KR101974373B1 - Biodegradable sphere polymer and method of preparing the same - Google Patents

Abstract

The present invention relates to a particulate biodegradable polymer having excellent embolic properties and a preparing method thereof. The particulate biodegradable polymer of the present invention comprises: a core part having the density of a first cross-linking bond greater than that of a second cross-linking bond; and a large outer part formed to surround the core part.

Description

TECHNICAL FIELD [0001] The present invention relates to a particulate biodegradable polymer and a method of producing the same. BACKGROUND ART [0002]

The present invention relates to a particulate biodegradable polymer and a method for producing the particulate biodegradable polymer. More particularly, the present invention relates to a particulate biodegradable polymer in the form of microspheres having a uniform particle size distribution and improved physical strength, and a method for producing the same.

A biodegradable polymer refers to a substance that is metabolized by metabolism of at least a part of the degradation or exacerbation process. Examples of the biodegradable polymer include gelatin, collagen, chitosan, hyaluronic acid, albumin, and the like. Among them, gelatin is excellent in biocompatibility, hydrophilic and non-toxic, so it is expected to be applied to various fields in biotechnology.

For example, gelatin can be used as an embolization agent for therapeutic vascular occlusion, or embolization. Embolism refers to a therapeutic technique that injects an embolus into the vasculature of a human or non-human animal to block blood flow. Embolization can be performed by injecting an embolus material into the bloodstream through a microcatheter. The embolization material can be used to normalize blood flow by selectively closing the vasculature, to minimize blood loss during surgical treatment, to block lesions leading to lesion necrosis, or to increase the efficacy of the drug to treat lesions .

Patent Document 1 discloses a gelatin sponge applied to carotid artery embolization and a method for manufacturing the same.

Korean Patent No. 10-1575563

The embolization agent can exert a therapeutic effect by selectively closing the target vessel. For this, the embolus material should be used in consideration of the size of the target vasculature. From this point of view, it may be desirable that the embolization material has a substantially uniform size and at the same time has a certain spherical particle shape.

Patent Document 1 discloses a gelatin sponge as drug-releasing microspheres effective for liver cancer. However, the gelatin sponge in the form of the patent document 1 has a problem that it is not suitable as an embolizing material because its shape is not constant.

For example, the gelatin sponge in the form of Patent Document 1 can not necessarily control the shape of the gelatin sponge in its manufacturing process, and its shape is further broken in the lyophilization process, resulting in irregular or non-uniform shape. Foam-shaped embolization materials with irregular shapes that do not have a constant shape can not completely shut off the target vasculature, and even in the process of vaso-occlusion, or after vaso-occlusion, continuous irritation may occur in the vasoconstriction, resulting in vasospasm damage.

On the other hand, embolization materials are required to have high physical strength and storage stability. For example, if the physical strength and storage stability of the embolization material is not sufficient, an increase in the rate of disintegration in the vasculature may result in failure to achieve the intended occlusion. Particularly, according to embolization sites to be embolized, very low decomposition rates are required for specific vasculature.

Accordingly, a problem to be solved by the present invention is to provide a microsphere-type particulate biodegradable polymer suitable for use as an embolization material and a method for producing the same.

The present invention has been made in view of the above problems, and it is an object of the present invention to provide a method of manufacturing the same.

In order to solve the above problems, the particulate biodegradable polymer according to an embodiment of the present invention has cross-linking derived from formaldehyde and cross-linking derived from glutaraldehyde.

At the center of the particulate biodegradable polymer, the density of the crosslinking derived from the formaldehyde may be greater than the density of the crosslinking derived from the glutaraldehyde.

The density of the cross-linking derived from the glutaraldehyde may be larger at the outer portion than at the central portion of the particulate biodegradable polymer.

The biodegradable polymer may be gelatin.

According to another aspect of the present invention, there is provided a particulate biodegradable polymer comprising formaldehyde and glutaraldehyde adsorbed on a surface of a biodegradable polymer.

The particulate biodegradable polymer according to another embodiment of the present invention for achieving the above object has a compressive force of 5 mN or more until a 30% reduction in diameter occurs when compressive force is applied to the particulate biodegradable polymer.

In addition, the biodegradable polymer may have a mass reduction rate of 2% or less after being stored in a normal cell (0.9%) at a temperature of 60 ° C for 24 hours.

