WO2022147877A1 - 一种淀粉基蓬松颗粒及其制备方法与应用 - Google Patents

一种淀粉基蓬松颗粒及其制备方法与应用 Download PDF

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WO2022147877A1
WO2022147877A1 PCT/CN2021/075416 CN2021075416W WO2022147877A1 WO 2022147877 A1 WO2022147877 A1 WO 2022147877A1 CN 2021075416 W CN2021075416 W CN 2021075416W WO 2022147877 A1 WO2022147877 A1 WO 2022147877A1
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starch
preparation
granules
carboxymethyl
based fluffy
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PCT/CN2021/075416
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English (en)
French (fr)
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汤顺清
王剑金
郭爱军
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珠海原妙医学科技股份有限公司
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Priority to AU2021385100A priority Critical patent/AU2021385100B2/en
Priority to EP21899301.2A priority patent/EP4056204A4/en
Priority to US17/783,086 priority patent/US20230241283A1/en
Publication of WO2022147877A1 publication Critical patent/WO2022147877A1/zh

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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
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0085—Porous materials, e.g. foams or sponges
    • 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
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/09—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in organic liquids
    • C08J3/091—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in organic liquids characterised by the chemical constitution of the organic liquid
    • 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
    • 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
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • 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
    • C08J2303/00—Characterised by the use of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08J2303/04—Starch derivatives
    • 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
    • C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • C08J2371/02—Polyalkylene oxides
    • 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
    • C08J2403/00—Characterised by the use of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08J2403/02—Starch; Degradation products thereof, e.g. dextrin

Definitions

  • the invention belongs to the technical field of hemostatic materials, in particular to a starch-based fluffy granule and a preparation method and application thereof.
  • starch-based materials are widely used in hemostatic materials due to their good biosafety, high water absorption, and degradability.
  • the original particle size of starch granules derived from plants such as corn and potato is generally distributed in the range of 10-50 ⁇ m, and the particle size of most particles is below 30 ⁇ m, even after chemical modification (etherification, gelatinization, cross-linking or carboxymethyl)
  • the particle size of starch granules did not change much after calcination.
  • starch granules and the chemical structure of starch will affect the water absorption rate and water absorption rate of starch aggregates.
  • carboxymethylated or etherified starch with the same particle size has a higher water absorption rate than the original starch, and the water absorption rate is higher.
  • starches with the same chemical structure are prepared into different particle sizes or aggregated forms, which also cause changes in water absorption speed and water absorption rate.
  • the particle diameter of AristaTM modified starch hemostatic powder produced by Medafor Company in the United States is less than 50 ⁇ m. Although the particle surface is porous, the water absorption speed is slow and the water absorption rate is low. Certain porous spherical aggregates, the particle size is between 10-1000 ⁇ m; the preferred particle size is between 50-500 ⁇ m, and it is found that the water absorption speed and water absorption rate are greatly improved when large particles are prepared.
  • HaemoCer starch granule hemostatic powder (composed of carboxymethylated potato starch) from BIOCER, Germany, has a particle size of 10-50 ⁇ m.
  • the water absorption is 20 times, although the initial water absorption speed is fast and the water absorption rate is high, the water retention capacity is insufficient in the later stage, and the gel is easy to become thin and flow.
  • microspheres invented by the Wenzhou Institute of Biomaterials and Engineering in China are emulsified and dispersed, physically cross-linked into spheres, and vacuum-dried at 60°C to obtain microspheres with adjustable particle size of 20-50 ⁇ m, which are used for hemostasis, but the hemostatic effect is still There are some deficiencies.
  • the prepared large-granule modified starch-based hemostatic materials still cannot fully meet the actual clinical hemostasis needs. , and can stop bleeding by coating or spraying trauma wounds, or starch-based hemostatic material for micro-leakage hemostasis in the human body under endoscope/minimally invasive.
  • the present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art.
  • the present invention proposes a starch-based fluffy granule and a preparation method and application thereof.
  • the starch-based fluffy granule is porous and fluffy, has a large particle gap, has excellent water absorption speed, water absorption rate and degradation rate, and can achieve rapid and efficient hemostasis and the starch-based fluffy granules have no added components such as dispersing agents, emulsifiers or cross-linking agents, and have the characteristics of safety and reliability, so they also meet the hemostasis requirements of the in vivo environment.
  • a preparation method of starch-based fluffy granules comprising the following steps:
  • the starch paste is usually directly freeze-dried to obtain the hemostatic sponge or block agglomerate structure, and then the hemostatic granules are finally obtained through the pulverization process.
  • the starch granules swell, and the molecular chains on the surface of the granules stretch after absorbing water and contact each other and diffuse to cause partial entanglement.
  • the starch granules lean against each other to form a whole block bonding.
  • the strength of the formed starch paste before freeze-drying is not high, and during the freeze-drying process, a ductile bulk or sponge-like product will be formed, and the starch molecules in the formed hemostatic sponge are entangled and difficult to disperse. It is not conducive to subsequent pulverization into uniform small particles, and the water absorption speed and water absorption rate of the prepared particles are poor, which does not meet the needs of hemostasis in practical applications.
