KR102031502B1 - Polymer-ceramic hybrid film having excellent mechanical property and method for preparation thereof - Google Patents

Abstract

The present invention relates to a polymer-ceramic hybrid film having excellent mechanical properties and a method of manufacturing the same. The polymer-ceramic hybrid material according to the present invention is a polymer-ceramic hybrid film having excellent mechanical properties, and can be applied as a medical structure or a food packaging container because it can maintain a film form for a long time while implementing excellent mechanical properties. In addition, the hydrogel used in the manufacturing process of the film can be very useful as a material for 3D printing.
The polymer-ceramic hybrid film according to the present invention may improve mechanical strength by changing the arrangement of ceramic particles in the hybrid material by changing the hybrid solution processing process. In addition, the method for producing a polymer-ceramic hybrid film according to the present invention includes a simple and easy manufacturing process and can produce a polymer-ceramic material even at room temperature.

Description

Polymer-ceramic hybrid film with excellent mechanical properties and manufacturing method thereof {POLYMER-CERAMIC HYBRID FILM HAVING EXCELLENT MECHANICAL PROPERTY AND METHOD FOR PREPARATION THEREOF}

The present invention relates to a polymer ceramic hybrid film having excellent mechanical properties and a method of manufacturing the same.

Currently, research is being actively conducted to create hybrid materials for ceramic (inorganic), metal, and polymer materials that have been classified as traditional materials. Hybrid in materials means that two or more materials that are considered heterogeneous, such as inorganic, metal, and polymer, are implemented in one system and have synergy effects for new performance while maintaining their performance. .

The most interesting areas of hybrid materials are hybrid materials of polymers and ceramics. The polymer is mainly composed of carbon main chains, and may be classified as a kind of organic material, and ceramic materials include oxides, hydroxides, carbonates, and phosphates of metal ions such as titanium dioxide (TiO ₂ ) and silicon dioxide (SiO ₂ ). It refers to a kind of mineral. Since organic and inorganic materials have heterogeneous aspects in various aspects such as bonding properties and physical properties, they may not be mixed well with each other. In fact, so-called "polymer-ceramic hybrid materials", in which polymers and inorganic materials are mixed with each other, are widely used in nature. Is found. The skeleton that maintains the skeleton of the human body is an inorganic material of hydroxyapatite (HAP), and the muscle tissue and soft tissue are composed of organic materials of collagen and polysaccharides. . In addition, the material forming the shell of algae is mostly calcium carbonate (calcium carbonate, calcite) is a hybrid material having a polymer film attached to the inner surface.

There are a wide variety of polymers and ceramics that can be used as hybrid materials. However, if the focus is on the medical material in the field of view, both the polymer and the ceramic should have biosafety and compatibility. For this purpose, the biocompatible polymer or easily decomposable polymer is suitable. Ceramic materials are also preferably biodegradable inorganic or biodegradable, and the degradation products are not toxic to the living body. Typical medical natural polymer materials include agarose, pectin, carrageenan, chitosan, alginate, gelatin, collagen and chondroitin sulfate. This is representative. In addition, the ceramic material itself is a compound that has many potential as a medical material or a biological application. Hydroxyapatite is an important component that forms the skeleton of the human body, and is an important material in the research of tissue engineering and artificial biomaterials. For example, clay and layered metal hydroxides are active materials for drug carriers.

On the other hand, in the case of the polymer-ceramic hybrid material, as described above, in order to be applied to a damaged part that requires a constant load for a certain period of time or to be applied to a field such as 3D bioprinting, which needs to maintain a constant shape after molding, the lamination is required. Possible mechanical properties are required. There is a need for a film having flexibility (for example, elasticity) that can be applied to cover complex tissues and organs of a patient, and polymer-ceramic hybrid materials are generally manufactured in gel or particle form. . However, other forms, such as hydrogels, films, and various forms, which have flexibility and strength, are required in order to be widely applied to the fields of the aforementioned medical or complex tissues and organs.

In addition, when preparing a polymer-ceramic hybrid material, there is an inconvenience in terms of the manufacturing method, such as a high temperature, a high pressure or a cross-linking agent and an initiator should be added because the process including the chemical reaction induction.

