WO2024001298A1 - 一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法 - Google Patents

一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法 Download PDF

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WO2024001298A1
WO2024001298A1 PCT/CN2023/081034 CN2023081034W WO2024001298A1 WO 2024001298 A1 WO2024001298 A1 WO 2024001298A1 CN 2023081034 W CN2023081034 W CN 2023081034W WO 2024001298 A1 WO2024001298 A1 WO 2024001298A1
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hydroxyapatite
preparation
microspheres
suspension
size
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吴铎
黄园园
尹全义
严珅
张盛宇
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苏州大学
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/327—After-treatment
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/88—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by thermal analysis data, e.g. TGA, DTA, DSC
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/03—Particle morphology depicted by an image obtained by SEM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/51—Particles with a specific particle size distribution
    • C01P2004/52—Particles with a specific particle size distribution highly monodisperse size distribution

Definitions

  • the invention belongs to the technical field of biological particles, and in particular relates to a hydroxyapatite microsphere with controllable morphology and size and a preparation method thereof.
  • Hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 , HAP) microspheres are aggregates of primary nanoscale or micron HAP. Due to their osteoconductivity, biocompatibility and biodegradability, Advantages: It has broad application prospects as a filler for bone tissue repair, protein separation and purification, drug delivery carrier, and liquid chromatography filling matrix.
  • Controlling the size and morphology of HAP microspheres is not only a core step in various scientific fields from colloidal chemistry to particle technology, but also largely determines the properties of particles used in various applications, including density, porosity, specificity surface area and other key parameters. Therefore, it is very necessary to prepare HAP microspheres with uniform and controllable morphology.
  • the preparation processes of HAP microspheres include microemulsion method, spray drying method, template method, etc.
  • spray drying is widely used due to its advantages of simple operation, high production efficiency and strong scalability.
  • Many studies have shown that the colloidal interactions between primary particles dispersed in suspension play a decisive role in the morphology of microspheres.
  • microspheres will be produced that vary greatly in size, morphology, and other physical and chemical properties. Therefore, it is difficult to compare the feed liquid formula and processing parameters with the physical and chemical properties of the microspheres. Accurate correlation, thereby affecting subsequent application performance, such as the uniformity of drug loading on microspheres, the stability of the protein separation and purification efficiency of microspheres, and the column efficiency as a chromatographic medium.
  • the object of the present invention is to provide a hydroxyapatite microstructure with controllable morphology and size.
  • Spheres and preparation methods thereof. The method can obtain hydroxyapatite microspheres with controllable morphology and size.
  • the invention provides a method for preparing hydroxyapatite microspheres with controllable morphology and size, which includes the following steps:
  • the stable hydroxyapatite suspension is sprayed using microfluidic atomization to obtain droplets, and after drying, hydroxyapatite microspheres are obtained.
  • the agglomerated hydroxyapatite particles are preferably stirred and dispersed in water to obtain a hydroxyapatite aqueous suspension.
  • the dispersant is selected from one or more of sodium polyacrylate, sodium citrate, Tween 80, polyethylene glycol, polyvinyl alcohol, sodium alginate and sodium carboxymethylcellulose;
  • the salt is selected from one or more of NaCl, Na 2 CO 3 , Na 2 SO 4 , Al(NO 3 ) 3 , K 2 SO 4 , NaHCO 3 and NH 4 HCO 3 ;
  • the dispersant accounts for 0.01 to 5% of the mass of the hydroxyapatite aqueous suspension
  • the concentration of the salt in the hydroxyapatite suspension is 0.01 to 5 mol/L.
  • the solid content of the hydroxyapatite aqueous suspension is 1 to 30 wt%.
  • the ultrasonic frequency is 20 to 40 kHz, and the ultrasonic time is 10 to 150 minutes;
  • the homogenization pressure is 200-600 bar, and the homogenization time is 10-120 minutes.
  • the working vibration frequency of the microfluidic atomization spray mode is 6 to 15 kHz, and the amplitude is 5 to 20 Vpp;
  • the drying pressure is 0.1-2kg/cm 3 .
  • the drying is carried out in a spray drying tower.
