Patent Description:
A hemostatic procedure in surgical trauma and operation is an important factor in clinic, in which a hemostatic material plays an important role. At present, a starch-based material is widely used as the hemostatic material due to a good biological safety, a high water absorption rate, a degradability, and the like. An original particle size of starch particles derived from plants such as corns and potatoes generally ranges from <NUM> to <NUM>, and the particle size of most of the particles is less than <NUM>. The particle size of the starch particles does not change greatly even after chemical modification (etherification, gelatinization, crosslinking or carboxymethylation). When these small-sized starch particles are aggregated, a capillary phenomenon occurs due to a small gap after aggregation of the particles, which leads to excellent water absorption. Due to the existence of air between the particles, it will hinder the water absorption caused by the capillary phenomenon, which leads to poor overall water absorption and easy aggregation during water absorption, thus resulting in difficult subsequent water penetration, so that a whole starch particle aggregate has a slow water absorption speed and a greatly reduced water absorption rate. When used in special occasions, for example, when used as hemostatic powder for spraying hemostasis, the starch particles have a poor hemostatic effect due to slow water absorption speed and low total water absorption rate.

Existing researches show that the particle size of the starch particles and the chemical structure of starch may both affect the water absorption speed and the water absorption rate of the starch aggregate. Generally, carboxymethylated starch or etherified starch with the same particle size has a higher water absorption rate and a faster water absorption speed than original starch. Starch aggregate with different particle sizes or aggregation forms prepared from the starch with the same chemical structure also have difference in water absorption speed and water absorption rate. Arista™ modified starch hemostatic powder produced by Medafor Company of America has a particle diameter less than <NUM>, and although the hemostatic powder has a porous particle surface, the hemostatic powder has a low water absorption speed and a low water absorption rate. In Chinese Patent <CIT>, a porous spherical aggregate having a particle size ranged from <NUM> to <NUM>,<NUM>, and preferably ranged from <NUM> to <NUM> is prepared by using original particles of modified starch, and it is found that a water absorption speed and a water absorption rate were greatly improved in the case of large particles.

There are many related starch hemostatic particle products, for example, HaemoCer starch particle hemostatic powder (composed of carboxymethylated potato starch) from BIOCER Company of Germany, whose particle size is10 µm to <NUM>, although a water absorption speed is fast in an initial stage and a water absorption rate is high (<NUM> times), a water retention capacity is insufficient in a later stage, and gel is easy to be thin to flow. Natural polysaccharide microspheres invented by Wenzhou Institute of Biomaterials and Engineering in China are prepared by emulsifying and dispersing, physically crosslinking into spheres, and vacuum drying at <NUM> to obtain microspheres with an adjustable particle size of <NUM> to <NUM> for hemostasis, but the hemostatic effect of the microspheres is still insufficient. <CIT> (<NUM>-<NUM>-<NUM>) discloses a preparation method comprising the process steps of centrifugation and freeze drying but the resulting product is not satisfactory and a material with improve characteristics is still needed, particularly in terms of water absorption rate and speed as well as gel strength properties.

Although existing starch-based hemostatic materials have been improved by various methods, the prepared large-particle modified starch-based hemostatic materials still cannot fully meet actual clinical hemostatic requirements. Therefore, it is urgent to develop a starch-based hemostatic material that has a high hemostatic performance, and can implement hemostasis of traumatic wounds by coating or spraying, or is used for hemostasis of in-vivo micro-leakage under endoscope/minimal invasion.

The present disclosure aims to solve at least one of the technical problems in the prior art above. Therefore, the present disclosure provides a starch-based fluffy particle, a preparation method and use thereof. The starch-based fluffy particles provided are porous and fluffy with a large particle gap, have excellent water absorption speed, water absorption rate and degradation rate, and can achieve the purpose of rapid and efficient hemostasis. In addition, the starch-based fluffy particles are free of dispersing agent, emulsifying agent or cross-linking agent, have the characteristics of safety and reliability, and can meet the hemostatic requirement of in-vivo environment.

A preparation method of a starch-based fluffy particle, comprises the following steps of:.

