WO2017166903A1 - 一种改性海藻酸钠栓塞微球的制备方法 - Google Patents

一种改性海藻酸钠栓塞微球的制备方法 Download PDF

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WO2017166903A1
WO2017166903A1 PCT/CN2017/071080 CN2017071080W WO2017166903A1 WO 2017166903 A1 WO2017166903 A1 WO 2017166903A1 CN 2017071080 W CN2017071080 W CN 2017071080W WO 2017166903 A1 WO2017166903 A1 WO 2017166903A1
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sodium alginate
modified
modified sodium
solution
embolization
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French (fr)
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张丽萍
倪才华
白雪
石刚
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江南大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • 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
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • 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
    • A61L24/08—Polysaccharides
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the invention relates to a preparation method of a biodegradable drug carrier, and relates to the field of biomedicine, in particular to a method for synthesizing modified sodium alginate embolization microspheres.
  • Hepatocellular tumors are one of the more common malignant tumors in stem cells. The cases of this tumor account for about 6% of the world's diagnosed cancer cases.
  • the common treatment of tumors is surgical resection, but for patients with advanced tumors.
  • Interventional therapy such as ranscatheter arterial chemoembolization (TACE) is an ideal treatment option.
  • TACE ranscatheter arterial chemoembolization
  • the embolization of the microspheres injected into the tumor tissue by the catheter not only blocks the nutrient supply to the tumor tissue but also releases the anti-tumor drug. As the concentration of the anticancer drug in the tumor tissue increases, the lesion site is inhibited, thereby achieving the effect of treating the tumor.
  • SA Modified sodium alginate
  • seaweed gum and alginic acid is a natural biomacromolecular sodium salt extracted from natural brown algae. Because of its non-toxicity and good biocompatibility, it is widely used in food, medicine and other industries. In particular, in the field of biomedical materials, it has attracted attention as a drug carrier.
  • this paper firstly modified sodium alginate with taurine (TA) to obtain modified sodium alginate (SA-TA), and then prepared modified sodium alginate embolization microspheres.
  • the embolic microspheres can interact with anti-tumor drugs as a drug carrier.
  • the sodium alginate embolization microspheres have the advantages of being non-toxic, having good biocompatibility, and having a wide range of raw materials.
  • the modified modified sodium alginate molecule contains a large amount of sulfonic acid groups.
  • the sulfonic acid group in the taurine molecule is a strong ionizing group and is highly hydrophilic.
  • the group is introduced into the sodium alginate molecule to improve the loading of the modified sodium alginate embolization microsphere to the drug doxorubicin. Drug rate.
  • the viscosity of the modified sodium alginate in aqueous solution is reduced to some extent, and it is possible to prepare sodium alginate embolization microspheres under high concentration conditions.
  • the cross-linking reaction in order to avoid the toxicity of the small molecule glutaraldehyde, the polyaldehyde-based cellulose is obtained by oxidation of the polymer, and the cross-linking agent is added to the modified sodium alginate solution, and is formed by an emulsion cross-linking process. Embedding microspheres.
  • the technical scheme of the invention is: a preparation method of modified sodium alginate embolization microspheres, which comprises the following steps in sequence:
  • Amino acid is obtained by amidation reaction of taurine and sodium alginate, and the catalyst used is 1-ethyl-(3- Dimethylaminopropyl)carbonyldiimide hydrochloride and N-hydroxysuccinimide, the reaction is carried out in a phosphate buffer solution of pH 6.0;
  • modified sodium alginate product is precipitated with isopropyl alcohol, re-dissolved with deionized water, purified, freeze-dried, and redissolved to obtain a modified aqueous sodium alginate solution;
  • a reverse phase emulsion cross-linking method a high concentration of the modified aqueous sodium alginate solution is dispersed in a mineral oil to emulsify, and then a polyaldol-based cellulose is added as a crosslinking agent to prepare a modified sodium alginate embolization microsphere.
  • the weight ratio of the sodium alginate to taurine is 5: 1.49 to 5: 5.96; the weight concentration of sodium alginate in the phosphate buffer solution 1.8 wt%; molar ratio of sodium alginate, 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride and N-hydroxysuccinimide is 1:1:1 ; mechanical stirring at 25 ° C, reaction for 24h.
  • the modified sodium alginate solution is precipitated with 2 to 3 volumes of isopropanol, and then re-dissolved into a saturated solution with deionized water, and the operation is repeated 3 times, and then After dialysis for 48 h and freeze drying, a modified sodium alginate product was obtained.