According to another aspect of the present invention, there is provided a method for producing a biodegradable polymer, the method comprising: forming an aggregate of a biodegradable polymer; subjecting the aggregate to a primary crosslinking with a first crosslinking agent; And secondarily crosslinking the crosslinked aggregate with a second crosslinking agent different from the first crosslinking agent.

The molecular weight of the first crosslinking agent may be smaller than the molecular weight of the second crosslinking agent.

The first crosslinking agent may include formaldehyde, and the second crosslinking agent may include glutaraldehyde.

The first cross-linking step is a step of providing an aqueous solution containing the first cross-linking agent in an oil-based medium in which the micelle is dispersed, and the second cross-linking step is a step in which the second cross- Wherein the concentration of the first crosslinking agent in the aqueous solution containing the first crosslinking agent may be less than the concentration of the second crosslinking agent in the aqueous solution containing the second crosslinking agent.

The step of forming the aggregate comprises the steps of preparing an oil medium in a reactor, providing an aqueous solution of a biodegradable polymer to the oil medium, providing a surfactant to the oil medium, and a step of providing an aqueous solution of the biodegradable polymer And stirring the oily medium provided with the surfactant at room temperature.

In the stirring step, the stirring speed may be 300 rpm to 450 rpm.

In addition, in the stirring step, micelles of the biodegradable polymer dispersed in the oil medium are formed, and the primary crosslinking step is a step of providing the first crosslinking agent to the oil medium in which the micelle is dispersed, The step of cross-linking is a step of providing the second cross-linking agent to the oil phase in which the micelle is dispersed, and the step of primary cross-linking and the step of secondary cross-linking may be successively performed in the reactor.

Also, the ratio of the number of moles of the first crosslinking agent provided in the primary crosslinking step to the number of moles of the second crosslinking agent provided in the secondary crosslinking step may be larger than 20: 1 and smaller than 180: 1.

The ratio of the number of moles of the first crosslinking agent to the number of moles of the second crosslinking agent may be 50: 1 to 70: 1.

The details of other embodiments are included in the detailed description and drawings.

The particulate biodegradable polymer according to an embodiment of the present invention has high physical strength and storage stability, so that the embolization property can be excellent.

According to the method for producing a biodegradable polymer according to an embodiment of the present invention, a granular biodegradable polymer having improved storage stability and embolism can be produced.

The effects according to the embodiments of the present invention are not limited by the contents exemplified above, and more various effects are included in the specification.

1 is a flowchart illustrating a method of manufacturing a biodegradable polymer according to an embodiment of the present invention.
FIGS. 2 to 6 are views for explaining a method of producing the biodegradable polymer of FIG. 1. FIG.
7 is a graph showing the results according to Experimental Example 2;
8 to 12 are diagrams showing the results according to Experimental Example 3.

BRIEF DESCRIPTION OF THE DRAWINGS The advantages and features of the present invention and the manner of achieving them will become apparent with reference to the embodiments described in detail below with reference to the accompanying drawings. The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. However, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. To fully disclose the scope of the invention to a person skilled in the art, and the invention is only defined by the scope of the claims.

In this specification, " and / or " includes each and every combination of one or more of the mentioned items. The numerical range indicated by using " to " represents a numerical range including the values described before and after the lower limit and the upper limit, respectively. &Quot; about " or " approximately " means a value or numerical range within 20% of the value or numerical range described thereafter.

Hereinafter, a method for producing the particulate biodegradable polymer and the biodegradable polymer according to the present embodiment will be described in detail with reference to the drawings.

1 is a flowchart illustrating a method of manufacturing a biodegradable polymer according to an embodiment of the present invention.

Referring to FIG. 1, a method for producing a biodegradable polymer according to an exemplary embodiment of the present invention includes forming an aggregate of a biodegradable polymer (S110), primary crosslinking the aggregate (S120) (S130). ≪ / RTI >

Hereinafter, a method for producing a biodegradable polymer according to this embodiment will be described in more detail with reference to FIGS. 2 to 6. FIG.

2 is a view showing a step S110 of forming an aggregate 300a of a biodegradable polymer of the biodegradable polymer production method of FIG.

In an exemplary embodiment, the step S110 of forming the aggregate 300a of the biodegradable polymer comprises the steps of preparing the oil medium 200a in the reactor 100, providing an aqueous solution of the biodegradable polymer to the oil medium 200a , Providing a surfactant to the oily medium 200a, and stirring the oily medium 200a.