Therefore, researches and research methods for various physical properties and forms of polymer-ceramic hybrid materials have been actively conducted (Non-Patent Document 1), and Patent Documents 1 and 2 have proposed related technologies.

Patent document 1, (a) distributing two or more biocompatible polymer struts side by side on a plate to form a strut layer; (b) distributing, on the distributed biocompatible polymer strut layer, the biosynthetic polymer struts spaced side by side in a direction crossing with the direction of the distributed biocompatible polymer strut; (c) Distributing struts of at least one natural biocompatible material selected from the group consisting of gelatin, fucoidan, collagen, alginate, chitosan and hyaluronic acid on which the cells are loaded between the biocompatible polymeric struts dispensed in step (b) Forming a crosslink in the biocompatible natural material to be dispensed while dispensing so as not to contact the biocompatible polymeric strut; And (d) sequentially repeating steps (b) and (c) to form a hybrid structure, wherein the cell-supported biocompatible polymer-biocompatible natural material hybrid structure was proposed.

Patent document 2, a) dissolving two different biodegradable polymers in an organic solvent to prepare a respective solution; b) preparing a nano / micro hybrid fiber sheet by simultaneously spinning the prepared nanofibers and microfibers of each biodegradable polymer in both directions using the electrospinning method; c) proposed a method of manufacturing a nano / micro hybrid fiber nonwoven fabric comprising the step of removing the residual solvent of the prepared hybrid fiber sheet.

However, although the physical properties required for the polymer-ceramic hybrid material produced by the patent documents 1 and 2, respectively, have been achieved to some extent, the manufacturing process cannot be achieved at room temperature, and in particular, the film form with controlled flexibility and mechanical properties. There was a problem such as that it can not be manufactured.

Accordingly, there is a need for a technology that can be produced by a simple manufacturing method in the form of a film while satisfying the mechanical properties of a polymer-ceramic hybrid material, and a technology that can produce a film without using a crosslinking agent or an initiator at room temperature.

Patent Document 1: Korean Patent Publication No. 10-1360942 Patent Document 2: Korea Patent Publication No. 10-1328645

Syntheses and Characterizations of Polymer-Ceramic Composites Having Increased Hydrophilicity, Air-Permeability, and Anti-Fungal Property (Journal of the Korean Chemical Society, 2010)

The present invention is to solve the above problems, an object of the present invention, the alginate biocompatible polymer containing a carboxyl group and a hydroxyl group (hydroxyl group), calcium phosphate (calcium phosphate) and 2 It includes a valent metal ion, and includes a crosslinking between the hydroxyl group of the alginate and the calcium phosphate and a crosslinking between the carboxyl group of the alginate and the divalent metal ion. In addition, the biocompatible polymer and calcium phosphate are mixed in a weight ratio of 1: 2 to 1:20, and to provide a polymer-ceramic hybrid film having pH dependent drug release.

However, the problem to be solved by the present invention is not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

Polymer-ceramic hybrid film according to an embodiment of the present invention, an alginate biocompatible polymer including a carboxyl group and a hydroxyl group, calcium phosphate and divalent metal ions And a double crosslink including a crosslink between the hydroxyl group of the alginate and the calcium phosphate and a crosslink between the carboxyl group of the alginate and the divalent metal ion. The biocompatible polymer and calcium phosphate are mixed at a weight ratio of 1: 2 to 1:20 and include those having pH dependent drug release.

According to an embodiment of the present invention, the pH-dependent drug release polymer-ceramic hybrid film may have a sustained release drug release in acidic conditions, and may have a rapid release drug release in basic conditions.

According to one embodiment of the present invention, the calcium phosphate may be 0.5 μm to 10 μm.

According to an embodiment of the present invention, the alginate biocompatible polymer has an interchain space, and the divalent metal is located in the space so that the carboxyl group of the alginate and the divalent metal ion It may be to form a crosslink.

According to one embodiment of the invention, the polymer-ceramic hybrid film, the opacity calculated by the following formula is 28.90 ± 1.72%, the transmittance may be 0.40 ± 0.11%.

[expression]

Opacity (%) = (absorbance at 600 nm / film thickness) x 100 (%).