  • a modified aqueous sodium alginate solution having a concentration of 8 to 10% by weight is used, and is dispersed in the mineral oil to control the volume ratio of the oil to water of 5:1 to 10: 1;
  • Stan 80 was added as a stabilizer at a concentration of 2% by volume, and dispersed at 30 ° C for 7 h.
  • the crosslinking agent polyaldehyde-based cellulose is added in an amount of 6 to 9% by weight of the modified sodium alginate, and the crosslinking agent polyaldehyde-based cellulose is previously dissolved in a volume ratio of 1 A mixed solvent of deionized water and ethanol of 1 was slowly added dropwise to the reaction system.
  • the preparation of the polyaldehyde-based cellulose is completed by the following steps:
  • a method for loading modified sodium alginate embolized microspheres for anticancer drug doxorubicin characterized in that: the method of loading drugs is ion exchange method, and the positively charged doxorubicin and negatively charged group sulfonic acid in solution The group is loaded by electrostatic adsorption, and the drug loading rate is as high as 35%.
  • the reaction system of the amidation reaction comprises a phosphate buffer solution (PBS, pH 6.0), 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride. Salt (EDC ⁇ HCl), N-hydroxysuccinimide (NHS), 25 ° C Mechanically stirred under conditions for 24 h, wherein the molar ratio of sodium alginate structural unit to 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride and N-hydroxysuccinimide was 1 :1:1.
  • PBS phosphate buffer solution
  • NDS N-hydroxysuccinimide
  • the modified alginate product after amidation is precipitated by isopropanol, redissolved three times, and then dialyzed against ultrapure water for 24 hours.
  • the modified sodium alginate aqueous solution is used as the water phase
  • the mineral oil (paraffin oil) is used as the oil phase
  • the oil-water ratio is controlled to be 5:1 to 10:1; the added volume percentage is 2 % of Span 80 is used as a stabilizer.
  • the polyaldehyde-based cellulose is added as a cross-linking agent for 20 h to obtain modified sodium alginate embolization microspheres.
  • the modified sodium alginate has a -COOH group in a phosphate buffer solution (pH 6.0), and the taurine molecule contains a -NH 2 group.
  • the amino group and the carboxyl group can be amidated under certain conditions to form an amidation.
  • the product when the molar amount of sodium alginate and taurine involved in the amidation reaction is different, can obtain amidation products of different reaction degrees. Therefore, in the design of the synthetic formulation, the present invention can effectively obtain the amidation product of the modified sodium alginate containing different sulfonic acid groups by adopting different molar ratios of sodium alginate and taurine.
  • the invention also provides a modified sodium alginate embolization microsphere for use in a chemotherapeutic drug carrier.
  • the modified sodium alginate embolization microspheres are directed to the blood vessels surrounding the tumor tissue, not only blocking the nutrient supply to the tumor tissue, but also releasing the anti-tumor drugs, which can kill the cancer as the concentration of the anticancer drug in the tumor tissue increases. cell.
  • the modified sodium alginate embolization microspheres can be completely degraded in the body and excreted by metabolism.
  • the present invention has at least the following advantages:
  • the surface of the plug microsphere contains a carboxyl group and a sulfonic acid group, the interaction with the antitumor drug doxorubicin can be enhanced, thereby increasing the load ratio of the carrier to the drug;
  • the surface of the plug microsphere contains a sulfonic acid group, the drug molecule is adsorbed, and the drug leakage caused by the physical adsorption of the surface of the plug microsphere is largely eliminated.
  • the cross-linking polyaldehyde-based cellulose replaces glutaraldehyde, avoiding toxicity.
  • Modified sodium alginate embolization microspheres are non-toxic, have good cell compatibility, and meet the safety standards for human use;
  • the amidated product is used for synthesizing embolization microspheres, the method is simple, the condition is mild, no catalyst and other additives are needed, no by-products are produced, the reaction is complete, and the product is pure.
  • Figure 1 shows the synthetic route of modified sodium alginate.
  • Figure 2 is an infrared spectrum of sodium alginate before and after modification, wherein a: sodium alginate (SA); b: taurine (TA); c: sea Sodium alginate and taurine amidation product ST11.
  • SA sodium alginate
  • TA taurine
  • ST11 sea Sodium alginate and taurine amidation product
  • FIG. 3 is an ultra-depth microscopic microscope photograph of modified sodium alginate embolization microspheres of the present invention, wherein a: before drug loading; b: 10 min after drug loading; c: 24 h after drug loading; d: cross-sectional view of embolization microspheres.
  • Figure 4 is a drug loading curve of the modified sodium alginate embolization microspheres of the present invention.
