CN114748680B - Gelatin-alginate composite drug-loaded embolism microsphere and application thereof - Google Patents
Gelatin-alginate composite drug-loaded embolism microsphere and application thereof Download PDFInfo
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- CN114748680B CN114748680B CN202210442044.4A CN202210442044A CN114748680B CN 114748680 B CN114748680 B CN 114748680B CN 202210442044 A CN202210442044 A CN 202210442044A CN 114748680 B CN114748680 B CN 114748680B
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- microsphere
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- gelatin
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- 229940072056 alginate Drugs 0.000 title description 3
- 229920000615 alginic acid Polymers 0.000 title description 3
- 238000011068 loading method Methods 0.000 claims abstract description 30
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- 239000008273 gelatin Substances 0.000 claims abstract description 21
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 17
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- 206010038389 Renal cancer Diseases 0.000 description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 2
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- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
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- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- A—HUMAN NECESSITIES
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Materials Engineering (AREA)
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a drug-loaded embolism microsphere, which is prepared by using sodium alginate and gelatin as water phase materials and oil phase containing an emulsifier to prepare microemulsion and then crosslinking the microemulsion by aldehyde crosslinking agents and ionic crosslinking agents. The drug-loaded embolism microsphere can load chemotherapeutic drugs through ionization, has controllable drug loading performance, greatly improves drug loading capacity compared with the existing embolism microsphere, can realize slow release of the chemotherapeutic drugs, can block nutrient source blood supply required by tumor growth, can also improve local drug concentration of focus parts, simultaneously reduces drug concentration in other organs, reduces toxic and side effects, realizes synergistic treatment effect of embolism treatment and chemotherapy, and has great commercial prospect.
Description
Technical Field
The invention belongs to the technical field of medical biopolymer materials, and in particular relates to a gelatin-alginate composite drug-loaded embolism microsphere and application thereof.
Background
The catheter arterial chemoembolization (Transcatheter Arterial Chemoembolization, TACE for short) refers to that under the assistance of medical imaging equipment, a microcatheter is inserted into a tumor blood supply target artery through a guide wire, and then a proper amount of embolization material is injected to occlude the target artery blood vessel and block the blood supply of tumor tissues, so that the purposes of inhibiting the growth of tumor cells, promoting the necrosis and apoptosis of the tumor cells are achieved. TACE therapy is rapidly developed into an important tumor treatment means in recent years, and has the advantages of small trauma, high selectivity, good patient tolerance, targeted control and administration and the like in the treatment of blood vessel enrichment solid tumors such as liver cancer, kidney cancer, hysteromyoma and the like. In the interventional therapy of treating tumor cells, embolic materials play an important role.
The first generation solid embolism products are gelatin sponge and polyvinyl alcohol (PVA) particles with irregular shapes, but the solid embolism products have the defects of easy aggregation, difficult injection, incomplete embolism of blood vessels and the like in clinical use due to the irregular shapes; the second generation is a spherical blank microsphere with regular shape, such as a polyvinyl alcohol microsphere, a gelatin microsphere, a sodium alginate microsphere and the like, so that the injection is easy in clinical use, and the embolism effect is better than that of the first generation; the third generation of embolism material is medicine-carrying embolism microsphere, which has the characteristics of regular shape and uniform particle size of the second generation of product, and has good elasticity, and can be injected through a thinner catheter. In addition, aiming at the fact that most first-line anti-cancer drugs are drugs with positive charges, the existing drug-loaded microspheres can modify the chemical structure of the microspheres by adding anionic functional groups, so that the purposes of loading the anti-cancer drugs through charge and releasing the drugs after embolism are achieved. The most dominant drug eluting microspheres CalliSpheres, hepaSphere and DC Bead in the current market have the highest drug loading rate of epirubicin loaded per 1 milliliter of microspheres between 25 and 40 mg. However, the microspheres are not degradable, and the drug is only released by about 30-40%, so that the bioavailability is low.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the drug-loaded hydrogel microsphere which has high drug-loading efficiency and ideal drug slow-release performance, and the microsphere also has excellent mechanical property and good biocompatibility. The specific technical scheme of the invention is as follows:
a medicine-carried suppository microballoon is prepared from sodium alginate and gelatin through preparing microemulsion from aqueous phase and oil phase containing emulsifier, and cross-linking by aldehyde cross-linking agent and ionic cross-linking agent.
