WO2014005402A1 - 一种具有多孔壳层的plga/碳酸钙复合微球及其制备方法 - Google Patents

一种具有多孔壳层的plga/碳酸钙复合微球及其制备方法 Download PDF

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WO2014005402A1
WO2014005402A1 PCT/CN2012/086491 CN2012086491W WO2014005402A1 WO 2014005402 A1 WO2014005402 A1 WO 2014005402A1 CN 2012086491 W CN2012086491 W CN 2012086491W WO 2014005402 A1 WO2014005402 A1 WO 2014005402A1
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plga
calcium carbonate
stirring
microspheres
aqueous solution
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王迎军
程德林
曹晓东
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South China University of Technology SCUT
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/20—Compounding polymers with additives, e.g. colouring
    • C08J3/205—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase
    • C08J3/21—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase
    • C08J3/212—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase and solid additives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
    • B01J13/125—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution by evaporation of the solvent
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
    • C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones

Definitions

  • the invention relates to a preparation method of a degradable composite microsphere, in particular to a preparation method of a PLGA/calcium carbonate composite microsphere having a porous shell layer.
  • Polylactic-glycolic acid is an FDA-approved biomaterial with good biocompatibility and degradability.
  • PLGA microspheres are good carriers for various drugs and genes, and can effectively achieve sustained release of drugs.
  • the degradation products of PLGA itself are acidic, which may inactivate the drug contained and may cause immune rejection in the body.
  • calcium phosphates such as HA and ⁇ -TCP are often compounded in the PLGA matrix.
  • the addition of calcium phosphate not only neutralizes the acidic degradation products of PLGA, but also improves the mechanical properties and osteoconductivity of the PLGA matrix.
  • calcium phosphates tend to degrade slowly, especially HA, and biodegradability is not ideal.
  • calcium carbonate is very biodegradable. Moreover, calcium carbonate also has good biocompatibility and osteoconductivity, and can form a good bonding surface with new bone. Many studies have also shown that calcium carbonate can effectively delay the degradation of polyester polymers. Ara M et al. (Ara M, Watanabe M, Imai Y. Biomaterials 2002; 23: 2479-2483) demonstrated that calcium carbonate can effectively inhibit the degradation of PLGA films; Kasuga T, Maeda H, Kato K, Nogami M, Hata K, Ueda M.
  • stents There are two main types of stents currently used for bone repair: preformed stents and injectable stents.
  • the preformed stent has good mechanical properties and structural diversity, but it needs to be implanted by surgery, which often causes greater trauma to the patient.
  • Injectable stents can be implanted in the body with minimal trauma and can accommodate irregularly shaped defects.
  • the polymer microspheres have good mechanical properties, sustained release properties of the drug, and pore conditions favorable for cell growth. Therefore, the application of microspheres as an injectable stent has received increasing attention.
  • Zhong Yanqiang et al (CN200610118183.2) disclosed VEGF sustained-release injection microspheres Preparation of the rack. Kim TK et al.
  • Porous PLGA injectable microspheres were prepared. Many studies have shown that the formation of pore structures on microspheres facilitates the loading and growth of cells on microspheres, so porous microspheres are more suitable as injectable stents than conventional solid microspheres. The current construction of pore structures in polyester-based microspheres often requires the addition of other components as pore formers. Gao Changyou et al.
  • CN200410052981.0 discloses a method for preparing polylactic acid porous microspheres by constructing a pore structure by adding a poor solvent to an organic solution; Yang Y, Bajaj N, Xu P, Ohn K , Tsifansky MD, Yeo Y. Biomaterials 2009; 30: 1947-1953) Porous PLGA microspheres were prepared by the addition of ammonium bicarbonate to the internal aqueous phase using the double emulsion method. The formation of the pore structure by the pore former requires complete removal of the pore former, otherwise the residual pore former will adversely affect the practical application of the microsphere. Summary of the invention
  • the object of the present invention is to overcome the deficiencies in the preparation of existing microspheres and to provide a method for preparing PLGA/calcium carbonate composite microspheres having a porous shell layer.
  • the calcium carbonate component has good biodegradability and can neutralize the acidic degradation products of PLGA.
  • the calcium carbonate component can build a porous structure on the surface of the composite microsphere without the need for any porogen.