  • the inlet temperature of the tower is 90-220°C
  • the outlet temperature of the tower is 40-100°C
  • the hot air flow rate in the tower is 100-400L/min.
  • the present invention also includes sintering the hydroxyapatite microspheres to obtain pure hydroxyapatite microspheres.
  • the sintering removes the dispersant and yields pure hydroxyapatite microspheres with a rough, porous structure.
  • the invention provides a hydroxyapatite microsphere with controllable morphology and size, which is prepared by the preparation method described in the above technical solution.
  • the hydroxyapatite microspheres with adjustable morphology and size can be used for drug loading.
  • the invention provides a method for preparing hydroxyapatite microspheres with controllable morphology and size, including The following steps: mix the hydroxyapatite aqueous suspension with a dispersant and/or salt, ultrasonic, and homogenize to obtain a stable hydroxyapatite suspension; use microfluidic mist to obtain the stable hydroxyapatite suspension A spray method is used to obtain liquid droplets, and after drying, hydroxyapatite microspheres are obtained.
  • the present invention adopts microfluidic spray drying technology to control the geometric size and morphology of dried microspheres by adjusting the type of dispersant, mass ratio of hydroxyapatite/dispersant, salt concentration and other parameters.
  • the dispersant is removed through the sintering step to prepare hydroxyapatite microspheres with controllable morphology and size. They have a porous structure and can be used as a carrier to load drugs in pharmaceutical applications.
  • the preparation process has low energy consumption and is easy to operate. Etc.
  • Figure 1 shows the D50 and Zeta potential diagrams of particles in the suspension when the hydroxyapatite content in the suspension is 1wt% and 5wt%, and PAAS is used in different amounts (0.01, 0.05, 0.1, 0.25 and 0.5wt%);
  • Figure 2 shows the scanning electron microscope images of spray-dried microspheres under different dispersant dosages (0.01, 0.05, 0.1, 0.25 and 0.5wt%) when the hydroxyapatite content in the suspension is 1wt% and 5wt%;
  • Figure 3 shows the size distribution of spray-dried microspheres under different dispersant dosages (0.01, 0.05, 0.1, 0.25 and 0.5wt%) when the hydroxyapatite content in the suspension is 1wt% and 5wt%;
  • Figure 4 shows the scanning electron microscope images of spray-dried microspheres obtained by adjusting different NaCl concentrations (0.015, 0.025, 0.05, 0.07 and 0.1 mol/L) when the hydroxyapatite content in the suspension is 5wt% and the PAAS dosage is 0.1wt%. ;
  • Figure 5 shows the size distribution of spray-dried microspheres obtained by adjusting different NaCl concentrations (0.015, 0.025, 0.05, 0.07 and 0.1 mol/L) when the hydroxyapatite content in the suspension is 5wt% and the PAAS dosage is 0.1wt%. ;
  • Figure 6 shows the XRD pattern of the dispersant PAAS before and after sintering
  • Figure 7 is the TGA chart of the dispersant PAAS at 700°C
  • Figure 8 shows the FTIR-ATR diagram of HAP microspheres before and after sintering
  • Figure 9 is a scanning electron microscope image of microspheres after sintering at different temperatures (700, 900, 1100°C) in Example 1 of the present invention with a HAP content of 1wt% and a PAAS dosage of 0.25wt%;
  • Figure 10 is a size distribution diagram of microspheres after sintering at different temperatures (700, 900, 1100°C) in Example 1 of the present invention with a HAP content of 1wt% and a PAAS dosage of 0.25wt%;
  • Figure 11 shows the mercury injection data ((a) pore size distribution, (b) ratio of microspheres after sintering at different temperatures (700, 900, 1100°C) in Example 1 of the present invention with a HAP content of 1wt% and a PAAS dosage of 0.25wt%. surface area).
  • hydroxyapatite microspheres with adjustable morphology and size and their preparation methods provided by the present invention are described in detail below in conjunction with the examples. However, they should not be understood as limiting the scope of the present invention. .
  • step (1) Add the dispersant PAAS in step (1).