Preferably, the aldehyde cross-linking agent is selected from one or more of formaldehyde, glutaraldehyde, dialdehyde starch and dextran aldehyde; the ionic crosslinking agent comprises divalent and/or trivalent metal ions and anionsThe divalent or trivalent metal ion is selected from Ca 2+ 、Sr 2+ 、Ba 2+ 、Zn 2+ 、Cd 2+ 、Gd 2+ 、Fe 2+ 、Cu 2+ 、Pb 2+ 、Fe 3+ 、Al 3+ One or more of anions selected from Cl - 、Br - 、NO 3 - 、HCO 3 - 、ClO - 、ClO 3 - 、ClO 4 - One or more of them.
Preferably, the mass ratio of the sodium alginate to the gelatin is 1:1 to 50, and more preferably, the mass ratio of the sodium alginate, the gelatin, the aldehyde cross-linking agent and the ionic cross-linking agent is 1:1 to 50:1 to 10:1 to 10.
Preferably, the emulsifier concentration in the oil phase is from 0.1 to 5%, more preferably from 0.5 to 2%.
Preferably, the volume ratio of the aqueous phase to the oil phase is from 1:2 to 1:20, more preferably from 1:5 to 1:10.
Preferably, the emulsifier is selected from one or more of span and tween; the oil phase is selected from one or more of soybean oil, sesame oil, liquid paraffin, silicone oil, or water-immiscible organic solvent.
The microsphere disclosed by the invention can be prepared by the following steps:
(1) Dissolving sodium alginate and gelatin in water to obtain aqueous phase solution, wherein the mass and volume percentage concentration of the sodium alginate is 0.1% -20% (g/ml), and the mass and volume percentage concentration of the gelatin is 0.1% -50% (g/ml);
(2) Adding the aqueous phase solution prepared in the step (1) into an oil phase containing an emulsifying agent at 50-60 ℃, stirring (30 min), reducing the temperature to 2-8 ℃, and continuously stirring (60 min);
(3) Carrying out solid-liquid separation on the feed liquid in the step (2), and washing the oil phase remained on the surfaces of the microspheres;
(4) Adding the microspheres obtained in the step (3) into an aqueous solution of an aldehyde cross-linking agent, stirring and dispersing uniformly, reacting at 2-8 ℃ for 0.1-24 hours, and then washing the microspheres with distilled water;
(5) Adding the microspheres obtained in the step (4) into an aqueous solution of an ionic cross-linking agent, stirring and dispersing uniformly, reacting at normal temperature (0.1-24 hours), and then washing with distilled water to obtain the microspheres.
The microspheres prepared by the method can be further stored in a freeze-drying way or in physiological saline or buffer solution.
The invention also discloses application of the microsphere in preparation of antitumor drug carriers.
The invention also discloses a drug-loaded embolism microsphere, which is characterized in that the microsphere is mixed with the drug with positive charges, and the drug is loaded by ionization.
Preferably, the positively charged drug is selected from one or more of doxorubicin hydrochloride, epirubicin, i Li Tikang, epirubicin, valrubicin, gemcitabine, bleomycin, vinorelbine, oxaliplatin.
The drug-loaded embolic microsphere can be used for preventing and treating tumors, such as liver cancer, colorectal cancer liver metastasis, renal cancer, hysteromyoma, hemangioma, breast malignant tumor and the like.
The microsphere is spherical, has a particle size ranging from 10 to 2000 mu m, and can be screened to have a particle size ranging from 10 to 100 mu m,100 to 300 mu m,300 to 500 mu m or 500 to 700 mu m.
The microsphere has excellent mechanical properties, and the elastic modulus is 20-200kPa, preferably 50-200kPa; the degradation time is 1 to 360 days, preferably 30 to 90 days.
The invention has the advantages that:
(1) The microsphere provided by the invention has a structure with negative charges naturally, has extremely strong affinity to medicines with positive charge groups, and has the advantages of high drug loading, elasticity and stable structure. The medicine can be stably wrapped in the microsphere, and can be stably released for a long time after being implanted into a human body, thereby avoiding the damage of the antitumor medicine to normal tissues and improving the treatment effect of the medicine.
(2) The microsphere has controllable mechanical property and can meet the requirements of catheter injection of various specifications. Meanwhile, the drug loading capacity is also controllable, and the maximum drug loading capacity is higher than that of the existing drug-loaded embolic microsphere products on the market. All the medicines of the medicine carrying microsphere can be completely released along with the degradation of the microsphere, the release amount of the medicines is large, and the bioavailability of the medicines is greatly improved.
Drawings
FIG. 1 is a photograph of microsphere light of experimental group 5 of example 1.
FIG. 2 is a photomicrograph of the microspheres of example 1, panel 5, after drug loading.