  • Another object of the present invention is to provide a PLGA/calcium carbonate composite microsphere of a porous shell layer prepared by the above method.
  • a method for preparing a PLGA/calcium carbonate composite microsphere having a porous shell layer comprises the following steps: a. Dissolving PLGA in an organic solvent of dichloromethane to obtain a PLGA oil phase; adding calcium carbonate powder to the PLGA oil phase In the middle, after stirring and sonication, an organic/inorganic homogeneous mixture is obtained;
  • the gluconolactone is dissolved in the PVA aqueous solution to obtain an acidic PVA aqueous solution;
  • the mixture obtained in the step a is dispersed in the acidic PVA aqueous solution in the step b under stirring to obtain an oil-in-water single emulsion;
  • step d Collect the microspheres in step d, wash them with deionized water, and freeze them.
  • the mass to volume ratio of PLGA to methylene chloride in step a is 1/30 to 1/4 g/ml; and the mass ratio of calcium carbonate to PLGA is 1/20 to 1/2.
  • the mass-to-volume ratio of PVA to water in the PVA aqueous solution of step b is 1/500 to 1/100 g/ml ; and the mass ratio of gluconolactone to PVA is 1/10 to 1/5.
  • the stirring rate under reduced pressure is 200 to 400 rpm, and the stirring time is
  • the temperature of the freeze-drying in step e is -24 ° C for 48 hours.
  • the stirring speed in step a is 250 to 400 rpm, and the stirring time is 5 to 15 minutes.
  • the ultrasonic power in step a is 250 to 350 w, and the ultrasonic time is 5 to 15 min.
  • the PLGA/calcium carbonate composite microspheres with porous shell layer prepared by the above method are mainly composed of PLGA and calcium carbonate, and also have calcium carbonate as a pore-forming agent, the composite microspheres have a solid structure inside, and the microspheres have pores on the surface thereof. Structure, microspheres are 100 ⁇ 500 um in diameter and have a pore size of l ⁇ 10 um.
  • the present invention neutralizes the acidic degradation products of PLGA by compounding a calcium carbonate having a better biodegradability than apatite in PLGA microspheres.
  • the pore structure is formed on the surface of the microsphere by using the calcium carbonate component, and no external pore former is introduced, thereby improving the preparation method of the microsphere and completely avoiding the problem of the pore former.
  • the composite microspheres obtained by the method not only have uniform morphology, but also a large number of regular open pores are formed on the surface of the microspheres to form a porous shell layer, which is more favorable for the growth of cells on the microspheres.
  • Figure 1 is a surface electron micrograph of the microsphere in Example 1;
  • Figure 2 is an internal sectional view of the microspheres in Example 1;
  • Figure 3 is a surface electron micrograph of the microspheres in Example 2.
  • Figure 4 is a surface electron micrograph of the microspheres in Example 3.
  • Fig. 5 is a graph showing the proliferation of osteoblastoma cells on the surface of pure PLGA and the composite microspheres of Example 1 of the present invention. detailed description
  • gluconolactone 0.5 g was weighed and dissolved in 500 ml of PVA aqueous solution to obtain an acidic PVA aqueous solution.
  • the PLGA/calcium carbonate mixture was added dropwise to the acidic PVA aqueous solution under stirring at 350 rpm to obtain an oil-in-water single emulsion.
  • the emulsion was continuously stirred (350 rpm) in a fume hood for 20 h to volatilize the methylene chloride in the emulsion and the oil droplets solidified into spheres.
  • the obtained microspheres were collected, washed 3 times with deionized water, and lyophilized at -24 °C for 48 hours, and the dried microspheres were stored.
  • gluconolactone 0.3 g was weighed and dissolved in a PVA aqueous solution to obtain an acidic PVA aqueous solution.
  • the PLGA/calcium carbonate mixture was added dropwise to the acidic PVA aqueous solution under stirring at 400 rpm to obtain an oil-in-water single emulsion.
  • the emulsion was continuously stirred (400 rpm) in a fume hood for 20 h to volatilize the methylene chloride in the emulsion and the oil droplets solidified into spheres.
  • the obtained microspheres were collected, washed 3 times with deionized water, and lyophilized at -24 °C for 48 hours, and the dried microspheres were stored.
  • gluconolactone 0.4 g was weighed and dissolved in a PVA aqueous solution to obtain an acidic PVA aqueous solution.
  • the PLGA/calcium carbonate mixture was added dropwise to an acidic PVA aqueous solution under stirring at 400 rpm to obtain an oil-in-water single emulsion.
  • the emulsion was continuously stirred (250 rpm) in a fume hood for 20 h to volatilize the methylene chloride in the emulsion and the oil droplets solidified into spheres.
  • the obtained microspheres were collected, washed 3 times with deionized water, and lyophilized at -24 ° C for 48 hours, and the dried microspheres were stored.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

