KR102256933B1 - Porous beads with synthetic polymer-natural polymer hybrid structure, and method for preparing thereof - Google Patents

Abstract

The present invention has a porous structure formed by blending synthetic and natural polymers, the surface of which is composed of micro-units, and the interior thereof has a porous structure of a mesh structure in which a plurality of pores are connected to each other. The present invention relates to a polymer-natural polymer hybrid structure of porous spherical particles and a method for producing the same.
In addition, in the present invention, in manufacturing porous spherical particles using a double injection nozzle device, the problem of poor compatibility between the two polymers is solved by well controlling the process of preparing a solution of a synthetic polymer and a natural polymer. It has become possible to produce spherical polymer particles. As a result, compared to the prior art using synthetic polymers alone or natural polymers alone, hybrid porous spherical particles composed of synthetic polymers and natural polymers as in the present invention can be more effectively used for regeneration of various tissues. .

Description

[Porous beads with synthetic polymer-natural polymer hybrid structure, and method for preparing thereof}

The present invention relates to a synthetic polymer-natural polymer hybrid porous spherical particle and a method for producing the same, and in detail, a synthetic polymer and a natural polymer are blended by preparing a controlled solution of incompatible synthetic polymers and natural polymers by a sophisticated method ( Hybrid) to have a porous structure and to a method of manufacturing the polymer spherical particles.

The material of the substrate or carrier used for the regeneration of human tissue must sufficiently play the role of a substrate or carrier so that tissue cells can adhere to the surface of the material to form a tissue having a three-dimensional structure. It must be well compatible with the tissues, there is no inflammatory reaction, and after a certain period of time, it must have excellent biocompatibility that does not remain as a foreign substance by decomposing itself.

Currently widely used biodegradable polymers include polylactic acid [poly(lactic acid), PLA], polyglycolic acid [poly(glycolic acid), PGA], and a copolymer thereof, polylactic acid-glycolic acid copolymer [poly(lactic acid), PLA]. -co-glycolic acid), PLGA], poly-ε-caprolactone (PCL) and polydioxanone (PDO).

Natural polymers are excellent in biocompatibility, but have disadvantages in that it is difficult to control the mechanical strength and decomposition rate, and because there are cases that degeneration and immune reactions are induced, the synthetic polymers listed above are widely used as materials for regeneration of human tissues. have.

When using the porous polymer spherical particles made using such a biodegradable polymer for tissue engineering, cell culture fluid and body fluid can smoothly penetrate into the particles, thereby providing a very effective environment in which tissue cells can efficiently adhere and proliferate.

In addition, the porous polymer spherical particles having the size of micro-units that can be injected by injection have the advantage that the culture medium is completely diffused to the inside of the porous spherical particles due to their small size, and the body can be transplanted through injection without surgery. It can be applied to all medical fields requiring tissue culture and transplantation, and has various uses such as bone substitutes and fillers for plastic surgery.

However, the synthetic polymers listed above have a disadvantage in that they have a large number of carbon atoms in their structure and are hydrophobic and have low cell adhesion.

Looking at the studies on this, in Patent Document 1, the particle surface has a dense structure in which pores having an average pore size of 1 to 100 nm are formed, and the inside of the particle has an average pore size than the average pore size of the particle surface. A technique for manufacturing a PCL polymer characterized by having an asymmetric structure in the particle surface and the inside, which is a porous structure in the form of a large column (column), was presented using a double injection nozzle device.

On the other hand, unlike the synthetic polymer, hyaluronic acid (HA), a natural polymer naturally synthesized in the body and present in a large amount in the extracellular matrix, is a hydrophilic material having a large number of hydroxyl groups (-OH). HA has been studied as a useful material for arthritis treatment, ophthalmic surgery, drug delivery and tissue engineering applications by regulating various physiological actions. Hyaluronic acid determines the hydration of tissues, forms a hydrated network with collagen fibers in the extracellular matrix, and is known to play an important role in the fluidity and differentiation of cells in wound healing and the process.

Therefore, there have been studies for the production of porous polymers that can exert a synergistic effect by exerting their respective properties, including both synthetic polymers used in various ways for tissue regeneration and HA, a natural polymer having excellent cell affinity.