According to an embodiment of the present invention, the polymer-ceramic hybrid film has a pH-dependent swelling degree, and the pH-dependent swelling degree may be in proportion to pH and swelling degree.

According to one embodiment of the invention, the calcium phosphate is calcium triphosphate, it may be one having a drug release rate proportional to the content of the calcium triphosphate.

According to one embodiment of the invention, the divalent metal ions may be calcium ions (Ca ²⁺ ).

According to an embodiment of another aspect of the present invention, the method for producing a polymer-ceramic hybrid film, (a) an alginate biocompatible polymer comprising a carboxyl group and a hydroxyl group and Preparing a hybrid solution in which calcium phosphate is mixed in a weight ratio of 1: 2 to 1:20; (b) inducing an arrangement of particles in the hybrid solution; and (c) divalent metal in the hybrid solution. Mixing with an ionic solution; comprising, a method for producing a polymer-ceramic hybrid film, cross-linking between the hydroxyl group of the alginate and the calcium phosphate and the carboxyl group of the alginate and the 2 It comprises a double crosslink comprising crosslinks between metal ions and has pH dependent drug release.

According to an embodiment of the present invention, the pH-dependent drug release polymer-ceramic hybrid film may have a sustained release drug release in acidic conditions, and may have a rapid release drug release in basic conditions.

The polymer-ceramic hybrid material according to the present invention is a polymer-ceramic hybrid film having excellent mechanical properties, and can be applied as a medical structure or a food packaging container because it can maintain a film form for a long time while implementing excellent mechanical properties. In addition, the hydrogel used in the manufacturing process of the film can be very useful as a material for 3D printing.

The polymer-ceramic hybrid film according to the present invention may improve mechanical strength by changing the arrangement of ceramic particles in the hybrid material by changing the hybrid solution processing process. In addition, the method for producing a polymer-ceramic hybrid film according to the present invention includes a simple and easy manufacturing process and can produce a polymer-ceramic material even at room temperature.

The effect of the present invention is not limited to the above-described effects, but the details of the present invention

It is to be understood that the present invention encompasses all possible effects deduced from the configuration of the invention described in the description or claims.

1 is a photograph showing a method for evaluating mechanical properties in an embodiment of the present invention.
Figure 2 is a photograph showing a hybrid film according to an embodiment of the present invention (Example 1, Example 2 and Example 3 in sequence from left photograph to right photograph).
3 is a photograph showing a hybrid film according to an embodiment of the present invention (left photograph is Example 4 and right photograph is Example 5).
4 is a photograph showing a hybrid film according to an embodiment of the present invention (left photograph is Example 6 and right photograph is Example 7).
5 is a photograph showing a hybrid film according to an embodiment of the present invention (Example 8, Example 9 and Example 10 in order from left photograph to right photograph).
6 is a photograph showing a hybrid film according to a comparative example of the present invention (a photograph on the right is Comparative Example 1 and a photograph on the left is Comparative Example 2).
7 is a photograph showing a hybrid film according to a comparative example of the present invention (a photograph on the right is Comparative Example 3 and a photograph on the left is Comparative Example 4).
8 is a photograph showing that the polymer-ceramic hybrid film according to an embodiment of the present invention maintains the film form even after 12 days have elapsed.
Figure 9 shows the manufacturing process of the polymer-ceramic hybrid film and the particle arrangement inside the film according to an embodiment of the present invention.
Figure 10 shows the results of the ATR-FTIR analysis of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
Figure 11 shows the results of ¹³ C NMR analysis of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
12 shows the results of XRD analysis of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
Figure 13 shows the results of TGA analysis of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
14 shows SEM and FESEM images of the polymer-ceramic hybrid film according to Examples and Comparative Examples of the present invention.
15 is a graph showing a correlation between tensile strength and elongation of a polymer-ceramic hybrid film according to Examples and Comparative Examples of the present invention.
Figure 16 shows the water content, swelling degree and water resistance of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
Figure 17 shows the UV-Vis analysis results of the polymer-ceramic hybrid film according to the Examples and Comparative Examples of the present invention.
Figure 18 shows the swelling degree according to the pH conditions of the polymer-ceramic hybrid film of the Examples and Comparative Examples of the present invention.
19 is a graph showing the drug release properties of bovine serum albumin (BSA) according to pH conditions of the polymer-ceramic hybrid films of Examples and Comparative Examples of the present invention.
20 is a graph showing TCN (tetracycline) drug release property according to pH conditions of the polymer-ceramic hybrid films of Examples and Comparative Examples of the present invention.
Figure 21 is a graph showing the drug release properties of dimethyloxaloylglycine (DMOG) according to the pH conditions of the polymer-ceramic hybrid film of the Examples and Comparative Examples of the present invention.