  • Figure 5 is a graph showing the cumulative release rate of the modified alginate drug-loaded embolic microspheres ST11 in a release medium of different pH in the present invention.
  • FIG. 6 is a drug release curve of a drug-loaded embolic microsphere produced by reacting taurine with sodium alginate in different molar ratios in a simulated body fluid in vitro, wherein ST10, ST11, ST12, and ST21 represent algae in the amidation reaction, respectively.
  • Figure 7 is a graph showing the cytotoxicity of modified sodium alginate embolized microspheres in the present invention.
  • reaction solution is precipitated with 2 to 3 volumes of isopropanol, and then re-dissolved into a saturated solution with deionized water, and the operation is repeated 3 times, followed by dialysis for 48 hours and freeze-drying to obtain a modified sodium alginate product.
  • the amount of taurine added was adjusted to obtain a series of modified sodium alginate products.
  • SA, TA represent sodium alginate and taurine, respectively.
  • the above modified sodium alginate ST10 is formulated into an aqueous solution having a weight concentration of 8%, and 5 mL of the solution is added to 50 mL of liquid paraffin containing 2% (v/v) Span 80, and after being uniformly dispersed, 3 mL of polyethylene is added. alcohol. After emulsification at 30 ° C for 4 h, the cross-linking polyaldehyde-based cellulose was added in an amount of 6 to 9% by weight of the modified sodium alginate, and dissolved in a mixed solvent of deionized water and ethanol in a volume ratio of 1:1. The mixture was slowly added dropwise to the reaction system, and the crosslinking reaction was carried out for 24 hours. After the completion of the reaction, the mixture was washed three times with n-hexane and isopropanol, filtered, and dried under vacuum.
  • the weight ratio of modified sodium alginate to taurine was 5: 1.49, and the other synthetic procedures were the same as in Example 1.
  • the weight ratio of the modified sodium alginate to taurine was 5: 2.98, and the other synthesis procedures were the same as in Example 1.
  • the weight ratio of the modified sodium alginate to taurine was 5: 5.96, and the other synthetic procedures were the same as in Example 1.
  • modified products ST10 and ST11 were weighed and prepared into aqueous solutions with mass fractions of 1%, 2%, 3%, 4%, 5%, 6%, and 8%, respectively, and viscosity changes were measured using a viscometer. .
  • Table 2 shows the change of the viscosity of the aqueous solution of sodium alginate before and after the modification at 25 ° C. It can be observed from the table that the viscosity of the modified sodium alginate is significantly lower than that of the unmodified sodium alginate. It is indicated that the modified sodium alginate has a reduced viscosity due to the presence of a sulfonic acid group. During the experiment, due to the reduced viscosity of the modified sodium alginate, it is possible to prepare a high concentration of modified aqueous sodium alginate solution.
  • Figure 2 shows that there are significant differences between the three curves a, b, and c.
  • a weaker-strength amide I band characteristic absorption peak appears at 1685 cm -1 , and an amide group will exhibit a characteristic absorption at 3500-3300 cm -1 .
  • Peaks, comparing a and c, show that the peak of c here is significantly enhanced, indicating the presence of the amide group in c. Comparing b and c, the double peak of the amino group at 3000 cm -1 disappeared, and the formation of the amide group was also confirmed from the side. It can be seen that the amide group was successfully introduced into the SA-TA.
  • a to c show the morphology of the embolized microspheres before drug loading, after 10 minutes of drug loading, and after drug loading for 24 hours. It can be seen from the figure that as the drug-loading time increases, the color of the embolized microspheres gradually deepens. This is mainly because the color of doxorubicin is red, and the amount of drug encapsulated in the microspheres increases with the increase of time during drug loading. The color of the embolic microspheres is deepened; the d-graph is an internal cross-sectional view of the embedding microspheres. It can be seen from the figure that there are many tiny hollow structures inside the embedding microspheres.
  • Figure 4 is a diagram showing the drug loading of modified sodium alginate embolized microspheres, in which ST10 has the lowest drug loading rate and ST21 has the highest drug loading rate.
  • the drug loading rate is very fast at the beginning of the load process, and tends to be gentle after about 10 hours. This is because the ion exchange method is used when the embolization microsphere is loaded with the drug, and the more the sulfonic acid group content in the embedding microsphere, the stronger the ion exchange capacity with the doxorubicin, and the higher the drug loading rate.
  • the figure shows the drug release of different modified sodium alginate plug microspheres in 0.01 M PBS (pH 7.4).