According to Patent Document 2, a method of preparing a biodegradable porous hybrid carrier is proposed by injecting a mixture of an organic solvent containing a biodegradable synthetic polymer and an aqueous hyaluronic acid solution into a mold and freeze-drying by emulsion. That is, in Patent Document 2, it is possible to prepare a carrier having a certain shape by injecting it into a certain mold, but there is no suggestion or description regarding the production of a polymer particle form including HA. Also, since a solution in which synthetic and natural polymers are uniformly dissolved is not used, it is a carrier in the form of dispersed HA hydrogel particles crushed in a biodegradable synthetic polymer carrier, and HA molecules are uniformly mixed and dispersed in the synthetic polymer. It is not in the form that there is.

In addition, according to Patent Document 2, in order to effectively emulsify and freeze-dry a biodegradable synthetic polymer solution, it is preferable to use an organic solvent in terms of chemical stability, and such organic solvents include acetonitrile, dichloromethane, chloroform, and tetrahydrofuran. And it is described that at least one selected from dioxane should be used.

In other words, it can be seen that the manufacturing process of the hybrid carrier of biodegradable synthetic polymer and HA using the emulsion freeze drying method according to Patent Document 2 is complicated, and the use of an organic solvent that is harmful to the human body is inevitable. It can be seen that the carrier is very unfavorable for the purpose of using it in the human body.

As discussed in the prior art above, efforts have been made to combine HA, which is a natural polymer, with a synthetic polymer, but due to the problem of poor compatibility between the synthetic polymer and HA, there is no case of successful development in the form of polymer particles yet. .

Korean Patent Publication 10-2015-0108956 Korean Patent Publication 10-2009-0075503

Therefore, in the present invention, non-immune hydrophilic natural polymers are used to take advantage of the biocompatibility as a tissue engineering material and the advantages of not requiring surgical removal because it is completely absorbed in the body over time. The purpose is to provide a synthetic polymer-natural polymer hybrid type porous spherical particle having a porous structure on both the surface and the interior by complementing it.

In addition, another object of the present invention is to provide a method for producing hybrid porous spherical particles using the synthetic polymer and the hydrophilic natural polymer, which are not compatible.

Synthetic polymer-natural polymer hybrid porous spherical particles according to the present invention have a porous structure formed by blending synthetic and natural polymers, the surface of which is composed of microscopic pores, and the inside of which is a mesh network in which a plurality of pores are connected to each other. It is characterized by having a porous structure of the structure.

The microscopic pores of the surface may have a size of 0.1 to 10 µm.

The synthetic polymer is polylactic acid [poly(lactic acid)], polyglycolic acid [poly(glycolic acid)], polycaprolactone, polydioxanone, polylactic acid-glycolic acid Copolymer [poly(lactic acid-co-glycolic acid)], polydioxanone-caprolactone copolymer (polydioxanone-co-ε-caprolactone), polylactic acid-caprolactone copolymer [poly(lactic acid-co-ε) -caprolactone)], polyhydroxybutyric acid-hydroxyvaleric acid copolymer (polyhydroxybutyric acid-co-hydroxyvaleric acid), polyphosphoester, polyethylene oxide-polylactic acid copolymer, polyethylene oxide-poly A biocompatible biodegradable polymer composed of one or a mixture of two or more selected from a lactic glycolic acid copolymer and a polyethylene oxide-polycaprolactone copolymer is preferred.

The natural polymer is hyaluronic acid (HA), collagen, elastin, gelatin, keratin, silk, alginic acid, pectin, carrageenin, gellan gum, carboxymethylcellulose (CMC), dextran, chondroitin sulfate, chitin, chitosan, fibrin And it may be one or more selected from the group consisting of derivatives thereof.

According to an embodiment of the present invention, the size of the spherical polymer particles of the hybrid structure may be 0.1 ~ 3,000 ㎛.

In addition, the method for preparing the porous spherical particles according to the present invention includes a first step of preparing a synthetic polymer solution, a second step of preparing a natural polymer aqueous solution, and the first step of preparing the synthetic polymer solution in the prepared natural polymer aqueous solution. The third step of preparing a first mixture of a solvent for preparing a natural polymer aqueous solution/synthetic polymer solution by adding and mixing the solvent for a synthetic polymer used at a volume ratio of 2 to 6 times the volume of the natural polymer aqueous solution, and maintaining the high temperature The polymer solution prepared through the fourth step of preparing a second mixture by mixing the synthetic polymer solution of the first step and the mixture of the natural polymer aqueous solution/synthetic polymer solvent of the second step using a double injection nozzle device. It is characterized in that it is manufactured by.