  • starch hemostatic materials on the market are used to form spheres by adding ingredients such as cross-linking agents and emulsifiers to the starch paste.
  • ingredients such as cross-linking agents and emulsifiers
  • the starch molecules can be linked in the form of chemical bonds to form a tight and stable structure, which can reduce the swelling rate and the degradation rate in vivo; however, since the cross-linking agent is insoluble in water, it is necessary to add an organic solvent as a
  • the auxiliary agent dissolves the cross-linking agent to make it work.
  • the organic solvent also adjusts the polarity of the reaction solution, so that the cross-linking agent can fully react with the main components of the hemostatic powder.
  • the hemostatic granules prepared by this method have the advantages of long retention time in the body, slow degradation rate and stability, but the disadvantage is that the cross-linking makes the original starch granules more compact, the hydrophobicity of starch is enhanced, and the pores between the granules and the granules are small. , resulting in a greatly reduced water absorption rate and a slow water absorption rate.
  • the prepared hemostatic granules do not meet the requirements for hemostasis and degradation within 48 hours in the digestive tract or minimally invasive surgery. Scope of application. It can be seen that when no cross-linking agent, emulsifier and other components are used in the starch material, there is no motive and reason for additionally adding an organic solvent.
  • the present invention is the first to discover and point out that by using an organic solvent to stir and disperse the starch paste before freeze-drying, the following effects can be achieved: 1. By introducing an organic solvent incompatible with the starch paste, and then stirring, the starch paste can be stirred and dispersed. The starch paste is dispersed into aggregates with small particle size, which is convenient for dispersion after drying, and uniform particles can be obtained by pulverization. 2The organic solvent has a dehydration effect, which can effectively reduce the moisture between the aggregates during the freezing process, so as to avoid bonding during the freezing and drying process, so that the small aggregates are stable and hardened, and the agglomeration particles in the aqueous medium are avoided.
  • the organic solvent will penetrate into the starch granules to further swell the starch granules, so that the interior of the starch granules after drying also forms holes, forming a porous and fluffy structure, thereby effectively improving the water absorption speed and water absorption rate of starch-based materials.
  • step (2) after the stirring is completed in step (2), by standing for a period of time, the starch granules are swelled by the diffusion of water molecules in the starch granules, and the surface starch molecular chains between the non-crosslinked starch granules are in a water-swollen state.
  • the lower part diffuses and entangles with each other to further improve its fluffy degree.
  • the modified starch in step (1) is selected from at least one of etherified starch, carboxymethylated starch, esterified starch or cross-linked starch.
  • the mass ratio of starch or modified starch to water in the starch paste in step (1) is 1:(3-40).
  • the organic solvent in step (2) is selected from at least one of methanol, ethanol, propanol, butanol, acetone, isopropanol or dimethyl sulfoxide. More preferably, the organic solvent is isopropanol, methanol, ethanol, or a combination of isopropanol and methanol.
  • isopropanol, methanol, ethanol, or the combination of isopropanol and methanol is selected as the organic solvent, the obtained starch-based fluffy granules have higher bulkiness and better water absorption effect.
  • the starch-based fluffy granules also contain hydrophilic polymer materials.
  • the addition of the hydrophilic polymer material will affect the stability, viscosity and hemostasis of the product to a certain extent, and the hydrophilic polymer material includes but is not limited to sodium carboxymethyl cellulose, hyaluronic acid , at least one of polyoxyethylene or collagen.
  • the organic solvent in step (2) also includes water. Due to actual configuration requirements or the difficulty in obtaining pure organic solvents, the volume fraction of water in the organic solvent may be 0-50%.
  • the stirring speed in step (2) is 100-3000r/min, and the stirring time is 0.5-2h.
  • the rotational speed of the centrifugation in step (2) is 2000-5000 r/min.
  • the purpose of centrifugation is to remove part of the organic solvent and water.
  • the freeze-drying step in step (3) is as follows: first freeze the precipitate at -30°C to -10°C for 3-24 hours, and then place it in a freeze dryer at -50°C to -30°C for lyophilization for 15 hours. -36h.
  • the vacuum freeze-drying process can directly remove the solid ice (bound water) and the residual organic solvent. Under freezing conditions, the freezing of water can further swell the particles and improve the bulkiness.
  • the low-temperature vacuum drying can maintain the original fluffy state of the particles. It can maintain the pore structure within and between starch granules.
  • a starch-based fluffy granule is prepared by the above preparation method; the particle size of the starch-based fluffy granule is 20-500 ⁇ m.
  • starch-based fluffy granules as a medical hemostatic material.
  • the starch-based fluffy granules can be used as hemostatic powder to coat or spray trauma wounds to stop bleeding, and can also be applied to digestive tract wounds and minimally invasive operations to stop bleeding.