As described later, the aggregate 300a of the biodegradable polymer can form micelles in the oil medium 200a. The kind of the oil medium 200a is not particularly limited as long as the aggregate 300a of the biodegradable polymer such as an aggregate of gelatin can form micelles. For example, the oil medium 200a includes canola oil, cherry oil, And the like.

The aqueous solution of the biodegradable polymer may include a biodegradable polymer dissolved in a solvent and a solvent. The biodegradable polymer may be gelatin and the aqueous solution of the biodegradable polymer may be an aqueous gelatin solution, but the present invention is not limited thereto. The solvent may include distilled water or normal celluloses. The biodegradable polymer content in the biodegradable polymer aqueous solution may be in the range of about 10.0 wt% to 40 wt%. If the biodegradable polymer is contained in an amount of more than 40% by weight, the density of the aggregate 300a of the biodegradable polymer becomes too large and it may be difficult to control the size of the particulate biodegradable polymer. In addition, when the biodegradable polymer is contained in an amount of less than 10% by weight, it may be difficult to form aggregates 300a of fully spherical biodegradable polymers.

In some embodiments, the volume ratio of the aqueous biodegradable polymer solution to be added and the oily medium 200a forming the reaction system may be about 3: 100 to 10: 100. If the addition volume of the biodegradable polymer aqueous solution is larger than 10: 100, aggregation phenomenon may occur between the agglomerates 300a of the biodegradable polymer. If the added volume of the biodegradable polymer aqueous solution is less than 3: 100, it may be difficult to form a stable biodegradable polymer aggregate 300a.

In some embodiments, the biodegradable polymer aqueous solution may further comprise a crosslinking agent. The crosslinking agent in the aqueous solution of the biodegradable polymer can preliminarily crosslink the aggregate 300a of the biodegradable polymer to help stabilize the aggregation 300a of the biodegradable polymer. The crosslinking agent may comprise at least one of formaldehyde or glutaraldehyde.

The surfactant can help the aqueous solution of the biodegradable polymer form micelles of the biodegradable polymer aggregate 300a, for example, a biodegradable polymer. The kind of the surfactant can be selected in consideration of the kind of the oil medium 200a. For example, the surfactant may include one or more of a fatty acid ester-based surfactant, a dimethicone-based surfactant, a pluronic-based surfactant, or a polysorbate-based surfactant. In some embodiments, the volume ratio of the surfactant to be added and the oily medium 200a forming the reaction system may be about 0.01: 100 to 0.1: 100, but the present invention is not limited thereto.

After the aqueous medium of the biodegradable polymer and the surfactant are provided in the oil medium 200a, the oil medium 200a may be agitated. The step of stirring the oily medium 200a may be a step of forming an aggregate 300a of the biodegradable polymer dispersed in the oily medium 200a. The step of stirring the oil medium 200a may be performed using an agitator 400 such as an impeller.

The step of stirring the oil medium 200a may be performed at room temperature. For example, stirring the oily medium 200a may be performed at about 15 ° C to 25 ° C, or about 20 ° C. When the oily medium 200a to which the aqueous solution of the biodegradable polymer is added is stirred at a temperature lower than 15 ° C, the rate of formation of the agglomerate 300a of the biodegradable polymer is excessively increased to control the size of the agglomerate 300a of the biodegradable polymer Can be difficult. In addition, when stirred at a temperature higher than 25 ° C, the biodegradable polymer may not form stable micelles.

In the step of stirring the oil medium 200a, the stirring speed of the stirrer 400 may be about 300 rpm to 450 rpm. If the agitation speed is higher than 450 rpm, the agglomerate 300a of the biodegradable polymer may not be able to maintain a stable spherical shape and may be decomposed. If the stirring speed is less than 300 rpm, micelles may not be formed.

The aggregate 300a of the biodegradable polymer formed in this step forms a droplet in the oil medium 200a and may be dispersed substantially uniformly.

Next, FIG. 3 is a view showing a first cross-linking step (S120) of the method for producing the biodegradable polymer of FIG. 1, and FIG. 4 is a schematic view showing an aggregate 300b of the first cross-linked biodegradable polymer of FIG.