FIG. 3 drug loading curves for microspheres of example 1, panels 3,4, 5.
Fig. 4 drug release profile for example 1 experimental groups 5, 11, 12, 14 drug-loaded microspheres.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are illustrative only and are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
EXAMPLE 1 preparation of alginate-gelatin microspheres
Aqueous phase: 10ml of an aqueous solution (dissolved by heating to 60 ℃ C.) was prepared with reference to Table 1.
An oil phase: liquid paraffin, 2% span80, 50ml (heated to 60 ℃).
The operation steps are as follows: adding the oil phase into a beaker, and stirring in a water bath at 60 ℃; adding the water phase, and stirring for 1 minute to realize emulsification; after emulsification, the mixture is transferred into an ice bath for cooling and stirring for 1 hour. Filtering with a screen, washing with n-hexane, washing with ethanol, and collecting. The mixture was transferred to 10ml of a 20% solution of crosslinking agent 1 (pH 8,4 ℃ C.) and stirred for 24hr to crosslink. After washing with water, the microspheres were transferred to 50ml of a 5% aqueous solution of crosslinker 2 and stirred for 3 hours for further crosslinking. The hydrogel microsphere suspension was wet screened. And observing the microsphere morphology under a light microscope. The hydrogel microspheres with regular round spheres can be obtained from each experimental group. FIG. 1 is a graph of microsphere light for experimental group 5. It can be seen that the microspheres with different particle sizes are screened out, the surface is smooth, and the particle size is uniform.
Hydrogel microspheres screened to be 2000 mu m in size are put into a fixed container and are tiled to be at a fixed height, and the elastic modulus corresponding to 30% deformation is measured by a texture analyzer. Transferring 0.25ml microsphere of each group of Table 1 into penicillin bottle, adding 1ml of 30mg/ml epirubicin water solution, respectively, and measuring medicine concentration from supernatant of 0.5hr,1hr,2hr,5hr, 18hr during soaking process to calculate medicine carrying amount. The elastic modulus and the maximum drug loading results of the composite hydrogel microspheres of each experimental group are shown in table 1. The microsphere still keeps smooth surface and uniform particle diameter after each group of drug is loaded. Fig. 2 is a photomicrograph of the microspheres of experimental group 5 after drug loading.
TABLE 1
The results show that: (1) The microsphere drug loading rate prepared by the aqueous phase material with single component is not ideal; (2) The crosslinking agent 1 can obviously improve the mechanical property of the microsphere, and the crosslinking agent 2 is beneficial to improving the drug loading rate of the microsphere; (3) The combination of sodium alginate and gelatin had a more desirable drug loading relative to the other component combinations (experimental groups 9 and 10). Wherein, the elastic modulus of the group 5 (2% sodium alginate and 10% gelatin, 20% glutaraldehyde and 5% calcium chloride are used as cross-linking agents) corresponding to 30% deformation is better than that of other groups, and the maximum drug loading is also obviously better than that of other groups.
Drug loading curves for experimental groups 3,4,5 are shown in fig. 3. The results show that the drug loading speed of the microspheres in the experimental group 5 is the fastest, the drug loading rate after 2 hours is gradually gentle, the maximum drug loading rate is 100.3mg per 1ml microsphere, and the maximum drug loading rate is far higher than that of the microspheres with 40mg/ml of the highest drug loading rate of the products on the market.
In the embodiment 2, gelatin and sodium alginate are used as water phase materials, aldehyde and ionic crosslinking agents are used for crosslinking, and the influence of the proportion of each component on mechanical properties and drug loading is examined.
Aqueous phase: 10ml of an aqueous solution (heated to 60 ℃ C. For dissolution) was prepared with reference to Table 2.
An oil phase: liquid paraffin, 2% span80, 50ml (heated to 60 ℃).
The operation steps are as follows: adding the oil phase into a beaker, and stirring in a water bath at 60 ℃; adding the water phase, and stirring for 1 minute to realize emulsification; after emulsification, the mixture is transferred into an ice bath for cooling and stirring for 1 hour. Filtering with a screen, washing with n-hexane, washing with ethanol, and collecting. The mixture was transferred to 10ml of a 20% solution of crosslinking agent 1 (pH 8,4 ℃ C.) and stirred for 24hr to crosslink. After washing with water, the microspheres were transferred to 50ml of a 5% aqueous solution of crosslinker 2 and stirred for 3 hours for further crosslinking. The hydrogel microsphere suspension was wet screened.