  • the present invention adopts organic solvent and water to prepare starch-based fluffy granules, the volatility of organic solvent and water is strong, it is easy to remove in the freeze-vacuum drying process, and the residue is few; and the present invention does not add chemical dispersant, emulsification agent Therefore, it is safer and more reliable, and can meet the needs of gastrointestinal wounds and minimally invasive hemostasis;
  • the precipitates collected in the preparation process of the present invention are brittle after freeze-drying, and are easily pulverized into aggregates of a desired size, and the starch-based fluffy particles finally obtained are compared with the same chemical
  • the structured starch aggregates have also been significantly improved in terms of water absorption speed and water absorption rate;
  • Modified starch can be selected as the starch raw material used in the present invention to further improve the water absorption rate, water absorption speed, adhesion, gel strength and other properties of starch-based aggregates.
  • Fig. 1 shows the microstructure of dried carboxymethyl corn starch aggregates and pulverized ones in Example 1; wherein A represents the microstructure of the dried carboxymethyl corn starch aggregates, and B represents the dried carboxymethyl corn starch aggregates Microstructure after crushing;
  • Figure 2 shows the results of carboxymethyl cornstarch-based fluffy granules and carboxymethyl cornstarch raw powder absorbing 20 times of water in Example 1; wherein A represents carboxymethyl cornstarch-based fluffy granules, and B represents carboxymethyl cornstarch raw powder ;
  • Figure 3 shows the gel stability results of different types of starch granules after 20 times of water absorption
  • C represents a German hemostatic powder (a kind of hemostatic powder obtained from potato starch through cross-linking technology)
  • D represents carboxymethyl without any treatment base potato starch
  • E represents the carboxymethyl potato starch-based fluffy granules prepared in Example 2
  • F represents the carboxymethyl cornstarch-based fluffy granules prepared in Example 1;
  • Figure 4 shows the gel stability results of different types of starch granules after absorbing water and standing for 48 hours; wherein G represents the carboxymethyl potato starch-based fluffy granules prepared in Example 2, and H represents the carboxymethyl corn prepared in Example 1 Starch-based fluffy granules, I represents a German product (a hemostatic powder obtained from potato starch through cross-linking technology);
  • Fig. 5 shows the gel stability results of the carboxymethyl potato starch-based fluffy granules obtained in Example 2 and a domestic marketed product under the condition of 20 times the water absorption; wherein J represents the carboxymethyl potato starch obtained in Example 2 Base fluffy particles, K represents a domestic marketed product (the product prepared according to the patent CN200610053680.9).
  • the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels unless otherwise specified, or can be obtained by existing known methods.
  • the present embodiment provides a carboxymethyl cornstarch-based fluffy granule, and its preparation method includes the following steps:
  • a in Fig. 1 shows the microstructure of the dried carboxymethyl corn starch aggregates obtained in this example
  • B in Fig. 1 shows the microstructure of the dried carboxymethyl corn starch aggregates obtained in this example after pulverization. It can be seen from Figure 1 that the starch granules inside the dried carboxymethyl corn starch aggregates are intertwined and connected with each other, and the interior is porous, and the large gap between the aggregates is not easy to produce capillary phenomenon.
  • A represents the result of water absorption of the carboxymethyl cornstarch-based fluffy granules prepared in this example by 20 times
  • B in Fig. 2 represents the result of water absorption of carboxymethyl cornstarch raw powder by 20 times. It can be seen from Figure 2 that the carboxymethyl corn starch raw powder has been in a fluid state, and the carboxymethyl corn starch-based fluffy granules prepared in this example can still maintain a certain shape, indicating that it has not yet reached the upper limit of water absorption.
  • the present embodiment provides a carboxymethyl potato starch-based fluffy granule, and its preparation method comprises the following steps:
  • the present embodiment provides a polyoxyethylene/carboxymethyl potato starch-based fluffy granule, and its preparation method includes the following steps:
  • the above-mentioned dried polyoxyethylene/carboxymethyl potato starch aggregates are pulverized and passed through an 80-mesh sieve to obtain aggregates with a particle size of less than 200 ⁇ m; then a 300-mesh sieve is passed to remove the aggregates less than 50 ⁇ m; that is, to obtain Polyoxyethylene/carboxymethyl potato starch based fluffy particles with particle size between 50-200 ⁇ m.
  • the present embodiment provides a carboxymethyl potato starch-based fluffy granule, and its preparation method comprises the following steps:
  • Figure 3 shows the gel stability results of different types of starch granules after 20 times of water absorption;
  • C represents a German hemostatic powder (a kind of hemostatic powder obtained from potato starch through cross-linking technology), D represents without any treatment Carboxymethyl potato starch, E represents the carboxymethyl potato starch-based fluffy granules prepared in Example 2, and F represents the carboxymethyl corn starch-based fluffy granules prepared in Example 1.
  • the carboxymethyl potato starch without any treatment is fluid and has poor water absorption capacity, and its performance is far inferior to a certain German hemostatic powder and starch-based fluffy granules prepared in Example 1-2.
  • Figure 4 shows the gel stability results of different types of starch granules after absorbing water and standing for 48 hours; wherein G represents the carboxymethyl potato starch-based fluffy granules prepared in Example 2, and H represents the carboxymethyl starch prepared in Example 1.
  • G represents the carboxymethyl potato starch-based fluffy granules prepared in Example 2
  • H represents the carboxymethyl starch prepared in Example 1.