In an exemplary embodiment, the primary crosslinking step (S120) may comprise providing a first crosslinker (500) to the oil medium (200b) in which aggregates of biodegradable polymers are dispersed. Specifically, the primary crosslinking step (S120) may include providing an aqueous solution containing the first crosslinking agent (500) in the oil medium (200b) in which aggregates of the biodegradable polymer are dispersed. By biasing the biodegradable polymer forming the micelle at least partially, it is possible to prevent agglomeration between the particulate biodegradable polymer and improve physical strength. Further, the physical / chemical stability of the particulate biodegradable polymer can be improved and the storage stability can be improved. The primary crosslinking step (S120) may be carried out in the oil medium (200b). That is, the primary crosslinking step (S120) can be continuously performed in the same reactor (100) after the agglomerated biodegradable polymer (300a in FIG. 2) is formed in the reactor (100). In addition, the crosslinking time of the primary crosslinking step (S120) may be performed for a time of about 30 minutes to 120 minutes or less, but the present invention is not limited thereto.

The first crosslinking agent 500 used in the primary crosslinking step S120 may be an aldehyde crosslinking agent. In an exemplary embodiment, the first crosslinker 500 may comprise formaldehyde. For example, the first crosslinking agent 500 may be provided in an aqueous solution state, that is, in a formaldehyde aqueous solution state.

When the first crosslinking agent 500 includes formaldehyde, internal crosslinking of the biodegradable polymer aggregate 300b as well as the outer surface of the aggregate 300b of the biodegradable polymer can be performed. That is, when formaldehyde is used as the primary crosslinking agent (i.e., the first crosslinking agent 500), the formaldehyde can sufficiently penetrate into the aggregate 300b of the biodegradable polymer. As a result, the cross-linking density of the biodegradable polymer in the aggregate 300b, for example, the center portion of the particulate biodegradable polymer, can be improved as compared with the case where another cross-linking agent (such as glutaraldehyde) is used as the primary cross-linking agent. It is possible to sufficiently prevent cross-linking of the center portion as well as the outer portion of the particulate biodegradable polymer, thereby preventing the biodegradable polymer material from leaching out of the particulate biodegradable polymer.

The density (for example, count) of crosslinking derived from formaldehyde in the aggregate 300b of the primary crosslinked biodegradable polymer may be substantially uniform, but the present invention is not limited thereto.

Next, FIG. 5 is a view showing a secondary crosslinking step (S130) of the method for producing the biodegradable polymer of FIG. 1, FIG. 6 is a view showing an aggregate 300c of the secondary crosslinked biodegradable polymer of FIG. 5, Is a schematic view showing the polymer 300c.

In an exemplary embodiment, the secondary crosslinking step (S130) may include providing a second crosslinker (600) to the oil medium (200c) in which aggregates of the primary crosslinked biodegradable polymer are dispersed. Specifically, the secondary crosslinking step (S130) may include providing an aqueous solution containing the second crosslinking agent (600) in the oil medium (200c) in which aggregates of the primary crosslinked biodegradable polymer are dispersed. By crosslinking the primary crosslinked biodegradable polymer at least partially, it is possible to prevent agglomeration between the particulate biodegradable polymer and further improve the physical strength. Further, the physical / chemical stability of the particulate biodegradable polymer can be improved and the storage stability can be further improved. The secondary crosslinking step (S130) may be performed in the oil medium (200c). That is, in the secondary crosslinking step S130, the agglomerated biodegradable polymer is first crosslinked (S120) in the reactor 100 to form an aggregate (300b in FIG. 3) of biodegradable primary crosslinked polymer, (100). Also, the crosslinking time of the secondary crosslinking step (S130) can be performed for a time of about 30 minutes to 120 minutes or less, but the present invention is not limited thereto.

The second crosslinking agent 600 used in the secondary crosslinking step (S130) may be an aldehyde crosslinking agent. In an exemplary embodiment, the second crosslinking agent 600 may have a higher molecular weight than the first crosslinking agent 500. The external crosslinking density of the aggregate 300c of the biodegradable polymer can be further improved. For example, the second crosslinking agent 600 may comprise glutaraldehyde.

The second crosslinking agent 600 may be provided in an aqueous solution state, that is, in an aqueous solution of glutaraldehyde. The concentration of the second crosslinking agent 600 in the aqueous solution containing the second crosslinking agent 600 may be smaller than the concentration of the first crosslinking agent 500 in the aqueous solution containing the first crosslinking agent 500. [ The outer surface of the biodegradable polymer aggregate can be intensively crosslinked in the secondary crosslinking step (S130) by making the concentration of the second crosslinking agent (600) lower than the concentration of the first crosslinking agent (500).