  • the amount of the dispersant is between 0.01 and 1wt% to obtain 100g of precursor suspension to adjust the final spray-dried particle morphology, and stir thoroughly for 2 hours. To ensure full contact between solid particles and dispersant;
  • step (3) Treat the suspension obtained in step (2) with an ultrasonic machine for 60 minutes to break up any flocculated or agglomerated particles that may appear in the suspension. And homogenize under a pressure of 600bar for 30 minutes to obtain a uniform colloidal suspension.
  • suspensions with different amounts of PAAS correspond to different D50 and zeta potential; see Figure 1, which shows that increasing the amount of PAAS reduces the D50 of the suspension and increases the absolute value of zeta potential.
  • step (3) Introduce the suspension precursor in step (3) into the liquid storage tank, connect the microfluidic atomizer through the catheter, and atomize the precursor into fine droplets.
  • the atomization pressure is 0.2kg/cm 3 and atomized.
  • the operating vibration frequency of the device is 10KHz and the amplitude is 15Vpp;
  • step (4) The droplets in step (4) are spray-dried to obtain particles with consistent particle sizes.
  • the tower inlet temperature is 190°C
  • the outlet temperature is 90°C
  • the hot air flow rate is set to 255L/min;
  • Figure 2 shows the scanning electron microscope images of spray-dried microspheres under different dispersant dosages (0.01, 0.05, 0.1, 0.25 and 0.5wt%) when the hydroxyapatite content in the suspension is 1wt% and 5wt%.
  • Figure 2 It can be seen that by adjusting the mass ratio of hydroxyapatite/dispersant, hydroxyapatite microspheres with controllable morphology and size are prepared;
  • Figure 3 shows the size distribution of spray-dried microspheres under different dispersant dosages (0.01, 0.05, 0.1, 0.25 and 0.5wt%) when the hydroxyapatite content in the suspension is 1wt% and 5wt%.
  • the narrow size distribution illustrates the uniformity of the microspheres
  • step (6) Sinter the microspheres collected in step (5) at high temperatures (700°C, 900°C and 1100°C) to remove the dispersant and obtain mesoporous hydroxyapatite microspheres.
  • XRD ( Figure 6), TGA ( Figure 7) and FTIR-ATR ( Figure 8) data can show that PAAS has been decomposed.
  • Figure 6 shows that the dispersant has been completely decomposed into Na 2 CO 3 after sintering;
  • Figure 7 shows that PAAS has been decomposed.
  • the first step is decarboxylation, that is, the carboxyl group of PAAS is removed first under heating conditions;
  • the second step is the depolymerization of the PAAS main chain, that is, the breakage of the carbon-carbon single bond.
  • Figure 8 shows that the carbon-carbon single bond characteristic peak of the dispersant PAAS disappears after sintering, indicating that the PAAS main chain has depolymerized, once again proving the decomposition of PAAS.
  • Figure 11 shows that as the sintering temperature increases, the specific surface area of the microspheres gradually decreases; the porosity of the microspheres reaches 12.0%, 11.6% and 9.8% respectively.
  • the prepared microspheres were used to load the antibiotic drug ciprofloxacin.
  • HxPy-700 H represents hydroxyapatite
  • P represents PAAS
  • x represents the mass content of H in the precursor liquid system
  • y represents the mass content of P in the precursor liquid system
  • 700 represents the calcination temperature
  • Drug loading (initial ciprofloxacin mass - ciprofloxacin mass in supernatant) / (initial ciprofloxacin mass - ciprofloxacin mass in supernatant + mass of particles) ⁇ 100%
  • Drug adsorption rate (initial ciprofloxacin mass - ciprofloxacin mass in supernatant)/initial ciprofloxacin mass ⁇ 100%
  • step (1) Add dispersant PAAS in step (1).
  • the amount of dispersant is between 0.01 and 1wt%.
  • add NaCl The amount of NaCl is between 0.01 and 5mol/L to obtain 100g of suspension. And stir thoroughly for 2 hours to fully contact the solid particles with the dispersant and electrolyte;
  • step (3) Treat the suspension obtained in step (2) with an ultrasonic machine for 60 minutes to break up any flocculated or agglomerated particles that may appear in the suspension. And homogenize under a pressure of 600bar for 30 minutes to obtain a uniform colloidal suspension;
  • step (3) Introduce the suspension precursor in step (3) into the liquid storage tank, connect the microfluidic atomizer through the catheter, and atomize the precursor into fine droplets.