  • I represents a German product (a hemostatic powder obtained from potato starch through cross-linking technology). It can be seen from Figure 4 that the German product melted and flowed, indicating that its gel stability is not as good as that of the starch-based fluffy granules prepared in Examples 1-2.
  • Figure 5 shows the gel stability results of the carboxymethyl potato starch-based fluffy granules prepared in Example 2 and a domestic marketed product under the condition of 20 times the water absorption; wherein J represents the carboxymethyl starch prepared in Example 2 Potato starch-based fluffy granules, K represents a domestic marketed product (the product prepared according to the patent CN200610053680.9).
  • J represents the carboxymethyl starch prepared in Example 2
  • K represents a domestic marketed product (the product prepared according to the patent CN200610053680.9).
  • the carboxymethyl potato starch-based fluffy granules prepared in Example 2 are in a gel state after water absorption, and a domestic listed brand is a thin suspension, indicating that the starch-based fluffy granules of the present invention have better coagulation. glue stability.
  • the starch-based fluffy granules prepared in Examples 1-4 were compared with carboxymethyl corn starch, carboxymethyl potato starch and three comparative products (ie, comparative products 1-3) for water absorption, gel strength and work of adhesion.
  • the test results are shown in Table 1.
  • the comparative product 1 is a hemostatic powder prepared from potato starch by cross-linking technology;
  • the comparative product 2 is the product obtained by the patent CN200610045441.9;
  • the comparative product 3 is the product obtained by the patent CN200610053680.9.
  • Water absorption rate water absorption (g or ml)/powder weight (g);
  • Water absorption speed the time required for 0.5g powder to absorb 10g water
  • Gel strength measure the gel strength after absorbing water and sealing for 48 hours
  • Adhesion work (g.mm): Adhesion work of the gel after saturated water absorption.

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Abstract