The synthetic polymer solution is preferably prepared in a concentration of 1 to 40% by weight.

The solvent used in preparing the synthetic polymer solution may be at least one selected from the group consisting of 1-methyl-2-pyrrolidinone (NMP), tetraglycol, triacetin, and benzyl alcohol.

The concentration of the natural polymer aqueous solution is preferably 0.05 to 5% by weight.

When preparing the second mixture in the fourth step, the high temperature is preferably 40 to 200°C.

The porous spherical particles are particles of a porous structure formed by blending synthetic polymers and natural polymers, and the surface is composed of microscopic pores, and the interior thereof is a synthetic polymer-natural polymer hybrid having a network structure in which a plurality of pores are connected to each other. It is desirable to have a structure.

The syringe pump speed of the double nozzle injection device may be 20 to 400 ml/h.

According to the present invention, it has a porous structure formed by blending synthetic polymers and natural polymers over the entire surface and interior of the particles, and has a porous structure composed of micro-sized pores on the surface, and a plurality of pores are connected to each other. Synthetic polymer-natural polymer hybrid porous spherical particles having a mesh-structured porous structure can be prepared.

In addition, in the present invention, in manufacturing porous spherical particles using a double injection nozzle device, the problem of poor compatibility of the two polymers is solved by well controlling the process of preparing a solution of a synthetic polymer and a natural polymer. It has become possible to produce spherical polymer particles.

As a result, compared to the prior art using synthetic polymers alone or natural polymers alone, hybrid porous spherical particles composed of synthetic polymers and natural polymers as in the present invention can be more effectively used for regeneration of various tissues. .

1 is a scanning electron microscope photograph of the surface and cross-section of porous PCL microparticles prepared according to Example 2 of Patent Document 1,
2 is a schematic diagram of the structure of a porous spherical particle having a hybrid structure of a synthetic polymer and a natural polymer according to the present invention,
Figure 3 is a schematic diagram showing a PCL / HA solution manufacturing process according to an embodiment of the present invention,
4 is a scanning electron micrograph of PCL/HA hybrid porous spherical particles prepared according to Examples 1 to 4 of the present invention.
5 is a scanning electron microscope photograph of the surface and cross-section of the PCL/HA hybrid porous spherical particles prepared according to Example 4 of the present invention.
6 is a scanning electron microscope photograph of the surface and cross-section of the PCL/ALG hybrid porous spherical particles prepared according to Example 5 of the present invention.
7 is a scanning electron microscope photograph of the surface and cross-section of the PCL/CMC hybrid porous spherical particles prepared according to Example 6 of the present invention.

Hereinafter, the present invention will be described in more detail.

The terms used in this specification are used to describe specific embodiments, and are not intended to limit the present invention.

As used herein, the singular form may include the plural form unless the context clearly indicates another case. In addition, when used herein, "comprise" and/or "comprising" refers to the presence of the mentioned shapes, numbers, steps, actions, members, elements, and/or groups thereof. And does not exclude the presence or addition of one or more other shapes, numbers, actions, members, elements and/or groups.

The present invention relates to a porous spherical particle having a structure in which a synthetic polymer and a natural polymer are hybridized, and a method for producing the same.

Schematic diagram of a spherical porous polymer particle having a hybrid structure of a synthetic polymer and a natural polymer according to the present invention, and then referring to FIG. 2, the synthetic polymer and the natural polymer are completely blended to have a porous structure over the surface and the entire interior, The surface has a microscopic porous structure, and the inside is characterized by having a mesh structure.

That is, the porous spherical particles according to the present invention have a porous structure both on the surface and inside by blending synthetic polymers and natural polymers, and the pores of the surface micro-units have a size of 0.1 to 10 µm. In the present invention, since synthetic polymers and natural polymers are randomly blended, it is shown that the pores on the surface have relatively large micro-units. Due to these micro-units, the body fluid is completely diffused to the inside of the spherical particle, and the surface of the spherical particle It is expected to have the advantage of providing a very effective environment in which tissue cells can adhere and proliferate efficiently.