The number of moles of the first crosslinking agent 500 (for example, formaldehyde) provided in the primary crosslinking step S120 may be controlled by controlling the number of moles of the second crosslinking agent 600 (for example, glutaraldehyde) supplied in the secondary crosslinking step S130 Aldehyde). The ratio of the number of moles of the first crosslinking agent (500) to the number of moles of the second crosslinking agent (600) may be greater than about 20: 1 and less than 180: 1. For example, the ratio of the number of moles of the first crosslinking agent 500 to the number of moles of the second crosslinking agent 600 may be about 50: 1 to 70: 1. This will be described later in conjunction with experimental examples.

When the second crosslinking agent 600 includes glutaraldehyde, the crosslinking density of the outer surface of the aggregate 300c of the biodegradable polymer can be selectively enhanced. That is, when glutaraldehyde is used as the secondary crosslinking agent (i.e., the second crosslinking agent 600), the glutaraldehyde can prevent the crosslinking ability of the biodegradable polymer on the outer surface of the agglomerate 300c of the biodegradable polymer, Lt; / RTI > As a result, the degree of crosslinking can be gradually increased from the central portion to the outer portion of the aggregate 300c of the biodegradable polymer, as compared with the case where other crosslinking agents (for example, formaldehyde) are used as the secondary crosslinking agent. The crosslinking density of the secondary crosslinked biodegradable polymer (300c), that is, the particulate biodegradable polymer (300c) is made larger at the outer periphery than at the central portion, so that the physical / chemical stability of the particulate biodegradable polymer And the storage stability can be improved.

Although the present invention is not limited thereto, when glutaraldehyde is used as the crosslinking agent used in the primary crosslinking step, non-uniform crosslinking of the biodegradable polymer aggregate may occur in the primary crosslinking step. For example, the cross-linking degree of the outer portion of the primary cross-linked biodegradable polymer aggregate may be larger than that of the central portion. When the outer part of the agglomerate of the biodegradable polymer is sufficiently crosslinked using glutaraldehyde, the crosslinking agent used in the second crosslinking step may be difficult to penetrate into the center of the agglomerate of the biodegradable polymer. That is, when primary crosslinking is performed using relatively small molecular weight formaldehyde (S120) as in the present embodiment, and secondary crosslinking is performed using relatively large molecular weight glutaraldehyde (S130) The center portion as well as the outer portion of the biodegradable polymer 300c can have a sufficient cross-link density.

The density (for example, count) of crosslinking derived from the glutaraldehyde in the aggregated body 300c of the secondary crosslinked biodegradable polymer, that is, the particulate biodegradable polymer 300c is smaller than the density . ≪ / RTI > Further, at the center of the particulate biodegradable polymer 300c, the density (e.g., count) of crosslinking derived from formaldehyde may be greater than the density (e.g., count) of crosslinking derived from glutaraldehyde.

For example, when the granular biodegradable polymer 300c is used as an embolization agent, the vessel can be completely obstructed, the stimulation of the inner wall of the vessel can be minimized, and the operation can be facilitated. The progress can be improved. In addition, the conventional foam or sponge type embolization material has a problem of coagulation between sponges due to its irregular shape, and there is a clinical problem that a suspension is unstable and a suspension should be formed immediately before embolization. However, the particulate biodegradable polymer 300c produced according to this embodiment having a substantially spherical shape unlike the sponge-type embolization material can minimize aggregation between particles. In addition, although the biodegradable polymer has a particulate shape that is not in the form of a sponge, the particulate biodegradable polymer 300c has cross-linking derived from formaldehyde and cross-linking derived from glutaraldehyde, excellent physical strength and storage stability Lt; / RTI > For example, even when a compressive force is applied to the particulate biodegradable polymer 300c, the compressive force until the reduction of 30% of the diameter occurs can be 5 mN or more and excellent compression strength can be obtained. Further, the mass reduction rate may be less than 2% even after storage for 24 hours in a normal cell (0.9% NaCl) at a temperature of 60 ° C.

In some embodiments, the particulate biodegradable polymer 300c produced in accordance with this embodiment is formed from formaldehyde and / or glutaraldehyde adsorbed physically / chemically near or within the surface of the particle (i.e., biodegradable polymer) . ≪ / RTI > The formaldehyde and the glutaraldehyde may be mixed with the particulate biodegradable polymer 300c in the first cross-linking step S120 and the second cross-linking agent 600 used in the second cross- It may remain on the surface, but the present invention is not limited thereto.