一种淀粉基蓬松颗粒及其制备方法与应用，属于止血材料技术领域。所述淀粉基蓬松颗粒的制备方法，包括以下步骤：(1)在淀粉或改性淀粉中加入水进行糊化，得到淀粉糊状物；(2)将所述淀粉糊状物加入至有机溶剂中，搅拌，静置后离心，收集沉淀物；(3)将所述沉淀物依次进行冷冻干燥、粉碎和过筛，制得所述淀粉基蓬松颗粒。所述淀粉基蓬松颗粒多孔蓬松、颗粒间隙大，具备优良的吸水速度、吸水率和降解速率，可实现快速、高效止血的目的；且所述淀粉基蓬松颗粒无分散剂、乳化剂或交联剂等成分添加，具有安全可靠的特点，因此还满足体内环境的止血要求。

Description

一种淀粉基蓬松颗粒及其制备方法与应用 技术领域
本发明属于止血材料技术领域，特别涉及一种淀粉基蓬松颗粒及其制备方法与应用。
背景技术
外科创伤和手术上的止血程序是临床的重要环节，其中止血材料发挥着重要作用。目前淀粉基材料以其生物安全性好、吸水率高、可降解等特性在止血材料得到广泛采用。其中玉米、马铃薯等植物来源的淀粉颗粒的原始粒径一般分布在10‐50μm，且大多数颗粒的粒径在30μm以下，即使经化学改构(醚化、糊化、交联或羧甲基化)后淀粉颗粒的粒径变化也不大。这些小粒径淀粉颗粒聚集时，因颗粒堆积后间隙小，产生毛细现象，导致在吸水过程中非常容易团聚导致后续水渗透困难，使整体淀粉颗粒聚集体吸水速度慢，吸水率也大大降低。在用于特殊场合‐譬如作为止血粉用于喷洒止血时，因吸水慢，总吸水率低，会导致止血效果较差。
现有研究表明，淀粉颗粒的大小以及淀粉的化学结构都会影响淀粉聚集体的吸水速度和吸水率，总体上粒径同样大小的羧甲基化或醚化淀粉比原始淀粉吸水率高，吸水速度快；同样化学结构的淀粉制备成不同颗粒大小或聚集形式也造成吸水速度和吸水率的变化。美国Medafor公司生产的AristaTM改性淀粉止血粉颗粒直径在50μm以下，尽管其颗粒表面多孔，但吸水速度慢，吸水率低；国内纪欣等在专利CN200710141944.0中将变性淀粉原始颗粒聚集制备成一定多孔球形聚集体，粒径介于10‐1000μm；优选粒径介于50‐500μm，比较发现制得大颗粒时其吸水速度和吸水率大大提高。
在相关淀粉止血颗粒产品中，德国BIOCER公司的HaemoCer淀粉颗粒止血粉(组成为羧甲基化马铃薯淀粉)，其颗粒大小为10‐50μm。在吸水20倍时，尽管初期吸水速度快，吸水速率高，但后期保水能力不足，凝胶容易变稀而流动。国内温州生物材料与工程研究所发明的天然多糖微球，采用乳化分散、物理交联成球、60℃真空干燥得到粒径在20‐50μm可调的微球，用于止血，但止血效果仍有所不足。
虽然现有淀粉基止血材料已经采用了种种的改进措施，但所制得的大颗粒改性淀粉基止 血材料仍不能完全满足实际临床上的止血需要，因而亟需开发出一种具备高效止血性能，并可通过涂覆或喷洒外伤创面止血，或在内窥镜/微创下用于人体内部微渗漏止血的淀粉基止血材料。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一种淀粉基蓬松颗粒及其制备方法与应用，所述淀粉基蓬松颗粒多孔蓬松、颗粒间隙大，具备优良的吸水速度、吸水率和降解速率，可实现快速、高效止血的目的；且所述淀粉基蓬松颗粒无分散剂、乳化剂或交联剂等成分添加，具有安全可靠的特点，因此还满足体内环境的止血要求。
一种淀粉基蓬松颗粒的制备方法，包括以下步骤：
(1)在淀粉或改性淀粉中加入水进行糊化，得到淀粉糊状物；
(2)将所述淀粉糊状物加入至有机溶剂中，搅拌，静置后离心，收集沉淀物；
(3)将所述沉淀物依次进行冷冻干燥、粉碎和过筛，制得所述淀粉基蓬松颗粒。
在相关技术中，通常是在制得淀粉糊状物后便直接进行冷冻干燥来制得止血海绵或块状团聚体结构，再经粉碎工艺最终制得止血颗粒。但在淀粉或改性淀粉中加入水进行糊化后，淀粉颗粒发生溶胀，颗粒表面分子链吸水后舒展并相互接触、扩散致部分交缠，此时的淀粉颗粒相互间靠在一起，形成整块的粘接体。所形成的淀粉糊状物在冷冻干燥前的强度不高，且在冷冻干燥过程中会形成有韧性的大块或海绵状产品，所形成的止血海绵内部淀粉分子之间发生缠结难以分散，不利于后续粉碎成均匀的小颗粒，且所制成的颗粒吸水速度和吸水率较差，不满足实际应用的止血需要。
除此以外，市面上还有些淀粉止血材料会通过在淀粉糊状物中加入交联剂和乳化剂等成分，用以形成球体。同时，通过引入交联剂使淀粉分子间能以化学键的形式链接，形成紧密、稳定的结构，可降低溶胀率和体内降解率；但又由于交联剂不溶于水，因此需要加入有机溶剂作为助剂对交联剂进行溶解才能使其发挥作用，有机溶剂还起到调整反应液的极性，便于交联剂与止血粉主成分充分反应。通过该方法制得的止血颗粒具有在体内保持时间长，降解速度慢稳定和稳定的优点，但缺点在于交联使淀粉原有颗粒更紧密，淀粉的疏水性增强，颗粒内与颗粒间孔隙小，导致吸水率大大减小，吸水速率慢，同时因交联的降解时间延长，导致所制得止血颗粒不符合消化道或微创手术中要求48小时内止血和降解完成的规定，限制了 其应用范围。由此可见，当淀粉材料中不使用交联剂、乳化剂等成分时，则无额外添加有机溶剂的动机和理由。