一种具有多孔壳层的PLGA/碳酸钙复合微球及其制备方法，包括以下步骤：a. 将PLGA溶解于二氯甲烷有机溶剂中，得到PLGA油相；将碳酸钙粉末添加到PLGA油相中，通过搅拌和超声处理后，得到有机/无机的均匀混合液；b. 将葡萄糖酸内酯溶解于PVA水溶液中，得到酸性PVA水溶液；c. 在搅拌条件下将步骤a得到的混合液分散到步骤b中的酸性PVA水溶液里，得到水包油的单乳液；d. 在减压条件下继续搅拌，使油相液滴中的二氯甲烷挥发，得到固化的复合微球；e. 收集步骤d中的微球，用去离子水洗涤，冷冻干燥即可。这种方法不引入成孔剂，制备的复合微球表面存在多孔结构，有利于细胞的生长。

Description

一种具有多孔壳层的 PLGA/a酸钙复合微球及其制备方法 技术领域
本发明涉及一种可降解复合微球的制备方法， 具体是具备多孔壳层的 PLGA/碳酸钙复合微球的制备方法。 背景技术
聚乳酸乙醇酸共聚物 （polylactic-glycolic acid, PLGA) 是一种得到 FDA 批准的生物材料， 具备良好的生物相容性和降解性。 PLGA微球是各种药物和 基因的良好载体， 能够有效实现药物的缓释。 然而 PLGA本身的降解产物为 酸性， 有可能使所载的药物失活， 在体内还可能引起免疫排斥反应。为了克服 这一问题， 人们常常在 PLGA基体中复合 HA、 β-TCP等磷酸钙类物质。 添加 磷酸钙类物质不仅能中和 PLGA的酸性降解产物， 还能提高 PLGA基体的力 学性能和骨传导性。 然而， 磷酸钙类物质往往降解较慢， 尤其是 HA, 生物降 解性不理想。相比之下， 碳酸钙的生物降解性很好。而且碳酸钙同样具备良好 的生物相容性和骨传导性， 能够与新生骨形成较好的结合面。许多研究也已经 证明碳酸钙能够有效延缓聚酯类聚合物的降解。 Ara M等（Ara M, Watanabe M, Imai Y. Biomaterials 2002; 23: 2479-2483 ) 证明碳酸钙能够有效抑制 PLGA薄 膜的降解； Kasuga T等（Kasuga T, Maeda H, Kato K, Nogami M, Hata K, Ueda M. Biomaterials 2003; 24: 3247-3253 ) 还证明碳酸钙不仅能提高 PLGA的力学性 能， 而且能够促进 PLGA的矿化。 然而目前这些关于聚合物 /碳酸钙复合物的 研究多集中于碳酸钙组分对复合薄膜物化性能的影响， 涉及聚合物 /碳酸钙复 合微球的研究还很少。
目前用于骨修复的支架主要有两种类型： 预成型支架和可注射支架。 预成 型支架力学性能和结构多样性较好，但需要通过手术植入，往往会给病人造成 较大的创伤。可注射支架能在尽可能减少创伤的前提下植入体内，而且能够适 应形状不规则的缺损部位。聚合物微球具备较好的力学性能、药物缓释性能以 及有利于细胞生长的孔隙条件。因此，微球作为一种可注射支架的应用也越来 越受到关注。 钟延强等 （CN200610118183.2 ) 公开了 VEGF缓释注射微球支 架的制备。 Kim TK等（Kim TK, Yoon JJ, Lee DS, Park TG. Biomaterials 2006,27: 152-159) 制备了多孔 PLGA可注射微球。 许多研究表明在微球上构建孔结构 有利于细胞在微球上的负载和生长， 因此相比于传统实心微球， 多孔微球更适 合作为可注射支架。目前在聚酯类微球中构建孔结构往往需要添加其他组分作 为成孔剂。 高长有等 （CN200410052981.0 ) 公开了一种制备聚乳酸多孔微球 的方法， 通过在有机溶液中添加不良溶剂构建孔结构）； Yang Y等 （Yang Y, Bajaj N, Xu P, Ohn K, Tsifansky MD, Yeo Y. Biomaterials 2009; 30: 1947-1953 ) 利用双乳液法， 通过在内水相中添加碳酸氢铵制备了多孔 PLGA微球。 通过 成孔剂构建孔结构需要彻底去除成孔剂，否则残留的成孔剂会对微球的实际应 用产生不利影响。 发明内容
本发明的目的在于克服现有微球制备存在的不足， 提供一种具有多孔壳层 的 PLGA/碳酸钙复合微球的制备方法。 碳酸钙组分具备较好的生物降解性， 而且可以中和 PLGA 的酸性降解产物。 同时， 碳酸钙组分可以在复合微球表 面构建多孔结构， 无需外加任何成孔剂。
本发明另一目的在于提供上述方法制备的多孔壳层的 PLGA/碳酸钙复合 微球。
本发明的目的通过以下技术方案实现：
一种具有多孔壳层的 PLGA/碳酸钙复合微球的制备方法， 包括以下步骤: a、 将 PLGA溶解于二氯甲垸有机溶剂中， 得到 PLGA油相； 将碳酸钙粉 末添加到 PLGA油相中， 通过搅拌和超声处理后， 得到有机 /无机的均匀混合 液；
b、 将葡萄糖酸内酯溶解于 PVA水溶液中， 得到酸性 PVA水溶液； c、在搅拌条件下将步骤 a得到的混合液分散到步骤 b中的酸性 PVA水溶 液里， 得到水包油的单乳液；