  • the atomization pressure is 0.2kg/cm 3 and atomized.
  • the operating vibration frequency of the device is 10kHz and the amplitude is 15Vpp;
  • step (4) The droplets in step (4) are spray-dried to obtain microspheres with consistent particle sizes.
  • the tower inlet temperature is 190°C
  • the outlet temperature is 90°C
  • the hot air flow rate is set to 255L/min.
  • Figure 4 shows the scanning electron microscope images of spray-dried microspheres obtained by adjusting different NaCl concentrations (0.015, 0.025, 0.05, 0.07 and 0.1 mol/L) when the hydroxyapatite content in the suspension is 5wt% and the PAAS dosage is 0.1wt%. , by adjusting the NaCl concentration, hydroxyapatite microspheres with controllable morphology and size were prepared.
  • Figure 5 shows the size distribution of spray-dried microspheres obtained by adjusting different NaCl concentrations (0.015, 0.025, 0.05, 0.07 and 0.1 mol/L) when the hydroxyapatite content in the suspension is 5wt% and the PAAS dosage is 0.1wt%. , whose narrow size distribution illustrates the uniformity of the microspheres.
  • hydroxyapatite microspheres in the published patent (CN 106458585) is as follows: first, in order to prepare the hydroxyapatite precursor, ammonium dihydrogen phosphate and phosphoric acid aqueous solution are slowly added to the suspension containing calcium hydroxide, and at the same time Stir vigorously and use a calcium/phosphorus stoichiometric ratio of 1.67. Then 7g polyacrylic acid Sodium was slowly added to 35 L of ground hydroxyapatite (approximately 10 wt%) suspension. Next, the dispersed suspension was spray-dried to prepare spherical secondary particles with an outlet temperature above 100°C.
  • the particle size of the hydroxyapatite microspheres collected by spray drying ranges from about 10 to 90 ⁇ m.
  • the microspheres were then placed in an oven with air flow and heated to 650°C for 4 h. Then use a sieve to classify the hydroxyapatite microspheres, for example, install two meshes of 35 ⁇ m and 45 ⁇ m to obtain hydroxyapatite microspheres with an average particle size of 40 ⁇ m. And compare it with Example 1.
  • Dispersants include, but are not limited to, phosphates (such as sodium hexametaphosphate), sodium silicate, and carbonate.
  • Short chain organic compounds include, but are not limited to, organic electrolytes (eg, citrate) and surfactants (eg, Tween 20, Tween 80, sodium lauryl sulfate).
  • examples of polymeric dispersants include, but are not limited to, polymer electrolytes (eg, polyacrylic acid and PVA). And compare it with Example 1.
  • Example 1 of the present invention hydroxyapatite microspheres with uniform size and controllable morphology can be obtained without using a sieving step, which greatly improves the yield of microspheres.
  • hydroxyapatite microspheres with controllable morphology can be prepared.
  • the present invention adjusts the interaction (D50 and zeta potential) between primary particles in the suspension by adjusting the type of dispersant, the mass ratio of hydroxyapatite/dispersant and the salt concentration, and uses microfluidic control Spray drying technology combined with post-sintering treatment can prepare hydroxyapatite microspheres with uniform size and controllable morphology.
  • the microsphere has a porous structure and good adsorption properties, and can be used as a carrier to load drugs in pharmaceutical applications.
  • the preparation process has the advantages of low energy consumption and easy operation.