然而本发明率先发现和指出，通过在冷冻干燥前便采用有机溶剂对淀粉糊状物进行搅拌分散，能够达到以下效果：①通过引入与淀粉糊状物不相溶的有机溶剂，再进行搅拌可将淀粉糊状物分散成小粒径的聚集体，便于干燥后的分散，经粉碎可得到均匀颗粒。②有机溶剂具有脱水效应，在冷冻过程中能有效减少聚集体之间的水分，以免在冷冻和干燥过程中发生粘结，使得小聚集体稳定、硬结，避免团聚颗粒之间在水介质中的再次缠结(便于后续粉碎球磨)。③再者，有机溶剂会渗透进淀粉颗粒内部进一步溶胀淀粉颗粒，使干燥后淀粉颗粒内部也形成孔洞，形成多孔蓬松的结构，从而有效提高淀粉基材料的吸水速度和吸水率。
在所述制备方法中，步骤(2)中在搅拌完成后，通过静置一段时间，利用水分子在淀粉颗粒中的扩散溶胀淀粉颗粒、且非交联淀粉颗粒间表面淀粉分子链水溶胀状态下互相扩散、交缠聚集，进一步提高其蓬松程度。
优选的，步骤(1)中所述改性淀粉选自醚化淀粉、羧甲基化淀粉、酯化淀粉或交联淀粉中的至少一种。
优选的，步骤(1)中所述淀粉糊状物中淀粉或改性淀粉与水的质量比为1：(3-40)。
优选的，步骤(2)中所述有机溶剂选自甲醇、乙醇、丙醇、丁醇、丙酮、异丙醇或二甲亚砜中的至少一种。更优选的，所述有机溶剂为异丙醇、甲醇、乙醇、或异丙醇与甲醇的组合。实验表明，当有机溶剂选用异丙醇、甲醇、乙醇、或异丙醇与甲醇的组合时，所制得的淀粉基蓬松颗粒的蓬松度更高，吸水效果更好。
优选的，所述淀粉基蓬松颗粒中还包含有亲水性高分子材料。所述亲水性高分子材料的加入在一定程度上会对产品的稳定性、粘性和止血性产生影响，所述亲水性高分子材料包括但不限于羧甲基纤维素钠，透明质酸、聚氧乙烯或胶原中的至少一种。
优选的，步骤(2)中所述有机溶剂中还包括有水。由于实际配置需要或纯有机溶剂难以获得，因而所述有机溶剂中水所占体积分数可为0-50％。
优选的，步骤(2)中搅拌的转速为100-3000r/min，搅拌的时间为0.5-2h。
优选的，步骤(2)中离心的转速为2000-5000r/min。离心的目的为去除部分有机溶剂和水。
优选的，步骤(3)中冷冻干燥的步骤为：先将沉淀物以-30℃至-10℃冷冻3-24小时，再置于冷冻干燥机中以-50℃至-30℃冻干15-36h。利用真空冷冻干燥工艺可直接把固态冰(结合水)及残留有机溶剂去除，在冷冻条件下水的结冰可进一步溶胀颗粒，提高蓬松度，而采用低温真空干燥可保持颗粒原有的蓬松状态，更能保持淀粉颗粒内及颗粒间的孔结构。
一种淀粉基蓬松颗粒，通过以上制备方法制得；所述淀粉基蓬松颗粒的粒径为20-500μm。
上述淀粉基蓬松颗粒在作为医疗止血材料中的应用。所述淀粉基蓬松颗粒可作为止血粉涂覆或喷洒外伤创面进行止血，也可应用在消化道创面、微创手术中进行止血。
相对于现有技术，本发明的有益效果如下：
(1)本发明采用了有机溶剂和水来制备淀粉基蓬松颗粒，有机溶剂和水的挥发性强，在冷冻真空干燥过程中容易除去，残留少；且本发明不添加有化学分散剂、乳化剂、交联剂等成分，因而更为安全可靠，能够满足消化道创面、微创止血的需求；
(2)通过有机溶剂的使用，本发明所述制备过程中所收集的沉淀物经冷冻干燥后显脆性，容易粉碎成所需大小的聚集体，最终得到的淀粉基蓬松颗粒相比于同样化学结构的淀粉聚集体，在吸水速度和吸水率等方面也得到显著提高；
(3)本发明所采用的淀粉原料可选用改性淀粉，以进一步改善淀粉基聚集体的吸水率、吸水速度、粘附性、凝胶强度等性能。
附图说明
图1表示实施例1中干燥羧甲基玉米淀粉聚集体及其粉碎后的显微结构；其中A表示干燥羧甲基玉米淀粉聚集体的显微结构，B表示干燥羧甲基玉米淀粉聚集体经粉碎后的显微结构；
图2表示实施例1中羧甲基玉米淀粉基蓬松颗粒和羧甲基玉米淀粉原粉吸水20倍的结果；其中A表示羧甲基玉米淀粉基蓬松颗粒，B表示羧甲基玉米淀粉原粉；
图3表示不同类型淀粉颗粒吸水20倍后的凝胶稳定性结果；其中C表示某德国止血粉(一种马铃薯淀粉经交联技术制得的止血粉)，D表示未经任何处理的羧甲基马铃薯淀粉，E表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒，F表示实施例1制得的羧甲基玉米淀粉基蓬松颗粒；
图4表示不同类型淀粉颗粒吸水后并放置48小时的凝胶稳定性结果；其中G表示实施 例2制得的羧甲基马铃薯淀粉基蓬松颗粒，H表示实施例1制得的羧甲基玉米淀粉基止蓬松颗粒，I表示德国产品(一种马铃薯淀粉经交联技术制得的止血粉)；
图5表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒与某国产上市产品在20倍吸水率条件下的凝胶稳定性结果；其中J表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒，K表示某国产上市产品(根据专利CN200610053680.9所制得的产品)。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案，现列举以下实施例进行说明。需要指出的是，以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例中所用的原料、试剂或装置如无特殊说明，均可从常规商业途径得到，或者可以通过现有已知方法得到。