  • the ST10 embolization microspheres reached the maximum within the first 12 h, and then gradually became gentle.
  • the other ratio of embolic microspheres was about 32h
  • the cumulative release amount of the embolized microspheres reached the maximum, indicating that the functionalized modified embolic microspheres had a sustained release effect.
  • the reason is mainly because the sulfonic acid group adsorbs the drug molecule through the charge, which greatly eliminates the sudden release caused by the physical adsorption of the surface of the embedding microsphere, and plays a role of sustained release drug.
  • 3T3 cells frozen at -80 ° C were quickly thawed, transferred to a centrifuge tube containing 7 mL of RPMI-1640 medium, centrifuged at 800 rpm, and containing 10% calf serum.
  • the RPMI-1640 medium was pipetted into a single cell suspension, which was transferred to a 50 mL culture flask and cultured at 37 ° C in a 5% CO 2 incubator.
  • the extract of modified sodium alginate embolized microspheres in physiological saline was used as the research object, and the cytotoxicity of the extract formed by MTT method was tested to treat mouse fibroblasts at about 1.2 ⁇ 105/mL.
  • Each set has 4 parallel holes. After the culture plate was taken out, the cell growth was observed by an inverted microscope. After adding MTT 20 ⁇ L, and continuing to culture for 4 hours, the liquid in the wells in the culture plate was exhausted, dimethyl sulfoxide was added, and the absorbance value (A) was measured at 570 nm with a microplate reader to calculate the cell survival rate. .

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Abstract

一种改性海藻酸钠栓塞微球的制备方法以及改性海藻酸钠栓塞微球对于抗癌药物阿霉素的负载方法，制备方法包括以下步骤：(1)用牛磺酸对海藻酸钠改性，合成改性海藻酸钠；(2)以高浓度改性海藻酸钠水溶液为水相，矿物油为油相，以多醛基纤维素为交联剂，通过反相乳化方法制备出改性海藻酸钠栓塞微球。通过牛磺酸对海藻酸钠改性，一方面在栓塞微球中引入磺酸基团，提高了药物的负载率，另一方面降低了海藻酸钠溶液粘度，有利于配制高浓度的海藻酸钠溶液，从而获得规整的海藻酸钠栓塞微球。

Description

一种改性海藻酸钠栓塞微球的制备方法 技术领域