Also, in some embodiments, the particulate biodegradable polymer 300c produced according to this embodiment may be formulated in the form of a suspension with suitable dispersing agents, such as, for example, nocelluline, and additives such as excipients, diluents, or the like, ≪ / RTI >

Hereinafter, the particulate biodegradable polymer 300c according to the present embodiment and its preparation method will be described in detail with reference to specific experimental examples.

<Production Example>

The gelatin micelles were formed using the system for producing particulate biodegradable polymers described in conjunction with FIGS. 1 to 6, and crosslinked to prepare particulate gelatin.

Specifically, 350 mL of canola oil and 20 mL of 20% gelatin aqueous solution were added to a 500 mL beaker and mixed. And 100 mu L of Tween-80 as a surfactant was further added. Then, the mixture was stirred at a speed of 400 rpm using an impeller to form gelatin micelles.

Then, primary crosslinking and secondary crosslinking were carried out for 60 minutes at room temperature under the conditions shown in Table 1 below to produce granular gelatin. In Table 1 below, FA means formaldehyde and GA means glutaraldehyde.

Primary bridge Secondary bridge Cross-linking agent Addition amount Cross-linking agent Addition amount Production Example 1 3.7% FA 30 mL 0.25% GA 10 mL Production Example 2 3.7% FA 20 mL 0.25% GA 20 mL Production Example 3 3.7% FA 10 mL 0.25% GA 30 mL

<Comparative Example>

Gelatin micelles were formed in the same manner as in the preparation examples. Then, cross-linking was carried out at room temperature under the conditions shown in Table 2 to prepare granular gelatin. In Table 1 below, FA means formaldehyde and GA means glutaraldehyde.

Primary bridge Secondary bridge Tertiary bridge Cross-linking agent Bridging time Cross-linking agent Bridging time Cross-linking agent Bridging time Comparative Example 1 0.25% GA / 40mL 120 minutes - - - - Comparative Example 2 0.0616% FA / 40mL 120 minutes - - - - Comparative Example 3 0.123% FA / 40mL 120 minutes - - - - Comparative Example 4 0.37% FA / 40mL 120 minutes - - - - Comparative Example 5 0.74% FA / 40mL 120 minutes - - - - Comparative Example 6 3.7% FA / 40mL 120 minutes - - - - Comparative Example 7 0.125% GA / 40mL 60 minutes 0.25% GA / 20 mL 60 minutes - - Comparative Example 8 0.125% GA / 30mL 30 minutes 0.25% GA / 5mL 30 minutes 0.25% GA / 20 mL 60 minutes Comparative Example 9 0.125% GA / 20mL 30 minutes 0.25% GA / 10 mL 30 minutes 0.25% GA / 20 mL 60 minutes Comparative Example 10 0.125% GA / 10 mL 30 minutes 0.25% GA / 15 mL 30 minutes 0.25% GA / 20 mL 60 minutes

<Experimental Example 1>

The particulate gelatin produced in the above Preparation Examples and Comparative Examples was observed under a microscope and the results are shown in Table 3 below.

The prepared particulate gelatin Production Example 1

Production Example 2

Production Example 3

Comparative Example 1

Comparative Example 2

Comparative Example 3

Comparative Example 4

Comparative Example 5

Comparative Example 6

Comparative Example 7

Comparative Example 8

Comparative Example 9

Comparative Example 10

Referring to Table 3, it can be confirmed that the particulate gelatin prepared according to Preparation Examples 1 to 3 has a microsphere shape. In particular, in Production Example 2 and Production Example 3, it can be confirmed that it has a very uniform particle size and a substantial spherical shape. Also, it was confirmed that Comparative Example 1 in which crosslinking was carried out using 40 mL of glutaraldehyde also formed microparticle particulate gelatin.

On the other hand, in the case of Comparative Examples 2 to 5 in which cross-linking was carried out at different concentrations of formaldehyde, it can be confirmed that microsphere-type particulate gelatin can not be formed. In Comparative Example 6 crosslinked using 0.74% formaldehyde, it can be confirmed that particulate gelatin having a microsphere shape is formed to a certain extent, but it is confirmed that the particle size distribution is very uneven and the degree of crosslinking is insufficient to maintain the shape .

In the case of Comparative Example 7 and Comparative Example 8 in which glutaraldehyde was used to perform crosslinking a plurality of times, it was confirmed that a plurality of particulate gelatins could not coagulate or aggregate without forming particulate gelatin.