Hereinafter, exemplary embodiments will be described in detail with reference to the accompanying drawings.

Various modifications may be made to the embodiments described below. The examples described below are not intended to be limited to the embodiments and should be understood to include all modifications, equivalents, and substitutes for them.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of examples. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprise" or "have" are intended to indicate that there is a feature, number, step, action, component, part, or combination thereof described on the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, components, or a combination thereof.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

In addition, in describing the embodiment, when it is determined that the detailed description of the related known technology may unnecessarily obscure the gist of the embodiment, the detailed description thereof will be omitted.

One embodiment of the present invention is a biocompatible polymer including a carboxyl group (hydroxyl group) and a hydroxyl group (hydroxyl group); Calcium phosphate; And divalent metal ions; wherein the biocompatible polymer and calcium phosphate are mixed at a weight ratio of 1: 2 to 1:20, to provide a polymer-ceramic hybrid film.

The biocompatible polymer may be at least one selected from the group consisting of alginate, hyaluronic acid, chondroitin sulfate, carboxycellulose, and collagen, preferably alginateyl. It may be, but is not limited thereto.

Ceramics may be used to form crosslinks with the hydroxyl groups of the alginates. The ceramic is not particularly limited as long as it is an inorganic material, and may be used, for example, calcium phosphate, and in the case of the calcium phosphate, monocalcium phosphate, dicalcium phosphate, and calcium triphosphate ( tricalcium phosphate, tetracalcium phosphate or hydroxyapatite, but preferably calcium triphosphate (TCP). At this time, the crosslinking between the hydroxyl group and the calcium phosphate of the alginate may be a hydrogen bond.

In addition, the ceramic may be titanium oxide or silicon oxide, and is not particularly limited. For example, the titanium oxide may be titanium dioxide (TiO ₂ ), and the silicon oxide may be silicon dioxide (SiO ₂ ). have.

The hybrid film may include the aforementioned biocompatible polymer and calcium phosphate at the same time. In this case, the biocompatible polymer and the ceramic may be mixed in a weight ratio of 1: 2 to 1:20.

When the biocompatible polymer and ceramic are mixed in the mixing ratio of the above range, the polymer-ceramic hybrid film including the same may maintain the film form while exhibiting excellent mechanical properties, and the film form may be maintained for a long time.

Meanwhile, the carboxyl group of the alginate may be crosslinked with the divalent metal ion. In this case, the divalent metal ion may be Ca ²⁺ , Be ²⁺ , Mg ²⁺ , Sr ²⁺ , Ba ²⁺ , Ra ^2+, or a combination thereof, preferably calcium ions (Ca ²⁺ ). Can be. The crosslinking between the carboxyl group of the alginate and the divalent metal ion may be an ionic bond.

That is, double crosslinking between the hydroxy group of the alginate and calcium phosphate, and crosslinking formed between the carboxyl group of the alginate and the divalent metal ion can be formed.

The hybrid film may carry a drug delivery function in vivo by supporting a drug therein. At this time, the hybrid film may exhibit a pH-dependent drug release.

Specifically, the hybrid film may exhibit slow release drug release in acidic conditions with low pH, while rapid release drug release may be exhibited in basic conditions with high pH. That is, since the drug release properties can be adjusted differently according to the pH environment to which the hybrid film is applied, the hybrid film can be selected and applied according to the pH of the application site.

Figure 9 shows the manufacturing process of the polymer-ceramic hybrid film and the particle arrangement inside the film according to an embodiment of the present invention.