In addition, it is characterized in that it has a mesh porous structure in which synthetic polymers and natural polymers are blended more complexly than the microscopic porous structure of the surface. The meaning of "the net porous structure", which describes the internal structure of the porous spherical particles according to the present invention, refers to forming a structure such that a number of pores are formed in the inside, and the numerous pores are connected to each other in a complicated manner like a mesh.

The synthetic polymers usable to form the porous spherical particles of the present invention are polylactic acid [poly(lactic acid)], polyglycolic acid [poly(glycolic acid)], polycaprolactone (poly-ε-caprolactone), and polydioxane. On (polydioxanone), polylactic acid-glycolic acid copolymer [poly(lactic acid-co-glycolic acid)], polydioxanone-caprolactone copolymer (polydioxanone-co-ε-caprolactone), polylactic acid-caprolactone Copolymer [poly(lactic acid-co-ε-caprolactone)], polyhydroxybutyric acid-hydroxyvaleric acid copolymer (polyhydroxybutyric acid-co-hydroxyvaleric acid), poly(phosphoester), polyethylene oxide -A biocompatible biodegradable polymer composed of one or a mixture of two or more selected from a polylactic acid copolymer, a polyethylene oxide-polylactic glycolic acid copolymer, and a polyethylene oxide-polycaprolactone copolymer may be preferably used.

Among them, polycaprolactone (PCL) is a hydrophobic polymer having a large number of carbon atoms in structure and is a polyester-based biodegradable synthetic polymer with a slow decomposition rate. PCL has excellent flexibility and elasticity, and has a low melting point of 60° C., so that it is easy to manufacture in a desired shape, and can be preferably used in the present invention. In addition, it is a polymer widely used in the field of tissue engineering along with PLA, PGA, PLGA and PDO. In addition, since it has a long decomposition period, it is a material that has a variety of potential applications for medical use, which is useful as a bone filler and drug-releasing material that is used for a long time.

In addition, the natural polymers included in the production of porous spherical particles are hyaluronic acid (HA), collagen, elastin, gelatin, keratin, silk, alginic acid, pectin, carrageenin, gellan gum, carboxymethylcellulose (CMC), At least one selected from the group consisting of dextran, chondroitin sulfate, chitin, chitosan, fibrin, and derivatives thereof may be preferably used.

Among the above natural polymers HA is a non-immune natural polymer synthesized in vivo as a main component of the extracellular matrix in vivo, and is a hydrophilic material with a large number of hydroxyl groups. This polymer reacts with the CD44 protein expressed in various epithelial cells and plays a key role in tissue regeneration, inflammatory response, and angiogenesis by regulating various physiological functions. It is used in various roles as a tissue engineering and medical material, and can be most preferably used in the present invention.

In the present invention, the porous spherical particles having a hybrid structure of the synthetic polymer and the natural polymer may have a distribution of 0.1 to 3,000 µm, and have various particle sizes, and thus may be selected and used to suit the purpose.

In addition, the present invention provides a method for producing hybrid porous spherical particles of a synthetic polymer having the above structure and a natural polymer using a finely controlled polymer solution as follows.

First, the polymer solution used to prepare the polymer particles is as shown in FIG. 3, and in FIG. 3, an example of using PCL as a synthetic polymer and HA as a natural polymer is schematically illustrated.

Referring to this, the first step of preparing a synthetic polymer solution, the second step of preparing a natural polymer aqueous solution, and a solvent for synthetic polymer used in preparing the synthetic polymer solution of the first step are added to the prepared natural polymer aqueous solution. A third step of preparing a first mixture of a solvent for preparing a natural polymer aqueous solution/synthetic polymer solution by adding and mixing at a volume ratio of 2 to 6 times the volume of the polymer aqueous solution, and the synthetic polymer solution of the first step while maintaining a high temperature. It is characterized in that it is manufactured using a double injection nozzle device through the fourth step of preparing a second mixture by mixing the mixture of the natural polymer aqueous solution/synthetic polymer solvent of the third step.

Conventionally, the applicant of the present invention has made various attempts to secure compatibility between the two solutions in each solution preparation step in order to prepare porous particles having a hybrid structure composed of a synthetic polymer and a natural polymer, but did not reach the desired level.

