyte, can form compound polyelectrolyte in sodium alginate micro ball by stronger electrostatic interaction, greatly degree has improved molecule crosslinked effect in the sodium alginate micro ball.In addition, because 4-aminomethyl phenyl formic acid and the aminomethyl naphthenic acid introduced 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 can obviously improve pliability and the chemical stability of sodium alginate gel microsphere as ion crosslinking agent.
The present invention also provide described medical sodium alginate gel microsphere as slow release or controlled release form for the preparation of the application in the medicine of topical therapeutic acute hemorrhage and chronic oozing of blood.Sodium alginate gel microsphere of the present invention is specially adapted to treat arterial hemorrhage, has hemostasis soon, eutherapeutic characteristics.4-aminomethyl phenyl formic acid-sodium alginate cross-linking microsphere by the present invention's preparation effectively is better than common suppository-sodium alginate embolism microball at viscoelasticity, tack, swelling ratio and thromboembolism aspect the time.Behind the 4-aminomethyl phenyl formic acid/enter in the body to aminomethyl naphthenic acid-sodium alginate cross-linking medicine carrying microballoons, to the abnormal bleeding in when operation, multiple 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 a good auxiliary treatment effect.
In addition, the present invention also provide described medical sodium alginate gel microsphere as injectable sustained-release or controlled release drug for the preparation of the application in the medicine for the treatment of tuberculosis, tumor and endocrinopathy.
The invention has the advantages that:
The present invention unites and uses cheap, avirulent hemorrhage (4-aminomethyl phenyl formic acid or to the 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 the small-molecule drug slow release, avoid univalent cation for the quick corrosion that causes with the independent crosslinked sodium alginate of bivalent metal ion.Medicine carrying sodium alginate gel microsphere of the present invention is implanted the experimental rat intraperitoneal, degrades gradually later on and disappears, and do not see inflammatory reaction in 4 months.
4-aminomethyl phenyl formic acid or to the 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 production and packing cost.The 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 can demonstrate fabulous curative effect as vascular occlusive agent aspect topical therapeutic acute hemorrhage and the chronic oozing of blood, has expanded the medical application scope of sodium alginate gel microsphere.
Description of drawings
Fig. 1 is the micro-image of microsphere among the embodiment 1, and wherein a is the micro-image of 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 sketch map relatively among the embodiment 1, and wherein A is the swelling ratio change curve of 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 among the embodiment 1, and wherein A is the drug release curve of Mycobutin-calcium alginate microsphere, and B is the drug release curve of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere.
The specific embodiment
The invention will be further described below by embodiment, 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 may further comprise the steps:
(1) Mycobutin medicated powder is crossed 160 mesh sieves after, it is standby to take by weighing 4g.
(2) take by weighing the 1.5g sodium alginate and be dissolved in the 100mL distilled water, obtain the sodium alginate soln that concentration is 1.5wt%.
(3) take by weighing 4-aminomethyl phenyl formic acid 2g, join in the 200mL distilled water, stir under the room temperature, obtain concentration and be 1% 4-aminomethyl phenyl formic acid solution.
(4) take by weighing anhydrous calcium chloride 8g, join in the 400mL distilled water, stir under the room temperature, obtain concentration and be 2% calcium chloride solution.
(5) the 4-aminomethyl phenyl formic acid solution that 200mL step (3) is obtained mixes with the calcium chloride solution equal-volume that 200mL step (4) obtains, and stirs under the room temperature, obtains composite solidification liquid.
(6) step (1) gained 4g Mycobutin medicated powder is distributed in the sodium alginate soln of step (2), splashes into by the high-pressure electrostatic drop generating device in the composite solidification liquid of step (5), the gel drop is solidified into ball.
(7) behind the 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, filter with buchner funnel, collect gel micro-ball, drying at room temperature 3 days obtains the 6.3g bag and carries a Mycobutin-calcium alginate-aminomethyl phenyl formic acid xerogel microsphere.50 xerogel microspheres of observation under the optical microscope, microsphere are than rounding, and it is coarse that the surface shows slightly, and particle size range is 153 μ m～207 μ m.Compare with common Mycobutin sodium alginate xerogel microsphere, be significantly improved aspect microsphere roundness and any surface finish, as shown in Figure 1.