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Abstract

本发明提供一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法，方法包括：将羟基磷灰石水悬浮液与分散剂和/或盐混合，超声，均质后，得到稳定羟基磷灰石悬浮液；将所述稳定羟基磷灰石悬浮液采用微流控雾化喷雾方式，得到液滴，干燥后，得到羟基磷灰石微球。本发明采用微流控喷雾干燥技术，通过调节分散剂种类，羟基磷灰石/分散剂的质量比，盐浓度等参数，从而控制干燥后微球的几何尺寸和形貌。另外，通过烧结步骤去除分散剂，制备出形貌、尺寸可调控的羟基磷灰石微球，其具有多孔结构，可作为制药应用中负载药物的载体，并且制备工艺具备能耗低，操作简便等优点。

Description

一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法
本申请要求于2022年06月30日提交中国专利局、申请号为202210762434.X、发明名称为“一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于生物颗粒技术领域，尤其涉及一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法。
背景技术
羟基磷灰石(Ca10(PO4)6(OH)2，HAP)微球是初级纳米级或微米级HAP的聚集体，由于其具有骨传导性、生物相容性和生物可降解性的优点，在作为骨组织修复的填充剂、蛋白质分离和纯化、药物递送载体和液相色谱填充基质等方面具有广阔的应用前景。
控制HAP微球的尺寸和形态不仅是从胶体化学到颗粒技术等各个科学领域的核心步骤，同时也在很大程度上决定了用于各种应用中颗粒的性质，包括密度、孔隙率、比表面积和其他关键参数。因此，制备具有均匀和可控形态的HAP微球是非常必要的。
目前HAP微球的制备工艺有微乳液法、喷雾干燥法、模板法等，其中，喷雾干燥由于其操作简单、生产效率高和可扩展性强等优点而被广泛应用。已有许多研究表明，分散在悬浮液中的初级粒子之间的胶体相互作用对微球的形态起着决定性的作用。然而，对于传统的喷雾干燥器，即使在同一批次样品中也会产生尺寸、形态和其他物理化学性质变化很大的微球，因此难以将料液配方和加工参数与微球的物理化学性质精确关联，从而影响后续应用性能，如药物在微球上的负载均匀性、微球对蛋白质的分离纯化效率稳定性和作为色谱介质的柱效等。
发明内容
有鉴于此，本发明的目的在于提供一种形貌、尺寸可调控的羟基磷灰石微 球及其制备方法，该方法能够获得形貌、尺寸可调控的羟基磷灰石微球。
本发明提供了一种形貌、尺寸可调控的羟基磷灰石微球的制备方法，包括以下步骤：
将羟基磷灰石水悬浮液与分散剂和/或盐混合，超声，均质后，得到稳定羟基磷灰石悬浮液；
将所述稳定羟基磷灰石悬浮液采用微流控雾化喷雾方式，得到液滴，干燥后，得到羟基磷灰石微球。
本发明优选将团聚的羟基磷灰石粒子在水中搅拌分散得到羟基磷灰石水悬浮液。
在本发明中，所述分散剂选自聚丙烯酸钠、柠檬酸钠、吐温80、聚乙二醇、聚乙烯醇、海藻酸钠和羧甲基纤维素钠中的一种或多种；
所述盐选自NaCl、Na2CO3、Na2SO4、Al(NO3)3、K2SO4、NaHCO3和NH4HCO3中的一种或多种；
所述分散剂占羟基磷灰石水悬浮液质量的0.01～5％；
所述盐在羟基磷灰石悬浮液中的浓度为0.01～5mol/L。
在本发明中，所述羟基磷灰石水悬浮液的固含量为1～30wt％。
在本发明中，所述超声的频率为20～40kHz，超声的时间为10～150min；
所述均质的压力为200～600bar，所述均质的时间为10～120min。
在本发明中，所述微流控雾化喷雾方式的工作振动频率为6～15kHz，幅值为5～20Vpp；
所述干燥的压力为0.1～2kg/cm3。