本发明涉及一种生物可降解的药物载体的制备方法，涉及生物医药领域，尤其涉及一种改性海藻酸钠栓塞微球的合成方法。
背景技术
肝细胞肿瘤是干细胞中比较常见的恶性肿瘤之一，患该肿瘤的病例约占世界上诊断出癌症病例的6％，常见的治疗肿瘤方案是采用手术切除法，但是对于中晚期的肿瘤患者来说,介入疗法如化学栓塞(ranscatheter arterial chemoembolization,TACE)是比较理想的治疗方案。在该方法中导管注射到肿瘤组织的栓塞栓塞微球不仅阻断对肿瘤组织的营养供给还可以释放抗肿瘤药物。随着肿瘤组织中抗癌药物浓度的升高，对病变部位起到抑制的作用，从而达到治疗肿瘤的效果。
改性海藻酸钠(SA)又名海藻胶、褐藻酸，是从天然褐藻中提取的天然生物大分子钠盐。因其具有无毒性和良好的生物相容性，来源广泛而被广泛应用于食品、医药等行业。特别是在生物医药材料方面，作为药物载体而备受关注。以海藻酸钠作为原料制备非载药栓塞栓塞微球已有一些报道，但是纯海藻酸钠用来制备载药栓塞微球尚有缺陷:一是缺乏合适的载药基团，海藻酸钠中的羧基是弱电离基团，与正电荷药物作用力不强，因此负载率有限，反应速度慢；二是纯海藻酸钠溶液粘度过高，乳化时间过长，栓塞微球制备困难。戊二醛是一种常用的交联剂，用来交联聚乙烯醇、壳聚糖等高聚物，但是由于其毒性，在医用材料应用领域具有一定局限性。
发明内容
针对上述缺陷，本文首先使用牛磺酸(TA)对海藻酸钠改性，得到改性海藻酸钠(SA-TA)，然后再制备改性海藻酸钠栓塞微球。该栓塞微球可以与抗肿瘤药物相互作用而作为药物载体。海藻酸钠栓塞微球具有无毒，生物相容性好，并且原料来源广泛等优点。改性后的改性海藻酸钠分子中含有大量的磺酸基团。牛磺酸分子中的磺酸基是强电离基团，亲水性极强，将该基团引入到海藻酸钠分子中，可以提高改性海藻酸钠栓塞微球对药物阿霉素的载药率。同时由于磺酸基团的存在，在一定程度上降低了改性海藻酸钠在水溶液中的粘度，对实现高浓度条件下制备海藻酸钠栓塞微球提供了可能。在交联反应中，为了避免小分子戊二醛的毒性，通过高聚物氧化得到多醛基纤维素，以此为交联剂加入到改性海藻酸钠溶液中，通过乳化交联工艺形成栓塞微球。
本发明的技术方案是：一种改性海藻酸钠栓塞微球的制备方法，依次包括以下步骤：
1)将牛磺酸和海藻酸钠通过酰胺化反应得到改性海藻酸钠，所用催化剂为1-乙基-(3- 二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺，反应在pH 6.0的磷酸盐缓冲溶液中进行；
2)将所述改性海藻酸钠产物用异丙醇沉淀、用去离子水重新溶解，经纯化后冷冻干燥，重新溶解得到改性海藻酸钠水溶液；
3)采用反相乳化交联方法，将高浓度的所述改性海藻酸钠水溶液分散在矿物油中乳化，再加入多醛基纤维素作为交联剂制备改性海藻酸钠栓塞微球。
作为一种优选的技术方案，所述步骤1)中，所述海藻酸钠与牛磺酸的重量比为5:1.49至5:5.96；海藻酸钠在磷酸盐缓冲溶液中的重量百分浓度为1.8wt％；海藻酸钠、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺的摩尔比为1：1：1；在25℃温度下机械搅拌，反应24h。
作为一种优选的技术方案，所述步骤2)中，改性海藻酸钠溶液用2～3倍体积的异丙醇沉淀，再用去离子水重新溶解成饱和溶液，循环操作3次，再经过透析48h和冷冻干燥，得到改性海藻酸钠产物。
作为一种优选的技术方案，所述步骤3)中，使用重量百分比为8～10％高浓度的改性海藻酸钠水溶液，分散在矿物油中，控制油水体积比例为5:1～10：1；添加体积百分浓度为2％的Span 80做稳定剂，在30℃条件下分散7h。
作为一种优选的技术方案，加入交联剂多醛基纤维素的用量是改性海藻酸钠重量的6～9％，将所述交联剂多醛基纤维素预先溶解在体积比为1:1的去离子水与乙醇的混合溶剂中，缓慢滴加到反应体系中去。
作为一种优选的技术方案，所述多醛基纤维素的制备通过下列步骤完成：
1)称取2.0g羧甲基纤维素钠粉末加入到250ml烧瓶中，所用羧甲基纤维素钠20g/L在水中的粘度为300-800mpa.s,再加入80mL蒸馏水，在25℃下不断搅拌使其溶解完全；
2)将1.5g高碘酸钠溶解在20ml蒸馏水中，再缓慢加入到所述烧瓶里，该反应在25℃下持续进行24小时；
3)然后加入20mL乙二醇到烧瓶中停止反应，30分钟后将混合物倒入透析袋(MWCO 3500)，在蒸馏水中彻底透析，最后通过冷冻干燥得到产物，即为多醛基纤维素。