d、 在减压条件下继续搅拌， 使油相液滴中的二氯甲垸挥发， 得到固化的 复合微球；
e、 收集步骤 d中的微球， 用去离子水洗涤， 冷冻干燥即可。
优选地， 步骤 a中 PLGA与二氯甲垸的质量体积比为 1/30〜1/4 g/ml; 碳 酸钙与 PLGA的质量比为 1/20〜1/2。 优选地， 步骤 b的 PVA水溶液中 PVA与水的质量体积比为 1/500〜1/100 g/ml; 葡萄糖酸内酯和 PVA的质量比为 1/10〜1/5。
优选地， 所述 PLGA分子量 Mw=30〜 10 kDa, LA/GA=50/50。
优选地， 步骤 d中减压条件下搅拌的速率为 200〜400 rpm, 搅拌时间为
12〜24 h。
优选地， 步骤 e中冷冻干燥的温度为 -24 °C， 时间为 48小时。
优选地， 步骤 a中搅拌速度 250〜400 rpm, 搅拌时间为 5〜15 min。
优选地， 步骤 a中超声功率 250〜350 w， 超声时间为 5〜15 min。
上述方法制备的具有多孔壳层的 PLGA/碳酸钙复合微球， 以 PLGA和碳 酸钙为主要材料， 同时还以碳酸钙为成孔剂， 该复合微球内部为实心结构， 微 球表面具有孔结构， 微球直径为 100~500 um， 孔径为 l~10 um。
本发明相对现有技术具备如下优点：
本发明通过在 PLGA微球中复合一种比磷灰石类物质具有更好生物降解 性的碳酸钙来中和 PLGA 的酸性降解产物。 同时利用碳酸钙组分在微球表面 构建孔结构， 无需引入外来的成孔剂， 从而改善了微球制备方法， 而且彻底避 免了成孔剂的残留问题。本法得到的复合微球不仅形貌均一，而且微球表面分 布着大量的规则开放小孔，形成一个多孔壳层，从而更有利于细胞在微球上的 生长。 附图说明
图 1是实施例 1中的微球表面电镜图；
图 2是实施例 1中微球的内部截面图；
图 3是实施例 2中微球的表面电镜图；
图 4是实施例 3中微球的表面电镜图；
图 5是成骨瘤细胞在纯 PLGA和本发明实施例 1复合微球表面的增殖情况 对比图。 具体实施方式
实施例 1
称取 1 g PLGA (50/50, Mw=30 kDa)溶解于 20 ml 二氯甲垸中，得到 20 ml PLGA有机溶液。 称取 0.5 g碳酸钙粉末加入到 PLGA有机溶液中，在 300 rpm 转速和 300 w超声功率下搅拌 10 min， 得到 PLGA/碳酸钙的混合液。 称取 5 g PVA加入到 500 ml去离子水中， 搅拌 15 min， 之后加热到 90 V使 PVA溶解， 冷却后得到 PVA水溶液。称取 0.5 g葡萄糖酸内酯溶解于 500 ml PVA水溶液， 得到酸性 PVA水溶液。 在 350 rpm搅拌条件下将 PLGA/碳酸钙混合液逐滴加 入到酸性 PVA水溶液中，得到水包油的单乳液。在通风橱中持续搅拌（350 rpm) 该乳液 20 h， 使乳液中的二氯甲垸挥发， 油滴固化成球。 收集所得微球， 用去 离子水洗涤 3遍， 在 -24 °C下冷冻干燥 48小时， 将干燥的微球储存。
实施例 2
称取 2 g PLGA (50/50, Mw=30 kDa)溶解于 10 ml 二氯甲垸中，得到 10 ml PLGA有机溶液。 称取 0.2 g碳酸钙粉末加入到 PLGA有机溶液中，在 300 rpm 转速和 300 w超声功率下搅拌 10 min， 得到 PLGA/碳酸钙的混合液。 称取 2 g PVA加入到 250 ml去离子水中， 搅拌 15 min， 之后加热到 90 V使 PVA溶解， 冷却后得到 PVA水溶液。 称取 0.3 g葡萄糖酸内酯溶解于 PVA水溶液， 得到 酸性 PVA水溶液。 在 400 rpm搅拌条件下将 PLGA/碳酸钙混合液逐滴加入到 酸性 PVA水溶液中， 得到水包油的单乳液。 在通风橱中持续搅拌 （400 rpm) 该乳液 20 h， 使乳液中的二氯甲垸挥发， 油滴固化成球。 收集所得微球， 用去 离子水洗涤 3遍， 在 -24 °C下冷冻干燥 48小时， 将干燥的微球储存。
实施例 3
称取 1 g PLGA (50/50, Mw=30 kDa)溶解于 10 ml 二氯甲垸中，得到 10 ml PLGA有机溶液。 称取 0.05 g碳酸钙粉末加入到 PLGA有机溶液中，高在 300 rpm转速和 300 w超声功率下搅拌 10 min，得到 PLGA/碳酸钙的混合液。称取 2 g PVA加入到 250 ml去离子水中， 搅拌 15 min， 之后加热到 90 V使 PVA溶 解， 冷却后得到 PVA水溶液。 称取 0.4 g葡萄糖酸内酯溶解于 PVA水溶液， 得到酸性 PVA水溶液。 在 400 rpm搅拌条件下将 PLGA/碳酸钙混合液逐滴加 入到酸性 PVA水溶液中，得到水包油的单乳液。在通风橱中持续搅拌（250 rpm) 该乳液 20 h， 使乳液中的二氯甲垸挥发， 油滴固化成球。 收集所得微球， 用去 离子水洗涤 3遍， 在 -24°C下冷冻干燥 48小时， 将干燥的微球储存。