2, bag carries the experiment of Mycobutin sodium alginate gel microspheres swell up
Precision weighing 50mg dry microspheres is poured into respectively in 2 100mL conical flasks from common Mycobutin-calcium alginate microsphere and Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere sample respectively, add the 50mL normal saline, be transferred to rapidly in the constant-temperature shaking culture case, at 20 ℃, 150rmin
-1Condition under vibrate.When 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, take a sample, observe microsphere diameter, microsphere breakage rate under the stereomicroscope, record the quality of total microsphere of this moment, calculate the microspheres swell up rate by following formula.
As seen from Figure 2, Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere in normal saline after about 60 hours swelling ratio reach 19, this moment gel micro-ball complete.Mycobutin-calcium alginate microsphere has reached 20 at 12 hours swelling ratios, has the 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 the normal saline
+The corrosion microsphere has opposing more by force, so the gel micro-ball good toughness.And Mycobutin-calcium alginate microsphere microsphere toughness in normal saline is relatively poor, Ca wherein
2+Easily by the Na in the normal saline
+Cement out rapidly, cause its quick corrosion, spheroid easily breaks.
3, medicine release in vitro performance
Release in vitro is measured Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere drug stripping curve with changeing the basket method.Concrete operations: take by weighing a certain amount of medicine carrying microballoons (particle diameter is more than 500 microns) in changeing basket, 37 ± 0.5 ℃ of water-baths, rotating speed 50rmin
-1Dissolution medium is simulated intestinal fluid.At the different time sections 1mL that takes a sample respectively, and add dissolution medium of the same race with volume simultaneously, be settled to 50.0mL, in 334nm place working sample ultraviolet absorptivity, calculate accumulative total stripping percentage rate by standard curve.Mycobutin-calcium alginate-aminomethyl phenyl formic acid gel micro-ball medicine stripping curve is seen Fig. 3.
As shown in Figure 3, medicine carrying microballoons preceding 20 hours in simulated intestinal fluid, Mycobutin-calcium alginate microsphere has that tangible medicine is prominent releases 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 that progressively tends towards stability subsequently, and most microspheres break after 40 hours, and this moment, the cumulative release rate about 70%.The drug release rate of Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere is comparatively mild all the time, reaches the release balance after about 120 hours, drug accumulation release rate about 75%.
4, bag carries experiment in Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere
Dog experiment: respectively 0.2g Mycobutin-calcium alginate microsphere and Mycobutin-calcium alginate-each 0.2g of aminomethyl phenyl formic acid microsphere of preparation sneaked in the 20mL syringe with the 18mL normal saline before the experiment, every part can be for 4 animals uses.Divide two groups of A, B with 8 beasle dogs.The A group gives Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere, and the B group gives Mycobutin-calcium alginate microsphere.The dog general anesthesia through the branchofiberoscope guiding, is slowly injected 2 kinds of medicine carrying gel micro-ball suspensions in the dog right lung bronchus every dog 4mL respectively respectively.Per 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 sees Table 1.
Table 1 Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere dog bronchus administration experimental result
Bag carries the Mycobutin gel micro-ball and becomes transparently fully by dark red in the dog bronchus, and Mycobutin discharges fully in the meaning gel micro-ball.The minimizing of dog bronchus inner gel microsphere content mostly is the gel micro-ball corrosion, and minority is by the outside expectoration of bronchus.Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere holdup time in the beasle dog bronchus reached more than 12 days, and medicament slow release was 10 days; And Mycobutin-calcium alginate microsphere has only 8 days respectively and 4 days aspect holdup time and the medicament slow release in bronchus, is equivalent to Mycobutin-calcium alginate-aminomethyl phenyl formic acid microsphere characterizes half.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 may further comprise the steps:
(1) with paclitaxel medicated powder through 160 mesh sieves after, take by weighing 2g.
(2) take by weighing the 2g sodium alginate and be dissolved in the 100mL distilled water, obtain the sodium alginate soln that concentration is 2.0wt%.
(3) take by weighing 1g4-aminomethyl phenyl formic acid, join in the 200mL distilled water, stir under the room temperature, obtain concentration and be 0.5% 4-aminomethyl phenyl formic acid solution.
(4) take by weighing the 6g anhydrous calcium chloride, join in the 400mL distilled water, stir under the room temperature, obtain concentration and be 1.5% calcium chloride solution.
(5) the calcium chloride solution 200mL equal-volume that 4-aminomethyl phenyl formic acid solution 200mL and the step (4) that step (3) is obtained obtains mixes, and stirs under the room temperature, obtains composite solidification liquid.
(6) step (1) gained 2g paclitaxel medicated powder is distributed in step (2) the gained solution, in the 50mL syringe of packing into, by the high-pressure electrostatic drop generating device, splashes in the composite solidification liquid of step (5) gained, the gel drop is solidified into ball.