一种改性海藻酸钠栓塞微球对于抗癌药物阿霉素的负载方法，其特征在于：负载药物的方式为离子交换法，溶液中含正电荷的阿霉素与负电荷基团磺酸基团通过静电吸附载药，载药率高达35％。
具体的，所述步骤1)中，酰胺化反应的反应体系包含磷酸盐缓冲溶液(PBS，pH 6.0)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)、N-羟基丁二酰亚胺(NHS)，25℃ 条件下机械搅拌24h，其中海藻酸钠结构单元与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺投料摩尔比为1：1：1。
具体的，所述步骤2)中，酰胺化后的改性海藻酸钠产物经异丙醇沉淀、重新溶解3次后，超纯水透析24h。
具体的，所述步骤3)中，将改性海藻酸钠水溶液作为水相，以矿物油(石蜡油)为油相，控制油水比例5:1～10：1；添加体积百分浓度为2％的Span 80做稳定剂，在30℃条件下分散7h后，加入多醛基纤维素做交联剂，反应20h,得到改性海藻酸钠栓塞微球。
改性海藻酸钠在磷酸盐缓冲溶液中(pH 6.0)中存在-COOH基团，牛磺酸分子中含有-NH2基团，氨基和羧基在一定条件下可以发生酰胺化反应，生成酰胺化产物，当参与酰胺化反应的海藻酸钠和牛磺酸的摩尔量不同时，可以得到不同反应程度的酰胺化产物。因此本发明在设计合成配方时，采取海藻酸钠和牛磺酸的不同投料摩尔比，可以有效地得到含有不同磺酸基含量的改性海藻酸钠的酰胺化产物。
本发明还提供一种改性海藻酸钠栓塞微球在化疗药物载体中的应用。改性海藻酸钠栓塞微球导向肿瘤组织周围的血管中，不仅阻断对肿瘤组织的营养供给，还可以释放抗肿瘤药物，随着肿瘤组织中抗癌药物浓度的升高，可杀灭癌细胞。改性海藻酸钠栓塞微球在体内可以完全降解，通过代谢排出体外。
借由上述方案，本发明至少具有以下优点：
1.由于该栓塞微球表面含有羧基和磺酸基团，可以增强与抗肿瘤药物阿霉素相互作用，因而可以提高载体对药物的负载率；
2.由于该栓塞微球表面含有磺酸基团，吸附药物分子，大大消除了栓塞微球表面物理吸附而引起的药物泄露。
3.交联剂多醛基纤维素代替戊二醛，避免了毒性。
4.改性海藻酸钠栓塞微球无毒，细胞相容性较好，符合人体使用的安全性标准；
5.将酰胺化产物用于合成栓塞栓塞微球，方法简单、条件温和，不需要任何催化剂和其他添加剂，无副产物产生，反应完全，产物纯净。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1改性海藻酸钠的合成路线。
图2改性前后海藻酸钠的红外谱图，其中a：海藻酸钠(SA)；b：牛磺酸(TA)；c：海 藻酸钠与牛黄酸酰胺化产物ST11。
图3为本发明中改性海藻酸钠栓塞微球的超景深显微镜照片，其中a：载药前；b：载药后10min；c：载药后24h；d：栓塞微球剖面图。
图4为本发明中改性海藻酸钠栓塞微球的载药曲线。
图5为本发明中改性海藻酸钠载药栓塞微球ST11在不同pH的释放介质中的累计释放率曲线。
图6为本发明中牛磺酸与海藻酸钠以不同摩尔比反应产生的载药栓塞微球在体外模拟体液中的药物释放曲线，其中ST10、ST11、ST12、ST21分别表示酰胺化反应中海藻酸钠与牛磺酸的投料重量比为5：0、5：1.49、5：2.98和5：5.96时的酰胺化产物制备的栓塞微球。
图7为本发明中改性海藻酸钠栓塞微球的细胞毒性结果。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1
1)改性海藻酸钠的制备；
将5g海藻酸钠(SA)加入300mL磷酸盐缓冲溶液(PBS，pH 6.0)中，完全溶解后加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)，机械搅拌20min后加入N-羟基丁二酰亚胺(NHS)和牛磺酸(TA)，其中海藻酸钠(SA)与1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)及N-羟基丁二酰亚胺(NHS)的投料摩尔比为1：1：1，在25℃下反应24h。待反应完成后用反应液2～3倍体积的异丙醇沉淀，再用去离子水重新溶解成饱和溶液，循环操作3次，再经过透析48h和冷冻干燥，得到改性海藻酸钠产物。如表1所示，调节牛磺酸的加入量，得到一系列的改性海藻酸钠产物。
表1 改性海藻酸钠合成配方及元素分析结果
Figure PCTCN2017071080-appb-000001
Figure PCTCN2017071080-appb-000002
SA,TA分别代表海藻酸钠和牛磺酸。
2)多醛基纤维素的制备：