在本发明中，所述干燥在喷雾干燥塔中进行，塔的入口温度为90～220℃，塔的出口温度为40～100℃，塔中热风流量为100～400L/min。
在本发明中，还包括将羟基磷灰石微球烧结，得到纯羟基磷灰石微球。所述烧结能够除去分散剂，得到纯羟基磷灰石微球，其具有粗糙、多孔结构。
本发明提供了一种形貌、尺寸可调控的羟基磷灰石微球，由上述技术方案所述制备方法制得。
所述形貌、尺寸可调控的羟基磷灰石微球，可用于药物负载。
本发明提供了一种形貌、尺寸可调控的羟基磷灰石微球的制备方法，包括 以下步骤：将羟基磷灰石水悬浮液与分散剂和/或盐混合，超声，均质后，得到稳定羟基磷灰石悬浮液；将所述稳定羟基磷灰石悬浮液采用微流控雾化喷雾方式，得到液滴，干燥后，得到羟基磷灰石微球。本发明采用微流控喷雾干燥技术，通过调节分散剂种类，羟基磷灰石/分散剂的质量比，盐浓度等参数，从而控制干燥后微球的几何尺寸和形貌。另外，通过烧结步骤去除分散剂，制备出形貌、尺寸可调控的羟基磷灰石微球，其具有多孔结构，可作为制药应用中负载药物的载体，并且制备工艺具备能耗低，操作简便等优点。
附图说明
图1为为悬浮液中羟基磷灰石含量1wt％和5wt％，PAAS在不同用量(0.01、0.05、0.1、0.25和0.5wt％)时悬浮液中粒子的D50和Zeta电位图；
图2为悬浮液中羟基磷灰石含量为1wt％和5wt％时，不同分散剂用量(0.01、0.05、0.1、0.25和0.5wt％)条件下喷雾干燥微球的扫描电镜图；
图3为悬浮液中羟基磷灰石含量为1wt％和5wt％时，不同分散剂用量(0.01、0.05、0.1、0.25和0.5wt％)条件下喷雾干燥微球的尺寸分布图；
图4为悬浮液中羟基磷灰石含量为5wt％，PAAS用量0.1wt％时，调节不同NaCl浓度(0.015、0.025、0.05、0.07和0.1mol/L)得到的喷雾干燥微球的扫描电镜图；
图5为悬浮液中羟基磷灰石含量为5wt％，PAAS用量0.1wt％时，调节不同NaCl浓度(0.015、0.025、0.05、0.07和0.1mol/L)得到的喷雾干燥微球的尺寸分布图；
图6为分散剂PAAS烧结前后的XRD图；
图7为分散剂PAAS在700℃条件下的TGA图；
图8为HAP微球烧结前后的FTIR-ATR图；
图9为本发明实施例1中HAP含量1wt％，PAAS用量0.25wt％，在不同温度(700、900、1100℃)烧结后微球的扫描电镜图；
图10为本发明实施例1中HAP含量1wt％，PAAS用量0.25wt％，在不同温度(700、900、1100℃)烧结后微球的尺寸分布图；
图11为本发明实施例1中HAP含量1wt％，PAAS用量0.25wt％，在不同温度(700、900、1100℃)烧结后微球的压汞数据((a)孔径分布、(b)比表面积)。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的一种形貌、尺寸可调控的羟基磷灰石微球及其制备方法进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
实施例1
按照如下步骤制备形貌、尺寸可调控的羟基磷灰石微球：
(1)称取5g纳米羟基磷灰石加入去离子水中，25℃下磁力搅拌，增强羟基磷灰石在水中的分散均匀性，其中，羟基磷灰石含量分别控制为1wt％和5wt％；
(2)在步骤(1)中加入分散剂PAAS，分散剂的加入量在0.01～1wt％之间，得到100g的前驱体悬浮液，以调节最终的喷雾干燥颗粒形貌，并充分搅拌2h，以使固体颗粒和分散剂充分接触；
(3)将步骤(2)中得到的悬浮液超声机处理60min，以打开悬浮液中可能出现的絮凝或团聚的颗粒。并在600bar的压力下均质30min，得到均匀的胶体悬浮液。
并且，不同PAAS用量的悬浮液对应着不同的D50和zeta电位；见图1，表明增加PAAS用量使悬浮液D50降低，zeta电位绝对值增大。
(4)将步骤(3)中的悬浮液前驱体导入储液罐，通过导管连接微流控雾化器，将前驱体雾化成细小的液滴，雾化压力0.2kg/cm3，雾化器工作振动频率为10KHz，幅值为15Vpp；