(7) behind the 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 the 5.5g bag carries paclitaxel.50 xerogel microspheres of observation under the optical microscope, microsphere is than 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 may further comprise the steps:
(1) with 17 beta estradiol medicated powder through 160 mesh sieves after, take by weighing 1g.
(2) take by weighing the 2g sodium alginate and be dissolved in the 100mL distilled water, obtain the sodium alginate soln that concentration is 2.0wt%.
(3) take by weighing 1g4-aminomethyl phenyl formic acid, join in the 200mL distilled water, stir under the room temperature, obtain concentration and be 0.5% 4-aminomethyl phenyl formic acid solution.
(4) take by weighing the 8g anhydrous calcium chloride, join in the 400mL distilled water, stir under the room temperature, obtain concentration and be 2% calcium chloride solution.
(5) 200mL step (3) gained 4-aminomethyl phenyl formic acid solution is mixed with the calcium chloride solution equal-volume of 200mL step (4) gained, stir under the room temperature, obtain composite solidification liquid.
(6) step (1) gained 1g17 beta estradiol medicated powder is distributed in step (2) the gained solution, in the 50mL syringe of packing into, by the high-pressure electrostatic drop generating device, splashes in the composite solidification liquid of step (5) gained, the gel drop is solidified into ball.
(7) behind the 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 the 4.8g bag carries 17 beta estradiols.50 xerogel microspheres of observation under the optical microscope, microsphere is than 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 may further comprise the steps:
(1) with diosmin medicated powder through 160 mesh sieves after, take by weighing 3g.
(2) take by weighing the 1.5g sodium alginate and be dissolved in the 100mL distilled water, obtain the sodium alginate soln that concentration is 1.5wt%.
(3) take by weighing the aminomethyl naphthenic acid of 4g, join in the 200mL distilled water, stir under the room temperature, obtain concentration and be 2.0wt% to aminomethyl naphthenic acid solution.
(4) take by weighing the 8g anhydrous calcium chloride, join in the 400mL distilled water, stir under the room temperature, obtain the calcium chloride solution that concentration is 2.0wt%.
(5) 200mL step (3) gained is mixed the calcium chloride solution equal-volume of aminomethyl naphthenic acid solution with 200mL step (4) gained, stir under the room temperature, obtain composite solidification liquid.
(6) the sharp medicated powder of step (1) gained 2g diosmin is distributed in step (2) the gained solution, in the 50mL syringe of packing into, by the high-pressure electrostatic drop generating device, splashes in the composite solidification liquid of step (5) gained, the gel drop is solidified into ball.
(7) behind the 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 filter, and collect gel micro-ball, and drying at room temperature 3 days obtains the 5.3g bag and carries a Mycobutin-calcium alginate-to aminomethyl naphthenic acid xerogel microsphere.Observation xerogel microsphere under the optical microscope, microsphere is than rounding, and the surface is more smooth, and particle size range is 153 μ m～207 μ m.
1, the preparation of 4-aminomethyl phenyl formic acid sodium alginate gel microsphere, preparation method may further comprise the steps:
(1) takes by weighing the 1.8g sodium alginate and be dissolved in the 100mL distilled water, get 1.8% sodium alginate soln.
(2) take by weighing 6g4-aminomethyl phenyl formic acid, join in the 200mL distilled water, stir under the room temperature, obtaining concentration is the 4-aminomethyl phenyl formic acid solution of 3.0wt%.
(3) take by weighing the 8g anhydrous calcium chloride, join in the 400mL distilled water, stir under the room temperature, 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%, stir under the room temperature, obtain composite solidification liquid.
(5) step (1) gained 1.8% sodium alginate soln is packed in the 50mL syringe, by the high-pressure electrostatic drop generating device, splash in the composite solidification liquid of step (4) gained, the gel drop is solidified into ball.
(6) behind the 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.Observe under the optical microscope, the microsphere rounding, the surface is more smooth, and particle size range is 185 μ m～206 μ m.