In the case of Comparative Example 9 and Comparative Example 10 in which glutaraldehyde was used to perform crosslinking a plurality of times, it was confirmed that particulate gelatin was formed to some extent, but reproducibility in repeated experiments was very low. Especially, the reproducibility was very low depending on the stirring speed and the capacity of the reactor. In other words, it was confirmed that gelatin masses having a very high degree of coagulation without frequent microsphere formation were frequently formed according to repeated experiments, and there was no possibility of industrial use.

That is, referring to Comparative Examples 2 to 6, it can be seen that when only formaldehyde is used as the crosslinking agent, the crosslinking degree is not sufficient and the microsphere shape can not be maintained. This may be due to insufficient crosslinking of formaldehyde. Also, referring to Comparative Examples 7 to 10, it can be seen that cross-linking or aggregation occurs between particles when glutaraldehyde is used to perform cross-linking a plurality of times, failing to form microspheres of uniform size.

<Experimental Example 2>

Among the above production examples and comparative examples, granular gelatin according to Production Example 2, Production Example 3, Comparative Example 1, Comparative Example 9 and Comparative Example 10 capable of forming particulate gelatin having a microsphere shape to some extent was used And the physical strength test was carried out.

Specifically, the particulate gelatin produced according to Production Example 2, Production Example 3, Comparative Example 1, Comparative Example 9, and Comparative Example 10 was classified to select particulate gelatin having a particle size of about 1,000 micrometers. And compressive force was applied to the particulate gelatin. At this time, a compressive force was measured until a reduction of 30% in diameter occurred, that is, until a particle size in the direction of compressive force was deformed to approximately 700 micrometers. The above experiment was repeated 10 times and the results are shown in Fig.

Referring to FIG. 7, it can be confirmed that the particulate gelatin prepared according to Production Example 2, Production Example 3, Comparative Example 9, and Comparative Example 10 has relatively high physical strength. In particular, in the case of Production Example 2, it can be confirmed that the compression force until the 30% deformation of the diameter was about 5.4 mN, that is, the compression force until the deformation of 30% of the diameter was 5.0 mN or more.

That is, in Production Examples 2 and 3, in which the ratio of the number of moles of formaldehyde to the number of moles of glutaraldehyde was about 60: 1 and about 20: 1, the molar ratio was about 180 : &Lt; sep &gt; 1 &lt; tb &gt; &lt; tb &gt; &lt; SEP &gt; It can also be seen that the physical strength of Preparation Example 2 having a molar ratio of formaldehyde to the number of moles of glutaraldehyde of about 60: 1 is higher than that of Preparation Example 3 having a molar ratio of about 20: 1.

On the other hand, in the case of the particulate gelatin prepared according to Comparative Example 1, the compressive force until the 30% deformation of the diameter occurred was only about 2.0 mN. That is, it can be seen that the physical strength is not sufficient in the case of Comparative Example 1 in which crosslinking is performed only with glutaraldehyde.

<Experimental Example 3>

The storage stability test was carried out using the particulate gelatin according to Production Example 2, Production Example 3, Comparative Example 1, Comparative Example 9, and Comparative Example 10.

Specifically, the mass reduction rates of the granular gelatin according to Production Example 2, Production Example 3, Comparative Example 1, Comparative Example 9 and Comparative Example 10 were stored in normal cell (0.9% NaCl) The results are shown in Figs. 8 to 12, respectively. It can be understood that when the mass reduction rate is large depending on the storage period, the gelatin material in the particulate gelatin is eluted. 8 to 12, RT means room temperature.

Comparing FIGS. 8 to 12, it can be confirmed that the granular gelatin produced according to Production Example 2, Production Example 3, Comparative Example 9, and Comparative Example 10 has excellent storage stability. Particularly, in the case of the particulate gelatin according to Production Example 2 and Production Example 3, the mass reduction rate after storage at 60 ° C for 24 hours was 2% or less, and the mass reduction rate after storage at 60 ° C for 7 days was about 20%. On the other hand, in the case of the particulate gelatin produced according to Comparative Example 1, the mass reduction rate after storage for 7 days at 60 ° C is about 30%. That is, it can be seen that Comparative Example 1 in which crosslinking was carried out only with glutaraldehyde had insufficient physical / chemical stability.