Claims

权 利 要 求 书
1、 一种具有多孔壳层的 PLGA/碳酸钙复合微球， 其特征在于， 该复合 微球以 PLGA和碳酸钙为主要材料， 同时还以碳酸钙为成孔剂， 该复合微球 内部为实心结构，微球表面具有孔结构，微球直径为 100~500 um，孔径为 1~10
2、一种具有多孔壳层的 PLGA/碳酸钙复合微球的制备方法，其特征在于， 包括以下步骤：
a、 将 PLGA溶解于二氯甲垸有机溶剂中， 得到 PLGA油相； 将碳酸钙粉 末添加到 PLGA油相中， 通过搅拌和超声处理后， 得到有机 /无机的均匀混合 液；
b、 将葡萄糖酸内酯溶解于 PVA水溶液中， 得到酸性 PVA水溶液； c、在搅拌条件下将步骤 a得到的混合液分散到步骤 b中的酸性 PVA水溶 液里， 得到水包油的单乳液；
d、 在减压条件下继续搅拌， 使油相液滴中的二氯甲垸挥发， 得到固化的 复合微球；
e、 收集步骤 d中的微球， 用去离子水洗涤， 冷冻干燥即可。
3、 根据权利要求 2所述方法， 其特征在于， 步骤 a中 PLGA与二氯甲垸 的质量体积比为 1/30〜1/4 g/ml; 碳酸钙与 PLGA的质量比为 1/20〜1/2。
4、根据权利要求 2所述方法， 其特征在于， 步骤 b的 PVA水溶液中 PVA 与水的质量体积比为 1/500〜1/100 g/ml; 葡萄糖酸内酯和 PVA 的质量比为 1/10〜1/5。
5、 根据权利要求 2或 3或 4所述方法， 其特征在于， 所述 PLGA分子量 Mw=30〜10 kDa, LA/GA=50/50。
6、 根据权利要求 2或 3或 4所述方法， 其特征在于， 步骤 d中减压条件 下搅拌的速率为 200〜400 rpm， 搅拌时间为 12〜24 h。
7、 根据权利要求 2或 3或 4所述方法， 其特征在于， 步骤 e中冷冻干燥 的温度为 -24 °C， 时间为 48小时。
8、 根据权利要求 2或 3或 4所述方法， 其特征在于， 步骤 a中搅拌速度 250 〜400 rpm， 搅拌时间为 5〜15 min。
9、 根据权利要求 2或 3或 4所述方法， 其特征在于， 步骤 a中超声功率 250〜350 w， 超声时间为 5〜15 minc
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