However, in the present invention, first, the synthetic polymers listed above are dissolved in one or more solvents selected from the group consisting of 1-methyl-2-pyrrolidinone (NMP), tetraglycol, triacetin, and benzyl alcohol, and 1 to 40% by weight. A synthetic polymer solution of concentration is prepared. The solvent used in the preparation of the synthetic polymer solution is preferably a polar aprotic solvent having a property of mixing well with water from the viewpoint of preparing a polymer solution in a uniform form.

The concentration of the synthetic polymer solution can be adjusted according to the ratio of the polymer and the solvent, and when the concentration exceeds 40% by weight, the viscosity of the polymer solution increases rapidly, which is not preferable for application to a double nozzle injection system.

In addition, in the second step, the natural polymers listed above are dissolved in purified water (water) to prepare an aqueous solution of natural polymers having a concentration of 0.05 to 5% by weight. When the concentration of the natural polymer aqueous solution is less than 0.05% by weight, it is difficult to expect hydrophilicity or the properties of the polymer used, and when it exceeds 5% by weight, it is difficult to uniformly mix with the synthetic polymer when blended, so natural polymer-synthetic polymer hybrid spherical particles It is difficult to expect the manufacture of, which is not preferable.

The third step is to add and mix the solvent for the synthetic polymer used in the preparation of the synthetic polymer solution in the first step to the prepared natural polymer aqueous solution at a volume ratio of 2 to 6 times the volume of the natural polymer aqueous solution. This is a step of preparing a first mixture of a solvent for preparing a synthetic polymer solution.

Conventionally, a method of completely dissolving the natural polymer in a solvent for a synthetic polymer, and then adding a synthetic polymer again to dissolve it, was used, but in this case, there was a problem that the compatibility of the two polymers was significantly deteriorated. That is, when preparing a polymer solution used in the preparation of a hybrid structure composed of two polymers that are not compatible, which polymer is dissolved in which solvent and how to mix them can be said to be a very important issue.

In addition, depending on the polymer solution, it is determined whether the surface and internal structures of the final polymer particles have a porosity or a non-porous (dense) structure, and there is a difference in the pore size and the porous structure. It is self-explanatory to

Therefore, in the present invention, after preparing each natural polymer and synthetic polymer solution, the solvent used for preparing the synthetic polymer solution is added at a volume ratio of about 2 to 6 times the volume of the natural polymer solution, and the prepared synthetic polymer solution It allows it to be well mixed with and has the effect of preventing the hydrophobic polymer from being precipitated by water. If the amount of the solvent for preparing the synthetic polymer solution added at this time is less than 2 times the volume of the natural polymer aqueous solution, mixing is difficult, and if it exceeds 6 times, the minimum viscosity for obtaining spherical particles with a double spray nozzle device cannot be reached. There is a problem and it is not desirable.

In the fourth step, a second mixture is prepared by mixing the synthetic polymer solution of the first step and the mixture of the natural polymer aqueous solution/synthetic polymer solvent of the third step while maintaining the high temperature.

The temperature at the time of preparing the second mixture in the fourth step is preferably maintained at about 40 to 200°C, which causes precipitation when the melting point of the synthetic polymer solvent and the synthetic polymer solvent meet water in the natural polymer aqueous solution. Therefore, it is to prevent sedimentation. However, when the temperature is less than 40° C., the synthetic polymer is not well soluble in a solvent, which is not preferable, and when the temperature exceeds 200° C., the polymer may be deformed by heat or the molecular chain may be broken, which is not preferable.

In the present invention, the solution is sprayed into small particles through a double spray nozzle spraying the prepared polymer solution with nitrogen gas, and the sprayed solution is immersed in an appropriate ratio of non-solvent and precipitated to form spherical particles. Is obtained as

At this time, the syringe pump speed (pressure) of the double injection nozzle device is 20 to 400 ml/h. It is preferable to have a particle diameter.

The spherical particles according to the present invention thus prepared have a porous structure on both the surface and the interior, and it is expected that various materials can be easily mounted due to the microscopic porous structure of the surface and the internal mesh structure.

Hereinafter, a preferred embodiment of the present invention will be described in detail. The following examples are for illustrative purposes only, and the scope of the present invention should not be construed as being limited by these examples. In addition, in the following examples, specific compounds are used for exemplification, but it is obvious to those skilled in the art that even when an equivalent thereof is used, an effect of an equivalent or similar degree can be exhibited.