As a result, it was found that the microsphere-type particulate gelatin having a very uniform particle size distribution can be formed in the case of Preparation Examples 1 to 3, particularly Preparation Example 2, in which crosslinking was carried out using formaldehyde and glutaraldehyde . Particularly, despite the repeated experiments, it was possible to form granular gelatin of the same shape. In addition, it can be seen that it has a relatively strong physical strength and storage stability. In particular, when compared with Comparative Example 1, the physical strength was increased by about 1.5 to 2.7 times, and the storage stability was also improved by 10%. This is because the formaldehyde penetrates into the granular gelatin sufficiently to improve the internal crosslinking density, thereby improving the stability of the gelatin itself and preventing the elution failure due to the increase of the cross-linking density, and further, the glutaraldehyde can increase the crosslinking density of the outer surface of the granular gelatin But the present invention is not limited to this.

While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but many variations and modifications may be made without departing from the spirit and scope of the invention. It will be appreciated that many variations and applications not illustrated above are possible. For example, each component specifically shown in the embodiments of the present invention can be modified and implemented. It is to be understood that all changes and modifications that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

100: reactor
200a: Oil medium
300a: aggregate of biodegradable polymer
400: stirrer
500: First crosslinking agent
600: Second crosslinking agent

Claims (15)

As a biodegradable polymer having a first crosslinking derived from formaldehyde and a second crosslinking derived from glutaraldehyde,
A core portion having a density of the first cross-linking greater than a density of the second cross-linking; And
And an outer frame portion formed to surround the core portion and having a density of the second cross-linking greater than a density of the second cross-linking of the core portion. delete delete The method according to claim 1,
Wherein the biodegradable polymer is gelatin. The method according to claim 1,
And further comprising formaldehyde and glutaraldehyde adsorbed on the outer surface of the granular biodegradable polymer. The method according to claim 1,
A biodegradable polymer of particulate nature having a compressive force of 5 mN or more until a 30% reduction in diameter occurs when applying compressive force. The method according to claim 6,
A granular biodegradable polymer having a mass reduction rate of 2% or less after being stored for 24 hours in a normal cell (0.9%) at a temperature of 60 ° C. Forming an aggregate of the biodegradable polymer;
Subjecting the aggregate to primary crosslinking with a first crosslinking agent; And
And second crosslinking the primary crosslinked aggregate with a second crosslinking agent different from the first crosslinking agent,
Wherein the molecular weight of the first crosslinking agent is smaller than the molecular weight of the second crosslinking agent. 9. The method of claim 8,
Wherein the molecular weight of the first crosslinking agent is smaller than the molecular weight of the second crosslinking agent. 10. The method of claim 9,
Wherein the first crosslinking agent comprises formaldehyde and the second crosslinking agent comprises glutaraldehyde,
Wherein the primary crosslinking step is a step of providing an aqueous solution containing the first crosslinking agent in an oil medium in which micelles are dispersed,
Wherein the second crosslinking step is a step of providing an aqueous solution containing the second crosslinking agent in an oil medium in which the micelle is dispersed,
Wherein the concentration of the first cross-linking agent in the aqueous solution containing the first cross-linking agent is greater than the concentration of the second cross-linking agent in the aqueous solution containing the second cross-linking agent. 9. The method of claim 8,
The step of forming the aggregate comprises:
Preparing an oil medium in the reactor,
Providing an aqueous solution of the biodegradable polymer in the oil medium,
Providing a surfactant to the oily medium, and
And agitating the aqueous solution of the biodegradable polymer and the oily medium provided with the surfactant at room temperature. 12. The method of claim 11,
Wherein the agitation speed is 300 rpm to 450 rpm in the step of agitating the biodegradable polymer. 12. The method of claim 11,
In the stirring step, micelles of the biodegradable polymer dispersed in the oil medium are formed,
Wherein the first crosslinking step is a step of providing the first crosslinking agent to the oil medium in which the micelle is dispersed,
Wherein the second crosslinking step is a step of providing the second crosslinking agent to the oil medium in which the micelle is dispersed,
Wherein the primary cross-linking step and the secondary cross-linking step are performed continuously in the reactor. 14. The method of claim 13,
The ratio of the number of moles of the first crosslinking agent provided in the primary crosslinking step to the number of moles of the second crosslinking agent provided in the secondary crosslinking step is not less than 20: 1 and less than 180: 1, Way. 15. The method of claim 14,
Wherein the ratio of the number of moles of the first crosslinking agent to the number of moles of the second crosslinking agent is 50: 1 to 70: 1.

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