实施例1
本实施例提供一种羧甲基玉米淀粉基蓬松颗粒，其制备方法包括以下步骤：
(1)将1g取代度为0.24的羧甲基玉米淀粉加入至10mL蒸馏水中，在室温下搅拌均匀，制得羧甲基玉米淀粉糊状物，备用；
(2)配制含95％甲醇水溶液，在室温、1000r/min的搅拌速度下，将羧甲基玉米淀粉糊状物转移至20mL甲醇溶液中，转移完成后继续搅拌0.5h后静置3h，倾倒掉上层液体，将含溶剂淀粉聚集体沉淀以3000r/min的转速进行离心，除去吸附在聚集体上的大部分溶剂，收集沉淀物；
(3)将收集的沉淀物在-20℃冰箱冷冻15h，然后在-50℃冷冻干燥机中冷冻干燥20h，得到干燥羧甲基玉米淀粉聚集体。
(4)将上述干燥羧甲基玉米淀粉聚集体经粉碎，过80目筛，得到粒径小于200μm的聚集体；再过300目筛，除去小于50μm的聚集体；即得到粒径介于50-200μm之间的羧甲基玉米淀粉基蓬松颗粒。
图1中A表示本实施例得到的干燥羧甲基玉米淀粉聚集体的显微结构，而图1中B表示本实施例得到的干燥羧甲基玉米淀粉聚集体经粉碎后的显微结构。由图1可知，干燥羧甲基玉米淀粉聚集体内部淀粉颗粒间互相交缠连接，内部多孔，聚集体间隙大不易产生毛细现象。
图2中A表示本实施例制得的羧甲基玉米淀粉基蓬松颗粒的吸水20倍的结果，图2中B 表示羧甲基玉米淀粉原粉吸水20倍的结果。由图2可知，羧甲基玉米淀粉原粉已呈流动态，而本实施例制得的羧甲基玉米淀粉基蓬松颗粒还能保持一定的形态，表明其仍未达到吸水上限。另有实验表明，与羧甲基玉米淀粉原粉相比，本实施例制备的羧甲基玉米淀粉基蓬松颗粒的吸水倍率平均提高4倍以上，且吸水速率加快，可从平均35秒降低到10秒。
实施例2
本实施例提供一种羧甲基马铃薯淀粉基蓬松颗粒，其制备方法包括以下步骤：
(1)将1g取代度为0.3的羧甲基马铃薯淀粉加入至10mL蒸馏水中，在室温下搅拌均匀，制得羧甲基玉米淀粉糊状物，备用；
(2)配制含90％乙醇水溶液，在室温、600r/min的搅拌速度下，将羧甲基马铃薯淀粉糊状物转移至20mL甲醇溶液中，转移完成后继续搅拌0.5h后静置3h，倾倒掉上层液体，将含溶剂淀粉聚集体沉淀以2000r/min的转速进行离心，除去吸附在聚集体上的大部分溶剂，收集沉淀物；
(3)将收集的沉淀物在-28℃冰箱冷冻20h，然后在-50℃冷冻干燥机中冷冻干燥24h，得到干燥羧甲基马铃薯淀粉聚集体。
(4)将上述干燥羧甲基马铃薯淀粉聚集体经粉碎，过80目筛，得到粒径小于200μm的聚集体；再过350目筛，除去小于30μm的聚集体；即得到粒径介于30-200μm之间的羧甲基马铃薯淀粉基蓬松颗粒。
将本实施例制得的羧甲基马铃薯淀粉基蓬松颗粒用于大白鼠断尾止血试验时，止血过程中小鼠的出血量小，且止血时间短，平均可在100秒内完全止血，止血速度要远优于国内、国外的止血粉产品(止血时间在210秒以上)。
实施例3
本实施例提供一种聚氧乙烯/羧甲基马铃薯淀粉基蓬松颗粒，其制备方法包括以下步骤：
(1)将0.1g分子量为5万的聚氧乙烯粉末分散在20mL蒸馏水中，然后加入1g取代度为0.3的羧甲基马铃薯淀粉，在室温下搅拌均匀，制得聚氧乙烯/羧甲基玉米淀粉糊状物，备用；
(2)配制含95％异丙醇水溶液50mL，在室温、1500r/min的搅拌速度下，将聚氧乙烯改性的聚氧乙烯/羧甲基玉米淀粉糊状物转移至异丙醇水溶液中，转移完成后继续搅拌0.5h后静 置3h，倾倒掉上层液体，将含溶剂淀粉聚集体沉淀以3000r/min的转速进行离心，除去吸附在聚集体上的大部分溶剂，收集沉淀物；
(3)将收集的沉淀物在-30℃冰箱冷冻10h，然后在-50℃冷冻干燥机中冷冻干燥24h，得到干燥的聚氧乙烯/羧甲基马铃薯淀粉聚集体。
(4)将上述干燥的聚氧乙烯/羧甲基马铃薯淀粉聚集体经粉碎，过80目筛，得到粒径小于200μm的聚集体；再过300目筛，除去小于50μm的聚集体；即得到粒径介于50-200μm之间的聚氧乙烯/羧甲基马铃薯淀粉基蓬松颗粒。
本实施例通过在羧甲基马铃薯淀粉中加入聚氧乙烯，进一步提高了羧甲基马铃薯淀粉凝胶的弹性。
实施例4
本实施例提供一种羧甲基马铃薯淀粉基蓬松颗粒，其制备方法包括以下步骤：
(1)将1g取代度为0.3的羧甲基马铃薯淀粉加入至10mL蒸馏水中，在室温下搅拌均匀，制得羧甲基玉米淀粉糊状物，备用；
(2)配制含50％异丙醇、45％甲醇的水溶液(即异丙醇-甲醇的水溶液)，在室温、600r/min的搅拌速度下，将羧甲基马铃薯淀粉糊状物转移至20mL异丙醇-甲醇的水溶液中，转移完成后继续搅拌0.5h后静置3h，倾倒掉上层液体，将含溶剂淀粉聚集体沉淀以2000r/min的转速进行离心，除去吸附在聚集体上的大部分溶剂，收集沉淀物；
(3)将收集的沉淀物在-28℃冰箱冷冻20h，然后在-50℃冷冻干燥机中冷冻干燥24h，得到干燥羧甲基马铃薯淀粉聚集体。