Examples 1-4: Preparation of porous PCL/HA hybrid spherical particles

1. Preparation of polymer solution

1) PCL solution preparation

10 wt% of PCL was added to NMP and stirred on a hot plate at a temperature of 60° C. to prepare a completely dissolved 10 wt% PCL/NMP solution.

2) Preparation of HA aqueous solution

30 mg of HA was stored at 4° C. by adding 2.97 g (1 wt%) of tertiary distilled water (total volume 3 ml). It was confirmed that HA was completely dissolved as it became completely transparent after 24 hours.

3) Preparation of the first mixed solution of HA aqueous solution/NMP

While stirring at an appropriate speed in a magnetic stirrer, 3 ml of NMP was injected into the HA aqueous solution at an interval of 1 hour for a total of 4 times. After 1 hour of injection of all 4 NMPs, it was confirmed that the HA aqueous solution and the NMP solvent were uniformly mixed.

4) Preparation of a second mixture of PCL solution and HA solution/NMP

The first mixture of the PCL solution prepared in 1) and the aqueous HA solution/NMP prepared in 3) was stirred at 120° C. for 30 minutes so that the final PCL:HA weight ratio (wt%) was 99:1, and PCL/ HA solution was prepared. At this time, the cap of the PCL solution was covered so that water in the HA aqueous solution was not evaporated due to high temperature, and the HA aqueous solution was injected using a syringe.

2. Manufacture of PCL/HA hybrid spherical particles using double nozzle spraying device

The syringe-nozzle portion of the double nozzle injection device was wrapped with a hot wire and the temperature was maintained at 120°C. A 70% ethanol solution was placed where the sprayed solution came out.

The first mixture of PCL/HA prepared in 1-4) was transferred to a syringe and installed in a syringe pump. The PCL/HA mixed solution injected by the syringe pump was sprayed while simultaneously coming out with nitrogen gas, split into water droplets, agglomerated in a 70% ethanol solution, and precipitated into spherical particles.

In the present invention, as shown in Examples 1 to 4 shown in Table 1 below, the particle size of the spherical particles was adjusted by adjusting the distance between the nozzle tip and the surface of the ethanol solution, the syringe pump speed, and the nitrogen gas injection speed, and then freeze after washing. Through drying, PCL/HA hybrid spherical particles each having the porosity of Examples 1 to 4 were prepared.

Example 1 Example 2 Example 3 Example 4 Separation distance (cm) 25 20 15 10 Syringe pump speed (ml/h) 30 100 200 400 Nitrogen gas injection speed (l/min) 20 15 10 5 Spherical particle size (㎛) 25~53 53~100 100~300 300~500

Example 5: Preparation of porous PCL/alginate (ALG) hybrid spherical particles

Instead of the HA aqueous solution of Example 1, an ALG aqueous solution was prepared at a concentration of 1 wt% (3 ml), and 3) NMP was injected into the ALG aqueous solution at a total of 6 ml each when preparing the first mixture of ALG aqueous solution/NMP. Except for that, porous PCL/alginate (ALG) hybrid spherical particles were prepared in the same manner as in Example 1.

Example 6: Preparation of porous PCL/carboxymethyl cellulose (CMC) hybrid spherical particles

In place of the HA aqueous solution of Example 1, a CMC aqueous solution was prepared at a concentration of 1 wt% (3 ml), and when the first mixture of CMC aqueous solution/NMP was prepared, NMP was injected into the ALG aqueous solution twice a total of 6 ml each. Except, PCL/carboxymethyl cellulose (CMC) hybrid spherical particles were prepared in the same manner as in Example 1.

Comparative Example 1: Preparation of porous spherical particles consisting only of PCL

It was compared using the porous PCL particles prepared according to Example 2 of Patent Document 1.

Experimental Example 1: Structure confirmation

Each surface structure of the PCL/HA hybrid spherical particles of the present invention prepared according to Examples 1 to 4 was measured with a scanning electron microscope, and the results are shown in FIG.

In addition, each surface photograph according to the magnification of the PCL/HA hybrid spherical particles prepared according to Example 4 and a cross-sectional photograph thereof are shown in FIG. 5, which is a scanning electron microscope photograph according to Comparative Example 1, followed by FIG. The structure was compared.