(5)步骤(4)中的液滴经喷雾干燥得到粒径一致的颗粒，其塔进口温度190℃，出口温度90℃，热风流量设置为255L/min；
图2为悬浮液中羟基磷灰石含量为1wt％和5wt％时，不同分散剂用量(0.01、0.05、0.1、0.25和0.5wt％)条件下喷雾干燥微球的扫描电镜图，由图2可以看出，通过调节羟基磷灰石/分散剂的质量比，制备出了形貌、尺寸可调控的羟基磷灰石微球；
图3为悬浮液中羟基磷灰石含量为1wt％和5wt％时，不同分散剂用量(0.01、0.05、0.1、0.25和0.5wt％)条件下喷雾干燥微球的尺寸分布图，其 较窄的尺寸分布说明了微球的均一性；
(6)将步骤(5)中收集的微球分别在高温(700℃、900℃和1100℃)进行烧结，以除尽分散剂，得到介孔羟基磷灰石微球。
另外，由XRD(图6)、TGA(图7)和FTIR-ATR(图8)数据可以表明PAAS已经分解。由图6表明烧结后分散剂已经完全分解，分解为Na2CO3；图7表明PAAS已经分解。第一步是脱羧，即在加热条件下，PAAS的羧基首先去除；第二步是PAAS主链的解聚，即碳-碳单键的断裂。图8表明烧结之后分散剂PAAS的碳-碳单键特征峰消失，表明PAAS主链发生解聚，再一次证明PAAS的分解。
图11表明，随着烧结的温度升高，微球的比表面积逐渐减小；微球的孔隙率分别达到12.0％、11.6％和9.8％。
药物负载过程：
将制备好的微球用于负载环丙沙星抗生素药物。
1.取不同组分且煅烧温度下为700℃的微球样品(样品命名方法为HxPy-700代表：H代表羟基磷灰石，P代表PAAS，x代表H在前驱液体系中的质量含量，y代表P在前驱液体系中的质量含量，700代表煅烧温度)：H1P0.01-700、H1P0.1-700、H5P0.01-700、H5P0.1-700、H5P0.5-700，浸渍于浓度为800μg/mL，体积为2mL的环丙沙星溶液中，负载时间为48h，置于37℃真空干燥器中自然浸渍；
2.浸渍完成后，采用离心机离心分离(8000rpm，3min)，收集上清液进行紫外光谱检测，在272nm处测量上清液吸光度值。通过环丙沙星浓度确定微粒的载药量、药物吸附率，计算公式如下：
载药量＝(初始环丙沙星质量-上清中环丙沙星质量)/(初始环丙沙星质量-上
清中环丙沙星质量+微粒的质量)×100％
药物吸附率＝(初始环丙沙星质量-上清中环丙沙星质量)/初始环丙沙星质
量×100％
实验结果：

实施例2
(1)称取5g纳米羟基磷灰石加入去离子水中，25℃下磁力搅拌，增强羟基磷灰石在水中的分散均匀性；
(2)在步骤(1)中加入分散剂PAAS，分散剂的加入量在0.01～1wt％之间，此外再加入NaCl，NaCl的用量在0.01～5mol/L之间，得到100g的悬浮液，并充分搅拌2h，以使固体颗粒与分散剂和电解质充分接触；
(3)将步骤(2)中得到的悬浮液使用超声机处理60min，以打开悬浮液中可能出现的絮凝或团聚的颗粒。并在600bar的压力下均质30min，得到均匀的胶体悬浮液；
(4)将步骤(3)中的悬浮液前驱体导入储液罐，通过导管连接微流控雾化器，将前驱体雾化成细小的液滴，雾化压力0.2kg/cm3，雾化器工作振动频率为10kHz，幅值为15Vpp；
(5)步骤(4)中的液滴经喷雾干燥得到粒径一致的微球，其塔进口温度190℃，出口温度90℃，热风流量设置为255L/min。
图4为悬浮液中羟基磷灰石含量为5wt％，PAAS用量0.1wt％时，调节不同NaCl浓度(0.015、0.025、0.05、0.07和0.1mol/L)得到的喷雾干燥微球的扫描电镜图，通过调节NaCl浓度，制备出形貌、尺寸可调控的羟基磷灰石微球。
图5为悬浮液中羟基磷灰石含量为5wt％，PAAS用量0.1wt％时，调节不同NaCl浓度(0.015、0.025、0.05、0.07和0.1mol/L)得到的喷雾干燥微球的尺寸分布图，其较窄的尺寸分布说明了微球的均一性。