(4)将上述干燥羧甲基马铃薯淀粉聚集体经粉碎，过80目筛，得到粒径小于200μm的聚集体；再过350目筛，除去小于30μm的聚集体；即得到粒径介于30-200μm之间的羧甲基马铃薯淀粉基蓬松颗粒。
产品效果测试
图3所示为不同类型淀粉颗粒吸水20倍后的凝胶稳定性结果；其中C表示某德国止血粉(一种马铃薯淀粉经交联技术制得的止血粉)，D表示未经任何处理的羧甲基马铃薯淀粉，E表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒，F表示实施例1制得的羧甲基玉米淀 粉基蓬松颗粒。由图3可知，未经任何处理的羧甲基马铃薯淀粉呈流动态，吸水能力较差，其性能远不如某德国止血粉和实施例1-2制得的淀粉基蓬松颗粒。
图4所示为不同类型淀粉颗粒吸水后并放置48小时的凝胶稳定性结果；其中G表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒，H表示实施例1制得的羧甲基玉米淀粉基蓬松颗粒，I表示德国产品(一种马铃薯淀粉经交联技术制得的止血粉)。由图4可知，德国产品发生融化流动，表明其凝胶稳定性不如实施例1-2制得的淀粉基蓬松颗粒。
图5所示为实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒与某国产上市产品在20倍吸水率条件下的凝胶稳定性结果；其中J表示实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒，K表示某国产上市产品(根据专利CN200610053680.9所制得的产品)。由图5可知，实施例2制得的羧甲基马铃薯淀粉基蓬松颗粒在吸水后呈凝胶状，而国产某上市品牌为稀悬浊液状，表明本发明淀粉基蓬松颗粒具备更好的凝胶稳定性。
将实施例1-4制得的淀粉基蓬松颗粒与羧甲基玉米淀粉、羧甲基马铃薯淀粉和三种对比产品(即对比产品1-3)进行吸水性能、凝胶强度和粘附功的测试，测试结果如表1所示。其中对比产品1为由马铃薯淀粉经交联技术制得的止血粉；对比产品2为专利CN200610045441.9所制得的产品；对比产品3为专利CN200610053680.9所制得的产品。
吸水倍率＝吸水量(g或ml)/粉体重量(g)；
吸水速度：0.5g粉吸收10g水所需时间；
凝胶强度：饱和吸收水后密封放置48小时测量凝胶强度；
粘附功(g.mm)：饱和吸收水后凝胶的粘附功。
表1不同类型淀粉颗粒的性能测试结果
Figure PCTCN2021075416-appb-000001
Figure PCTCN2021075416-appb-000002
由表1可知，相比于未经任何处理的羧甲基玉米淀粉、羧甲基马铃薯淀粉，本发明实施例1-4制得的淀粉基蓬松颗粒吸水性能、凝胶强度和粘附功均取得明显更好的效果。虽然该德国品牌产品的性能要优于国内某品牌1和2，但要劣于实施例1-4制得的淀粉基蓬松颗粒，表明本发明所制得产品具备比市面上常规国内外产品更好的止血性能，能够作为医疗止血材料被广泛应用于体内和体外，实现快速、高效止血的目的。

Claims (11)

  1. 一种淀粉基蓬松颗粒的制备方法，其特征在于，包括以下步骤：
    (1)在淀粉或改性淀粉中加入水进行糊化，得到淀粉糊状物；
    (2)将所述淀粉糊状物加入至有机溶剂中，搅拌，静置后离心，收集沉淀物；
    (3)将所述沉淀物依次进行冷冻干燥、粉碎和过筛，制得所述淀粉基蓬松颗粒。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤(1)中所述改性淀粉选自醚化淀粉、羧甲基化淀粉、酯化淀粉或交联淀粉中的至少一种。
  3. 根据权利要求1所述的制备方法，其特征在于，步骤(1)中所述淀粉糊状物中淀粉或改性淀粉与水的质量比为1：(3-40)。
  4. 根据权利要求1所述的制备方法，其特征在于，步骤(2)中所述有机溶剂选自甲醇、乙醇、丙醇、丁醇、丙酮、异丙醇或二甲亚砜中的至少一种。
  5. 根据权利要求4所述的制备方法，其特征在于，步骤(2)中所述有机溶剂为异丙醇、甲醇、乙醇、或异丙醇与甲醇的组合。
  6. 根据权利要求1所述的制备方法，其特征在于，所述淀粉基蓬松颗粒中还包含有亲水性高分子材料。
  7. 根据权利要求1所述的制备方法，其特征在于，步骤(2)中搅拌的转速为100-3000r/min，搅拌的时间为0.5-2h。
  8. 根据权利要求1所述的制备方法，其特征在于，步骤(2)中离心的转速为2000-5000r/min。
  9. 根据权利要求1所述的制备方法，其特征在于，步骤(3)中冷冻干燥的步骤为：先将沉淀物以-30℃至-10℃冷冻3-24小时，再置于冷冻干燥机中以-50℃至-30℃冻干15-36h。
  10. 一种淀粉基蓬松颗粒，其特征在于，通过权利要求1-9中任一项所述的制备方法制得；所述淀粉基蓬松颗粒的粒径为20-500μm。
  11. 权利要求10所述淀粉基蓬松颗粒在作为医疗止血材料中的应用。
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