In addition, the structures of the surfaces and cross sections of the PCL/ALG and PCL/CMC hybrid spherical particles prepared according to Examples 5 and 6, respectively, were measured with a scanning electron microscope, and the results are shown in the following 6 and 7 respectively.

Next, referring to FIG. 1, in the case of a porous particle composed of only PCL according to Example 2 of Patent Document 1, both the surface and the interior have a porous structure, but the surface has a porous structure having a size of 5 to 50 nm, and the interior is a large pillar. It can be seen that it has a (column) structure. (Refer to the description of paragraphs [0087] to [0093] of Patent Document 1)

However, it can be seen that the porous spherical particles prepared according to Examples 1 to 4 and 5 to 6 of the present invention have a porous structure in both the surface and the interior, and have a network structure in which a plurality of pores are connected to each other. These results confirmed that the same results were obtained when various natural polymers such as HA, ALG, and CMC were mixed with PCL, a synthetic polymer.

On the other hand, after showing the structure of the PCL porous particles of Comparative Example 1, and then showing the structure of the PCL/HA hybrid porous particles of Fig. 1 and Examples 1 to 4 of the present invention, from the scanning electron microscope of Fig. 4, the pore size formed on the surface It can be seen that the present invention Example and Comparative Example 1 are significantly different.

In addition, various surface photographs and cross-sectional photographs according to the magnification of the PCL/HA porous spherical particles prepared according to Example 4 are shown, and then the surface and cross-sectional photographs of the PCL spherical particles according to Fig. 5 and Comparative Example 1 are shown. Even when comparing Fig. 1, it can be seen that the internal structures are also different from each other.

This difference can be explained by the mixing of the natural polymer HA in the present invention to form larger microscopic pores on the surface, and to form a mesh porous structure inside by random blending of them.

Therefore, from these results, it was confirmed that the porous spherical particles prepared according to the present invention formed a hybrid structure by appropriately blending the synthetic polymers PCL and the natural polymers HA, ALG, and CMC.

Claims (12)

The first step of preparing a synthetic polymer solution using poly-ε-caprolactone,
The second step of preparing a natural polymer aqueous solution selected from hyaluronic acid (HA), alginic acid, and carboxymethylcellulose (CMC),
For preparing a natural polymer aqueous solution/synthetic polymer solution by adding and mixing the synthetic polymer solvent used in the preparation of the synthetic polymer solution in the first step to the prepared natural polymer aqueous solution at a volume ratio of 2 to 6 times the volume of the natural polymer aqueous solution A third step of preparing a first mixture in which the solvent is uniformly mixed, and
A fourth step of preparing a second mixture by mixing the first mixture in which the synthetic polymer solution in the first step and the natural polymer aqueous solution/solvent for the synthetic polymer in the third step are uniformly mixed while maintaining 40 to 200°C. It is manufactured with a double injection nozzle device using the polymer solution prepared through the process;
The use of the polymer solution prevents the precipitation of synthetic polymers by water, so that the synthetic polymers and natural polymers that are not compatible are blended to form porous spherical particles having a hybrid structure,
The porous spherical particles have a porous structure over the entire surface and inside,
Its surface is made of pores with a size of 0.1 to 10 µm,
Synthetic polymer-natural polymer hybrid structure porous spherical particles, characterized in that the interior has a porous structure of a mesh structure in which a plurality of pores are connected to each other.
delete delete delete The method of claim 1,
The size of the porous spherical particles of the hybrid structure is 0.1 ~ 3,000 ㎛ of the synthetic polymer-natural polymer porous spherical particles of a hybrid structure.
delete The method of claim 1,
The synthetic polymer solution is prepared in a concentration of 1 to 40% by weight of a synthetic polymer-natural polymer hybrid structure of porous spherical particles.
The method of claim 1,
The solvent used in the preparation of the synthetic polymer solution is 1-methyl-2-pyrrolidinone (NMP). Synthetic polymer-natural polymer hybrid porous spherical particles.
The method of claim 1,
The concentration of the natural polymer aqueous solution is 0.05 to 5% by weight of the synthetic polymer-natural polymer hybrid structure of porous spherical particles.
delete delete delete

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