Hydrogel microspheres screened to be 2000 mu m in size are put into a fixed container and are tiled to be at a fixed height, and the elastic modulus corresponding to 30% deformation is measured by a texture analyzer.
The modulus of elasticity of the composite hydrogel microspheres of each experimental group is shown in table 2. 0.25ml of each microsphere was transferred to a penicillin bottle, 1ml of 30mg/ml epirubicin aqueous solution was added, and the maximum drug loading was measured, and the results are shown in Table 2.
TABLE 2
The result shows that the mass ratio of the sodium alginate to the gelatin is 1:1, the preparation has better drug-loading rate, and on the basis, the mechanical property and the drug-loading rate are obviously increased along with the increase of the proportion of gelatin. If the proportion of sodium alginate is higher than that of gelatin, the drug loading rate is obviously reduced. Wherein, the group 5 (2% sodium alginate and 10% gelatin, 20% glutaraldehyde and 5% calcium chloride are used as cross-linking agents) has the corresponding elastic modulus better than other groups when deformed by 30%, and the drug loading is highest. The mechanical properties and the maximum drug loading of the microspheres prepared by the experimental groups 5, 11 and 12 with high gelatin concentration in the water phase are obviously superior to those of other experimental groups.
EXAMPLE 3 investigation of drug release behavior of drug-loaded microspheres according to the invention
The cumulative drug release profile was calculated by transferring 0.25ml microspheres of the loaded test groups 5, 11, 12, 14 of example 2 to a centrifuge tube containing 40ml physiological saline and placing the tube in a 37 ℃ water bath shaker for drug release test, and measuring the drug content in the extract at fixed time points of 0.5hr,1hr,2hr,5hr,24hr,48hr and 72 hr. The results are shown in FIG. 4. The results show that the drug release of each experimental group can reach a plateau within 3 days, and the accumulated released drug amount is more than 30%. The cumulative release rate of the microspheres in the experimental group 5 reaches 38% within 3 days, which is equivalent to that of the microspheres carrying medicine of each 1mL, and the microspheres can release 38mg of epirubicin within 3 days, which is far higher than the products of the microspheres carrying medicine on the market (the microspheres carrying medicine of each 1mL release 16mg of epirubicin at most).
Claims (3)
1. The epirubicin-loaded embolic microsphere is characterized in that sodium alginate and gelatin are used as water phase materials to prepare microemulsion with an oil phase containing an emulsifier, and the microsphere is crosslinked by an aldehyde crosslinking agent and an ionic crosslinking agent, and the embolic microsphere is prepared by the following method:
(1) Dissolving sodium alginate and gelatin in water to obtain water phase solution, wherein the mass and volume percentage concentration of the sodium alginate is 2%, and the mass and volume percentage concentration of the gelatin is 10%;
(2) Adding the aqueous phase solution prepared in the step (1) into an oil phase containing an emulsifier at 50-60 ℃, stirring, then reducing the temperature to 2-8 ℃, continuously stirring, wherein the mass and volume percentage concentration of the emulsifier in the oil phase is 0.5-2%, and the volume ratio of the aqueous phase to the oil phase is 1:5-1:10;
(3) Carrying out solid-liquid separation on the feed liquid in the step (2), and washing the oil phase remained on the surfaces of the microspheres;
(4) Adding the microspheres obtained in the step (3) into an aqueous solution of glutaraldehyde with the mass and volume percentage concentration of 20%, stirring and dispersing uniformly, reacting at 2-8 ℃, and then washing the microspheres with distilled water;
(5) Adding the microspheres obtained in the step (4) into an aqueous solution of an ionic crosslinking agent with the mass volume percentage concentration of 5%, stirring and dispersing uniformly, reacting at normal temperature, and then washing with distilled water to obtain the microspheres, wherein the ionic crosslinking agent is Ca 2+ And an anion selected from Cl - 、Br - 、NO 3 - 、HCO 3 - 、ClO - 、ClO 3 - 、ClO 4 - One or more of the following; the mass ratio of the sodium alginate to the gelatin to the aldehyde cross-linking agent to the ionic cross-linking agent is 1:1 to 50:1 to 10:1 to 10;
(6) And (3) adding the microspheres prepared in the step (5) into an aqueous solution of epirubicin, and loading the epirubicin through ionization.
2. Microsphere according to claim 1, characterized in that the emulsifier is selected from one or more of span, tween; the oil phase is selected from one or more of soybean oil, sesame oil, liquid paraffin or silicone oil.
3. Use of the microsphere according to claim 1 or 2 for the preparation of an antitumor drug carrier.
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