称取2.0g的羧甲基纤维素钠粉末加入到250ml烧瓶中，20g/L羧甲基纤维素钠在水中的粘度为300-800mpa.s，再加入80mL蒸馏水，在25℃下不断搅拌使其溶解完全；将1.5g高碘酸钠溶解在20ml蒸馏水中，再缓慢加入到烧瓶里.该反应在25℃下持续进行24小时；然后加入20mL乙二醇到烧瓶中停止反应，30分钟后将混合物倒入透析袋(MWCO 3500)，在蒸馏水中彻底透析，最后通过冷冻干燥得到产品，即为多醛基纤维素。
3)改性海藻酸钠栓塞微球的制备:
将上述改性海藻酸钠ST10配成重量浓度为8％的水溶液，取5mL该溶液加入到50mL含2％(v/v)Span 80的液体石蜡中，待分散均匀后加入3mL的聚乙二醇。30℃条件下乳化4h，加入交联剂多醛基纤维素，其用量是改性海藻酸钠重量的6～9％，预先溶解在体积比为1:1的去离子水与乙醇的混合溶剂中，缓慢滴加到反应体系中去，交联反应24h，反应结束后依次用正己烷、异丙醇洗涤3次，过滤后真空干燥。
实施例2
改性海藻酸钠与牛磺酸重量比为5：1.49，其他合成过程和实施例1相同。
实施例3
改性海藻酸钠与牛磺酸重量比为5：2.98，其他合成过程和实施例1相同。
实施例4
改性海藻酸钠与牛磺酸重量比为5：5.96，其他合成过程和实施例1相同。
实施例5
分别称取一定量的改性产物ST10、ST11，配制成质量分数分别为1％、2％、3％、4％、5％、6％、8％的水溶液，使用粘度计分别测量其粘度变化。
表2 改性前后海藻酸钠水溶液粘度变化
Figure PCTCN2017071080-appb-000003
Figure PCTCN2017071080-appb-000004
表2是在25℃条件下改性前后海藻酸钠的水溶液粘度的变化情况，从表中可以观察到改性后的海藻酸钠粘度较之未改性的海藻酸钠的粘度明显降低，这说明改性海藻酸钠由于磺酸基团的存在，粘度降低。在实验过程中，由于改性海藻酸钠的粘度降低，为高浓度改性海藻酸钠水溶液的制备提供了可能。
实施例6
分别将SA、TA、ST11提纯冷冻干燥后，使用全反射傅里叶红外光谱仪在4000～500cm-1的波数范围内进行红外扫描，得到红外谱图。
图2显示，a、b、c三条曲线存在明显差异，c在1685cm-1处出现一较弱强度的酰胺Ⅰ带特征吸收峰，同时酰胺基会在3500～3300cm-1处会出现一特征吸峰，对比a和c可以看出，c在此处的峰得到了明显加强，说明了c中酰胺基的存在。对比b和c，c中氨基在3000cm-1处的双峰消失了，也从侧面证明了酰胺基的生成。由此可知：酰胺基成功引入到SA-TA中。
实施例7
精确称取20mg干燥过筛后的空白栓塞微球加入到10mL浓度为1.5mg/mL的盐酸阿霉素溶液中，室温下避光磁力搅拌，盐酸阿霉素溶液颜色逐渐变浅，栓塞微球呈深红色。通过使用紫外/可见分光光度计，检测波长在483nm处栓塞微球中盐酸阿霉素的含量，并绘制栓塞微球负载药物曲线。
图3中a～c分别表示载药前、载药10min后和载药24h后的栓塞微球形态。从图中可以看出随着载药时间的增加，栓塞微球颜色逐渐加深，这主要是因为阿霉素的颜色为红色，载药过程中随着时间的增加，栓塞微球包载药物增多，栓塞微球的颜色随之加深；d图是栓塞微球的内部剖面图，从图中可以看出栓塞微球内部存在很多微小的空洞结构。
图4是改性海藻酸钠栓塞微球的药物负载情况图，其中ST10载药率最低，ST21载药率最高。在负载过程中开始时载药速度很快，约在10h后开始趋于平缓。这是因为栓塞微球负载药物时采用的是离子交换法，栓塞微球中磺酸基团含量越多，与阿霉素之间离子交换能力越强，载药率越高。
实施例8
分别称取20mg载药栓塞微球ST10、ST21、ST11、ST12于20mL 0.01M PBS(pH 7.4)的溶液中，将其置于恒温水浴振荡器中，温度控制在37±0.5℃，定点量取5mL上清液，通过紫外/可见分光光度计检测缓冲液中药物含量，重复操作3次取平均值，按下式计算累积释放量。每次取样后补加相同体积的新鲜释放液。
该图显示了不同的的改性海藻酸钠栓塞微球在0.01M PBS(pH 7.4)中的药物释放情况，图中ST10栓塞微球在开始的12h内释放达到最大，随后慢慢趋于平缓，而其他比例栓塞微球在约32h时，栓塞微球的药物累计释放量达到最大，表明功能化的改性栓塞微球具有缓释效果。其原因主要是由于磺酸基团通过电荷吸附药物分子，大大消除了栓塞微球表面物理吸附而引起的突释，起到了缓释药物的作用。
实施例9
改性海藻酸钠栓塞微球的细胞毒性：