Referring to Figure 9, another embodiment of the present invention is (a) a biocompatible polymer comprising a carboxyl group and a hydroxyl group (hydroxyl group) and calcium phosphate (calcium phosphate) 1: 2 to 1: Preparing a hybrid solution mixed at a weight ratio of 20; (b) inducing an arrangement of particles in the hybrid solution; It provides a method for producing a polymer-ceramic hybrid film, comprising; and (c) mixing the hybrid solution with a divalent metal ion solution.

In the step (a), the biocompatible polymer and the ceramic may be mixed in a weight ratio of 1: 2 to 1:20. When mixed within this range, mechanical properties can be improved, and specific effects are the same as described above.

In the step (a), the biocompatible polymer may be at least one selected from the group consisting of alginate, hyaluronic acid, chondroitin sulfate, carboxycellulose and collagen. Preferably, it may be alginate, but is not limited thereto.

In the step (a) the alginate may be mixed in a solution state, wherein the concentration of the alginate may be, for example, 1% to 10%, 2.5% to 8.5% or 5% to 7%, preferably May have a concentration of about 6%.

The biocompatible polymer and ceramic may each be prepared in the form of a solution first and then mixed by mixing both solutions, and may be prepared as a suspension by such mixing.

In the hybrid solution prepared in step (a), a hydroxyl group of the alginate may be crosslinked with the calcium phosphate. At this time, the calcium phosphate may be calcium triphosphate (TCP, tricalcium phosphate). The kind of ceramics which can be used besides calcium phosphate is as described above.

In addition, the calcium phosphate mixed in the step (a) may be applied to have a variety of particle diameters ranging from nano size to micro size, specifically may be 0.5㎛ to 10㎛, but is not limited thereto.

In the step (b), the crystallinity may be improved by inducing the arrangement of the particles present in the hybrid solution, specifically, the biocompatible polymer and the calcium phosphate particles. At this time, by screeding the hybrid solution on the support, it is possible to induce the arrangement of the internal particles.

As used herein, the term “screeding” is a process for inducing the arrangement of ceramic particles and smoothing the surface, and applying the hybrid solution onto a support such as a slide glass and then using a cover such as a cover glass. To physically push the process.

Inducing the arrangement of the particles through the screening process, a certain space is secured in the biocompatible polymer chain forming a bond with calcium phosphate, the penetration of divalent metal ions to be described later and further crosslinking through this easily proceeds Can be.

At this time, the screening speed may be 5 cm 2 / s to 10 cm 2 / s. The screening speed means a speed of pushing using a cover, if the speed is less than 5 cm 2 / s may not be sufficient particle induction, if more than 10 cm 2 / s cross-linking between the biocompatible polymer and calcium phosphate The bond can be broken.

The concentration of the divalent metal ion solution in step (c) may be 0.05M to 5M, preferably 0.075M to 1M, more preferably 0.1M. The calcium ions may be gelled by curing the biocompatible polymer-ceramic hybrid solution, and when the concentration is in the above-described range, a biocompatible polymer-ceramic hybrid film in the form of a film may be prepared through a sufficient gelling process more rapidly. .

In the gel prepared in step (c), a carboxyl group of the alginate may be crosslinked with the divalent metal ion. In this case, the divalent metal ion may be Ca ²⁺ , Be ²⁺ , Mg ²⁺ , Sr ²⁺ , Ba ²⁺ , Ra ^2+, or a combination thereof, preferably calcium ions (Ca ²⁺ ). Can be. Crosslinking between the carboxyl group and the divalent metal ion of the alginate may be an ionic bond, thereby gelating the hybrid solution.

The gelling process of step (c) may be performed for 0.1 minutes to 30 minutes, 1 minute to 25 minutes or 3 minutes to 15 minutes, but is not particularly limited thereto, preferably 5 minutes to 10 minutes. Can be.

After the step (c), the gel may be dried and separated from the support to finally obtain a polymer-ceramic hybrid film. Specifically, the drying may be performed in a vacuum oven for about 48 hours.