2, arterial thrombosis experiment
Get 20mg sterilization calcium alginate-aminomethyl phenyl formic acid xerogel microsphere earlier, immerse in an amount of normal saline.Anaesthetize 13 bitches, femoral artery puncture is inserted into my son palace medium-sized artery with the 4F conduit.Draw 2mL calcium alginate-aminomethyl phenyl formic acid gel micro-ball suspension with syringe, through the 4F conduit with the gel micro-ball thromboembolism in my son palace medium-sized artery.Other gets commercially available KMG sodium alginate micro ball vascular embolism agent 1.0g, adds an amount of normal saline, and is stand-by after washing 2 times.Anaesthetize 14 bitches, through same method with KMG sodium alginate micro ball thromboembolism my son palace medium-sized artery tremulous pulse.Regularly adopt Digital Subtraction technology for detection bitch mid-uterine artery thromboembolism state, experimental result sees Table 2.
Two kinds of gel micro-ball thromboembolisms of table 2 my son palace medium-sized artery experimental result
Claims (7)
1. 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 wherein is 4-aminomethyl phenyl formic acid or to the aminomethyl naphthenic acid.
2. medical sodium alginate gel microsphere according to claim 1 is characterized in that, described bivalent metal ion is Ca
2+, Ba
2+And Sr
2+In one or more.
3. medical sodium alginate gel microsphere according to claim 1, it is characterized in that, described medical sodium alginate gel microsphere intermediate ion cross-linking agent 4-aminomethyl phenyl formic acid or to the mass fraction 1.0～5.0wt% of aminomethyl naphthenic acid, the mass fraction 14.0～68.0wt% of sodium alginate, mass fraction 20～the 65.0wt% of water-insoluble drug, the mass fraction 4.0～16.0wt% of water.
4. 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.
5. the preparation method of the described medical sodium alginate gel microsphere of claim 1 is characterized in that, may further comprise the steps:
(1) is the 4-aminomethyl phenyl formic acid of 0.5～3.0wt% with concentration or is that the divalent metal saline solution equal-volume of 2.0～6.0wt% mixes to the aqueous solution of aminomethyl naphthenic acid and concentration, obtain composite solidification liquid;
(2 desire bag medicine carrying powder or medicament are distributed in the sodium alginate aqueous solution of 1.0～4.0wt% in the ratio of mass fraction 0.1%～8.0wt%, behind the 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 gel micro-ball rapidly;
(3) after gel micro-ball is detained 1～24h in composite solidification liquid, gel micro-ball is filtered, change in the divalent metal saline solution of 2.0～6.0wt%, continue to solidify 0.5～4h;
(4) collect gel micro-ball, through distilled water wash 1～3 time, dehydration, drying obtain described medical sodium alginate gel microsphere, and particle size range is 80 μ m～1000 μ m.
The described medical sodium alginate gel microsphere of claim 1 as slow release or controlled release form for the preparation of the application in the medicine of the local acute hemorrhage for the treatment of and chronic oozing of blood.
The described medical sodium alginate gel microsphere of claim 1 as injectable sustained-release or controlled release drug for the preparation of the application in the medicine for the treatment of tuberculosis, tumor and endocrinopathy.
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| CN109464700A (en) * | 2018-11-22 | 2019-03-15 | 深圳先进技术研究院 | For the slurry of 3D printing, 3D structural body and its preparation method and application |
| CN110478247A (en) * | 2019-08-27 | 2019-11-22 | 哈尔滨工业大学 | A kind of micro-nano motor capsule and preparation method thereof |
| CN110734745A (en) * | 2019-11-28 | 2020-01-31 | 浙江海洋大学 | Cold chain coolant for tunas and preparation method thereof |
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| CN107467672A (en) * | 2017-06-27 | 2017-12-15 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of ferrous composite gel microsphere |
| CN109464700A (en) * | 2018-11-22 | 2019-03-15 | 深圳先进技术研究院 | For the slurry of 3D printing, 3D structural body and its preparation method and application |
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| CN110478247A (en) * | 2019-08-27 | 2019-11-22 | 哈尔滨工业大学 | A kind of micro-nano motor capsule and preparation method thereof |
| CN110734745A (en) * | 2019-11-28 | 2020-01-31 | 浙江海洋大学 | Cold chain coolant for tunas and preparation method thereof |
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| 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 |
| CN112972664A (en) * | 2021-02-08 | 2021-06-18 | 武汉大学 | Device and method for preparing gel droplet monocyte vaccine from blood based on microfluidic chip |
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| CN112956473A (en) * | 2021-03-10 | 2021-06-15 | 吉林省强参生物技术有限公司 | Artificial transparent belt and preparation method thereof |
| 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 |
| CN114306724A (en) * | 2021-12-30 | 2022-04-12 | 上海汇禾医疗科技有限公司 | Embolism microsphere capable of slowly releasing medicine and preparation method thereof |
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