在温度为37℃的水浴锅中，迅速解冻-80℃冻存的3T3细胞，将其移入到含有7mL的RPMI-1640培养液的离心管中，以800rpm速度离心，用含有10％小牛血清的RPMI-1640培养液吹打细胞制成单细胞悬液，将其移入到50mL的培养瓶中，在37℃，5％CO2孵箱中培养。
以改性海藻酸钠栓塞微球在生理盐水中的浸提液为研究对象，采用MTT法对其形成的浸提液的细胞毒性进行测试，以约1.2×105/mL将小鼠成纤维细胞接种于96孔板，每孔100μL，分别培养24h和48h，吸出每孔中的原培养液，每孔加入100μL的阴性对照液(样品组是含10％小牛血清的RPMI-1640培养液)、阳性对照液(0.64％苯酚培养基)、样品组(样品组分别含t＝24h和t＝48h的10％小牛血清的RPMI-1640培养液)，继续置于37℃、5％CO2培养箱中培养，分别培养24h、48h。每组设4个平行孔。取出培养板后通过倒置显微镜观察、评价细胞生长状况。后加入MTT 20μL，继续培养4h后，将培养板中的小孔内的液体吸尽后，加入二甲基亚砜，用酶标仪于570nm处测其吸光度值(A)，计算细胞存活率。3T3在不同浓度的栓塞微球浸提液中的细胞存活率,在37℃下，24h和48h的栓塞微球浸提液中培养的3T3细胞，孵育24h后，其细胞的相对增值率均达到90％以上，这表明3T3细胞在以浸提液稀释的细胞培养基中生长状态良好，表明该栓塞微球无细胞毒性，细胞相容性良好。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (7)

  1. 一种改性海藻酸钠栓塞微球的制备方法，其特征在于：包括以下步骤：
    1)将牛磺酸与海藻酸钠通过酰胺化反应得到改性海藻酸钠产物，所用催化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺，反应在pH 6.0的磷酸盐缓冲溶液中进行；
    2)将所述改性海藻酸钠产物用异丙醇沉淀、用去离子水重新溶解，经纯化后冷冻干燥，重新溶解得到改性海藻酸钠水溶液；
    3)采用反相乳化交联方法，将高浓度的所述改性海藻酸钠水溶液分散在矿物油中乳化，再加入多醛基纤维素作为交联剂制备改性海藻酸钠栓塞微球。
  2. 根据权利要求1所述的改性海藻酸钠栓塞微球的制备方法，其特征在于：所述步骤1)中，所述海藻酸钠与牛磺酸的重量比为5:1.49至5:5.96；海藻酸钠在磷酸盐缓冲溶液中的重量百分浓度为1.8wt％；海藻酸钠、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和N-羟基丁二酰亚胺的摩尔比为1：1：1；在25℃温度下机械搅拌，反应24h。
  3. 根据权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于：所述步骤2)中，改性海藻酸钠水溶液用2～3倍体积的异丙醇沉淀，再用去离子水重新溶解成饱和溶液，循环操作3次，再经过透析48h和冷冻干燥，得到改性海藻酸钠产物。
  4. 根据权利要求1所述的改性海藻酸钠栓塞微球的制备方法，其特征在于:所述步骤3)中，使用重量百分比为8～10％高浓度的改性海藻酸钠水溶液，分散在矿物油中，控制油水体积比例为5:1～10：1；添加体积百分浓度为2％的Span 80做稳定剂，在30℃条件下分散7h。
  5. 根据权利要求1所述改性海藻酸钠栓塞微球的制备方法，其特征在于:加入交联剂多醛基纤维素的用量是改性海藻酸钠重量的6～9％，将所述交联剂多醛基纤维素预先溶解在体积比为1:1的去离子水与乙醇的混合溶剂中，缓慢滴加到反应体系中去。
  6. 根据权利要求1所述的改性海藻酸钠栓塞微球的制备方法，其特征在于:所述多醛基纤维素的制备通过下列步骤完成：
    1)称取2.0g羧甲基纤维素钠粉末加入到250ml烧瓶中，所用羧甲基纤维素钠20g/L在水中的粘度为300-800mpa.s,再加入80mL蒸馏水，在25℃下不断搅拌使其溶解完全；
    2)将1.5g高碘酸钠溶解在20ml蒸馏水中，再缓慢加入到所述烧瓶里，该反应在25℃下持续进行24小时；
    3)然后加入20mL乙二醇到烧瓶中停止反应，30分钟后将混合物倒入透析袋(MWCO 3500)，在蒸馏水中彻底透析，最后通过冷冻干燥得到产物，即为多醛基纤维素。
  7. 一种改性海藻酸钠栓塞微球对于抗癌药物阿霉素的负载方法，其特征在于：负载药物 的方式为离子交换法，溶液中含正电荷的阿霉素与负电荷基团磺酸基团通过静电吸附载药，载药率高达35％。
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