In the related prior art, the prepared starch paste is usually directly freeze-dried to prepare a hemostatic sponge-like or lumpy aggregate structure, and then crushed to finally prepare hemostatic particles. However, after adding water into starch or modified starch for gelatinization, starch particles swell, molecular chains on particle surfaces stretch after water absorption and contact with each other, and diffuse to entangle partially, and at the moment, the starch particles lean against each other to form a whole adhesive body. The strength of the formed starch paste before freeze-drying is not high, and a flexible lumpy or sponge-like product may be formed during freeze-drying, so starch molecules in the formed hemostatic sponge are entangled with each other and difficult to be dispersed, which is not beneficial for subsequent crushing into uniform small particles. Moreover, the water absorption speed and the water absorption rate of the prepared particles are poor, so that the hemostatic requirement of practical use cannot be met.

In addition, there are some starch hemostatic materials on the market, which are formed into spheres by adding the crosslinking agent and the emulsifying agent into the starch paste. The starch molecules can be linked in a form of chemical bond by introducing the cross-linking agent to form a compact and stable structure, which can reduce the swelling rate and the in-vivo degradation rate. However, since the cross-linking agent is insoluble in water, it is necessary to add the organic solvent as an assistant to dissolve the cross-linking agent to make it work. The organic solvent also plays a role of adjusting the polarity of the reaction solution, which is convenient for the cross-linking agent to fully react with main ingredients of hemostatic powder. The hemostatic particles prepared by this method have the advantages of a long in-vivo retention time, a slow degradation speed and a stable property, and the disadvantages of more compact original starch particles caused by cross-linking, an enhanced hydrophobicity of the starch, and small pores inside and between particles, leading to a greatly reduced water absorption rate and a slow water absorption speed. Meanwhile, the degradation time of the hemostatic particles is prolonged due to cross-linking, which leads to the prepared hemostatic particles not meeting regulations of finishing hemostasis and degradation within <NUM> hours in a digestive tract or minimally invasive operation, so that the use of the hemostatic particles is limited. Thus, it can be seen that when the cross-linking agent, the emulsifying agent and other ingredients are not used in a starch material, there is no motivation or reason for adding the organic solvent.

However, the present disclosure first discovers and points out that, by using the organic solvent to stir and disperse the starch paste before freeze-drying, the following effects can be achieved: <NUM>. by introducing the organic solvent insoluble with the starch paste, and then stirring, the starch paste may be dispersed into several granular precipitates, which is convenient for drying and crushing, to obtain uniform particles. The organic solvent has a dehydration effect, which can effectively reduce a water content between the precipitates during freezing to avoid adhesion phenomenon caused by the re-entanglement of the precipitates due to the presence of water during freezing and drying. The precipitates are stable and hard, which is convenient for subsequent crushing and ball milling. Furthermore, the organic solvent may penetrate inside the precipitates to further swell the precipitates, so that pores are also formed inside the dried precipitates to form a porous fluffy structure, thus effectively improving the water absorption speed and the water absorption rate of the starch-based material.

In the preparation method, after finishing the stirring in step (<NUM>), by standing for a period of time, water molecules diffuses into the precipitates, and the organic solvent penetrates into the interior of the precipitates and swells the precipitates to disperse the starch molecules in the precipitates, thus further improving the fluffy degree.

Preferably, in step (<NUM>), the modified starch is at least one selected from the group consisting of etherified starch, carboxymethylated starch, esterified starch and crosslinked starch.

Preferably, in step (<NUM>), a mass ratio of the starch or the modified starch to the water in the starch paste is from <NUM>:<NUM> to <NUM>:<NUM>.

Preferably, in step (<NUM>), the organic solvent is at least one selected from the group consisting of methanol, ethanol, propanol, butanol, acetone, isopropanol, and dimethyl sulfoxide. More preferably, the organic solvent is isopropanol, methanol, ethanol, a combination of isopropanol and methanol, dimethyl sulfoxide or acetone. Experiments show that when the organic solvent is isopropanol, methanol, ethanol, the combination of isopropanol and methanol, dimethyl sulfoxide or acetone, the prepared starch-based fluffy particle has a higher fluffy degree and a better water absorption effect.

Preferably, the starch-based fluffy particle further comprises a hydrophilic polymer material. Addition of the hydrophilic polymer material may affect the stability, adhesion and hemostasis properties of the product to a certain extent, and the hydrophilic polymer material is, but is not limited to sodium carboxymethyl cellulose, hyaluronic acid, polyoxyethylene or collagen. In some embodiments, the hydrophilic polymer material is at least one selected form group consisting of sodium carboxymethyl cellulose, hyaluronic acid, polyoxyethylene, and collagen.