对比例1
公开专利(CN 106458585)中制备羟基磷灰石微球的操作为：首先，为制备羟基磷灰石前体，将磷酸二氢铵与磷酸水溶液缓慢加入到含有氢氧化钙的悬浮液中，同时剧烈搅拌，所用钙/磷化学计量比为1.67。然后将7g聚丙烯酸 钠缓慢加入到35L研磨的羟基磷灰石(约10wt％)悬浮液中。接下来喷雾干燥上述分散好的悬浮液以制备球形次级颗粒，出口温度高于100℃。喷雾干燥收集到的羟基磷灰石微球粒径范围约10～90μm。然后将微球置于空气流的炉中加热至650℃保持4h。然后使用筛分器对羟基磷灰石微球进行分级，例如安装35μm和45μm两个筛网，得到平均粒径40μm的羟基磷灰石微球。并将其与实施例1进行对比。
在研磨的羟基磷灰石悬浮液中加入分散剂。分散剂包括但不限于磷酸盐(例如六偏磷酸钠)、硅酸钠、碳酸盐。短链有机化合物包括但不限于有机电解质(例如柠檬酸盐)和表面活性剂(例如吐温20、吐温80、十二烷基硫酸钠)。聚合物分散剂的示例包括但不限于聚合物电解质(例如聚丙烯酸和PVA)。并将其与实施例1进行对比。
表1实施例1和对比例1的不同之处
本发明实施例1无需使用筛分步骤即可获得尺寸均一、形貌可控的羟基磷灰石微球，大大提高了微球的产率。另外，通过分散剂的用量调节悬浮液的D50和zeta电位，能够制备形貌可调控的羟基磷灰石微球。
由以上实施例可知，本发明通过调节分散剂种类、羟基磷灰石/分散剂的质量比和盐浓度，来调节悬浮液中初级粒子间的相互作用(D50和zeta电位)，利用微流控喷雾干燥技术并结合烧结后处理等，制备出尺寸均一、形貌可控的羟基磷灰石微球。该微球具有多孔结构及较好的吸附性，可作为制药应用中负载药物的载体，并且制备工艺具备能耗低，操作简便等优点。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰， 这些改进和润饰也应视为本发明的保护范围。

Claims (9)

  1. 一种形貌、尺寸可调控的羟基磷灰石微球的制备方法，包括以下步骤：
    将羟基磷灰石水悬浮液与分散剂和/或盐混合，超声，均质后，得到稳定羟基磷灰石悬浮液；
    将所述稳定羟基磷灰石悬浮液采用微流控雾化喷雾方式，得到液滴，干燥后，得到羟基磷灰石微球。
  2. 根据权利要求1所述的制备方法，其特征在于，所述分散剂选自聚丙烯酸钠、柠檬酸钠、吐温80、聚乙二醇、聚乙烯醇、海藻酸钠和羧甲基纤维素钠中的一种或多种；
    所述盐选自NaCl、Na2CO3、Na2SO4、Al(NO3)3、K2SO4、NaHCO3和NH4HCO3中的一种或多种；
    所述分散剂占羟基磷灰石水悬浮液质量的0.01～5％；
    所述盐在羟基磷灰石悬浮液中的浓度为0.01～5mol/L。
  3. 根据权利要求1所述的制备方法，其特征在于，所述羟基磷灰石水悬浮液的固含量为1～30wt％。
  4. 根据权利要求1所述的制备方法，其特征在于，所述超声的频率为20～40kHz，超声的时间为10～150min；
    所述均质的压力为200～600bar，所述均质的时间为10～120min。
  5. 根据权利要求1所述的制备方法，其特征在于，所述微流控雾化喷雾方式的工作振动频率为6～15kHz，幅值为5～20Vpp；
    所述干燥的压力为0.1～2kg/cm3。
  6. 根据权利要求1所述的制备方法，其特征在于，所述干燥在喷雾干燥塔中进行，塔的入口温度为90～220℃，塔的出口温度为40～100℃，塔中热风流量为100～400L/min。
  7. 根据权利要求1所述的制备方法，其特征在于，还包括将羟基磷灰石微球烧结，得到纯羟基磷灰石微球。
  8. 根据权利要求7所述的制备方法，其特征在于，所述烧结的温度为500～1200℃。
  9. 一种形貌、尺寸可调控的羟基磷灰石微球，由权利要求1～8任一项所述制备方法制得。
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