Preferably, in step (<NUM>), the organic solvent further comprises water. Due to an actual preparation requirement or the difficulty in obtaining a pure organic solvent, based on the total amount of the organic solvent and the water being 100vol%, the amount of the water is about 0vol% to 50vol%.

Preferably, in step (<NUM>), the stirring is performed at a rotating speed of <NUM> r/min to <NUM>,<NUM> r/min, and lasts for <NUM> hour to <NUM> hours.

Preferably, in step (<NUM>), the centrifuging is performed at a rotating speed of <NUM>,<NUM> r/min to <NUM>,<NUM> r/min. The centrifuging is intended to remove a part of organic solvent, ora part of organic solvent and water.

Preferably, in step (<NUM>), the freeze-drying comprises the steps of: freezing the precipitates at -<NUM> to -<NUM> for <NUM> hours to <NUM> hours first, and then freeze-drying the precipitates in a freeze dryer at -<NUM> to -<NUM> for <NUM> hours to <NUM> hours. Solid ice (bound water) and residual organic solvent may be directly removed by using the vacuum freeze-drying process, and freezing of the water under the freezing condition may further swell the particles, thus improving the fluffy degree. In addition, the original fluffy state of the particles may be kept by low-temperature vacuum drying, which can better keep the porous structure inside and between the starch particles.

A starch-based fluffy particle prepared by the preparation method above is provided, wherein a particle size of the starch-based fluffy particle is from <NUM> to <NUM>.

Use of the starch-based fluffy particle above as a medical hemostatic material is provided. The starch-based fluffy particle may be coated or sprayed on a traumatic wound as hemostatic powder for hemostasis, and may also be applied to a digestive tract wound and a minimally invasive operation for hemostasis.

Compared with the prior art, the present disclosure has the following beneficial effects:.

In order to make those skilled in the art better understand the technical solutions of the present disclosure, the following examples are now provided for description. It should be pointed out that the following examples do not limit the scope of protection claimed in the present disclosure.

Unless otherwise specified, the raw materials, reagents or devices used in the following examples may all be obtained in conventional commercial ways, or obtained by existing known methods.

The example provided a carboxymethyl corn starch-based fluffy particle, and a preparation method of the carboxymethyl corn starch-based fluffy particle comprised the following steps.

In <FIG>, A represents the micro-structure of the dried carboxymethyl corn starch-based precipitates obtained in this example, and in <FIG>, B represents the micro-structure of the dried carboxymethyl corn starch-based precipitates obtained in this example after crushing. It can be seen from <FIG> that the starch particles inside the dried carboxymethyl corn starch-based precipitates are entangled and connected with each other, with a porous interior, and there are large gaps between the dried carboxymethyl corn starch-based precipitates, so that it is not easy to cause a capillary phenomenon. in <FIG> represents the result of the carboxymethyl corn starch-based fluffy particles prepared this example after <NUM> times of water adsorption, and in <FIG> represents the result of the carboxymethyl corn starch raw powder after <NUM> times of water adsorption. It can be seen from <FIG> that the carboxymethyl corn starch raw powder is in a flowing state, while the carboxymethyl corn starch-based fluffy particles prepared in this example can still be kept in a certain form, which indicates that an upper limit of water adsorption is still not reached. Another experiment shows that, compared with the carboxymethyl corn starch raw powder, the water absorption rate of the carboxymethyl corn starch-based fluffy particles prepared in this example is increased by more than <NUM> times on average, and the water absorption speed is accelerated, which can be reduced from <NUM> seconds to <NUM> seconds on average.

The example provided a carboxymethyl potato starch-based fluffy particle, and a preparation method of the carboxymethyl potato starch-based fluffy particle comprised the following steps.

When the carboxymethyl potato starch-based fluffy particles prepared in this example were used in a hemostasis experiment of a broken tail of a mouse. The bleeding volume of the mouse during hemostasis was low, and the hemostasis time was short. Complete hemostasis could be realized within <NUM> seconds on average, and the hemostasis speed was much faster than that of Chinese and foreign hemostatic powder products that have a hemostasis time of more than <NUM> seconds.

The example provided a polyoxyethylene/carboxymethyl potato starch-based fluffy particle, and a preparation method of the polyoxyethylene/carboxymethyl potato starch-based fluffy particle comprised the following steps.

In this example, the flexibility of carboxymethyl potato starch gel was further improved by adding polyoxyethylene into the carboxymethyl potato starch.

<FIG> shows the gel stability results of different types of starch particles after <NUM> times of water adsorption, wherein C represents a German hemostatic powder (hemostatic powder prepared from potato starch by a cross-linking technology), D represents the carboxymethyl potato starch without any treatment, E represents the carboxymethyl potato starch-based fluffy particles prepared in Example <NUM>, and F represents the carboxymethyl corn starch-based fluffy particles prepared in Example <NUM>. It can be seen from <FIG> that the carboxymethyl potato starch without any treatment is in a flowing state, with a poor water absorption capacity, and the performance of the carboxymethyl potato starch without any treatment is far inferior to those of the German hemostatic powder and the starch-based fluffy particles prepared in Examples <NUM> to <NUM>.

<FIG> shows the gel stability results of different types of starch particles after water adsorption and standing for <NUM> hours, wherein G represents the carboxymethyl potato starch-based fluffy particles prepared in Example <NUM>, H represents the carboxymethyl corn starch-based fluffy particles prepared in Example <NUM>, and I represents the German product (the hemostatic powder prepared from potato starch by the cross-linking technology). It can be seen from <FIG> that the German product is melt to flow, which indicates that the gel stability of the German product is not as good as those of the starch-based fluffy particles prepared in Examples <NUM> to <NUM>.

<FIG> shows the gel stability results of the carboxymethyl potato starch-based fluffy particles prepared in Example <NUM> and a Chinese market product after <NUM> times of water adsorption, wherein J represents the carboxymethyl potato starch-based fluffy particles prepared in Example <NUM>, and K represents the Chinese market product (a product prepared according to the Chinese patent <CIT>). It can be seen from <FIG> that the carboxymethyl potato starch-based fluffy particles prepared in Example2 are gel-like after water absorption, while the Chinese market product is dilute suspension, which indicates that the starch-based fluffy particles of the present disclosure have a better gel stability.

Tests, including water absorption, gel strength and adhesion work were performed on the starch-based fluffy particles prepared in Examples <NUM> to <NUM>, the carboxymethyl corn starch, the carboxymethyl potato starch and three comparative products (which were namely comparative products <NUM> to <NUM>). Test results are shown in Table <NUM>. The comparative product <NUM> is hemostatic powder prepared from potato starch by a cross-linking technology; the comparative product <NUM> is a product prepared according to the Chinese patent <CIT>; and the comparative product <NUM> is a product prepared according to the Chinese patent <CIT>.

It can be seen from Table <NUM> that, compared with the carboxymethyl corn starch without any treatment and the carboxymethyl potato starch without any treatment, the starch-based fluffy particles prepared in Examples <NUM> to <NUM> of the present disclosure all have significantly better effects in water absorption, gel strength and adhesion work. In addition, compared with the gel strength of carboxymethyl corn starch, carboxymethyl potato starch and Comparative products <NUM>-<NUM>, the starch-based fluffy particles of Example <NUM> have more excellent gel strength due to containing polyoxyethylene, which indicates that the starch-based fluffy particles of Example <NUM> have superior elasticity, compared to the elasticity of carboxymethyl corn starch, carboxymethyl potato starch and Comparative products <NUM>-<NUM>.

It can be seen from the water absorption rate and water absorption speed of Examples <NUM> to <NUM> and Comparative product <NUM> that, under the carboxymethyl potato starch as the main raw material, compared with Comparative product <NUM>, the water absorption speed and water absorption rate of the starch-based fluffy particles of the present application are significantly improved.

Claim 1:
A preparation method of a starch-based fluffy particle, comprising the following steps of:
(<NUM>) adding water into starch or modified starch for gelatinization to obtain a starch paste;
(<NUM>) adding the starch paste into an organic solvent that does not dissolve the starch paste so that the starch paste is dispersed into several precipitates in the organic solvent and the precipitates are swelled, stirring, standing and centrifuging to collect precipitates; and
(<NUM>) freeze-drying, crushing and sieving the precipitates in sequence to prepare the starch-based fluffy particle.