Polymer-ceramic hybrid film according to an embodiment of the present invention, an alginate biocompatible polymer including a carboxyl group and a hydroxyl group, calcium phosphate and divalent metal ions And a double crosslink including a crosslink between the hydroxyl group of the alginate and the calcium phosphate and a crosslink between the carboxyl group of the alginate and the divalent metal ion. The biocompatible polymer and calcium phosphate are mixed at a weight ratio of 1: 2 to 1:20 and include those having pH dependent drug release.

According to one side, the carboxyl group or hydroxy group of the alginate biocompatible polymer may form crosslinks, preferably hydrogen bonds, with calcium phosphate to enhance physical properties of the film.

According to one side, the double crosslinking may improve the mechanical properties of the hybrid film compared to a single crosslinking.

According to one side, the biocompatible polymer and calcium phosphate are mixed in a weight ratio of 1: 2 to 1:20, compared to when mixed in a mixing ratio outside the numerical range, while showing excellent mechanical properties and flexible film form Can be maintained.

According to one side, the hybrid film having a pH-dependent drug release, can carry a drug delivery function in vivo by supporting the drug therein.

According to an embodiment of the present invention, the pH-dependent drug release polymer-ceramic hybrid film may have a sustained release drug release in acidic conditions, and may have a rapid release drug release in basic conditions.

According to one side, the polymer-ceramic hybrid film having pH-dependent drug release may more specifically exhibit sustained release drug release in acidic conditions with low pH, while rapid release drug in basic conditions with high pH. It may indicate the release, which can be controlled differently depending on the pH environment, so that the hybrid film can be selected and applied in various ways depending on the pH of the application site.

According to one embodiment of the present invention, the calcium phosphate may be 0.5 μm to 10 μm.

According to one side, the calcium phosphate of the size is to have an appropriate size, the physical properties through the cross-linking of the hydroxyl group of the alginate in the hybrid solution can be improved.

According to an embodiment of the present invention, the alginate biocompatible polymer has an interchain space, and the divalent metal is located in the space so that the carboxyl group of the alginate and the divalent metal ion It may be to form a crosslink.

According to one side, the constant space is secured by the effect of inducing particle arrangement through the screening process, unlike the case of bonding without screed, the penetration of divalent metal ions into the particle arrangement through the glass rod and Further crosslinking through may proceed easily.

According to one embodiment of the invention, the polymer-ceramic hybrid film, the opacity calculated by the following formula is 28.90 ± 1.72%, the transmittance may be 0.40 ± 0.11%.

[expression]

Opacity (%) = (absorbance at 600 nm / film thickness) x 100 (%).

According to one side, the hybrid film having an opacity of 28.90 ± 1.72% and transmittance of 0.40 ± 0.11% can effectively block light and prevent the destruction of nutrients from ultraviolet rays, as well as a food packaging container. But it can be widely used in various fields.

According to an embodiment of the present invention, the polymer-ceramic hybrid film has a pH-dependent swelling degree, and the pH-dependent swelling degree may be in proportion to pH and swelling degree.

According to one side, the hybrid film having a swelling ratio proportional to the pH may increase the space inside the film with increasing pH, thereby increasing the drug release rate as the pH-dependent drug release property and the space inside the film increase. have.

According to one side, when the pH is lowered, on the contrary, the space inside the film is narrowed, and the drug release property is inferior, so that selective application may be possible.

According to one embodiment of the invention, the calcium phosphate is calcium triphosphate, it may be one having a drug release rate proportional to the content of the calcium triphosphate.

According to one side, with reference to Figures 19 to 21, as the content of calcium triphosphate increases, the pH is lowered and the drug release rate is reduced, it may be advantageous for the sustained release drug release.

According to one embodiment of the invention, the divalent metal ions may be calcium ions (Ca ²⁺ ).

According to one side, when the divalent metal ions are calcium ions, compared to other divalent metal ions, while binding more strongly with the carboxyl group, stability can be secured.

According to an embodiment of another aspect of the present invention, the method for producing a polymer-ceramic hybrid film, (a) an alginate biocompatible polymer comprising a carboxyl group and a hydroxyl group and Preparing a hybrid solution in which calcium phosphate is mixed in a weight ratio of 1: 2 to 1:20; (b) inducing an arrangement of particles in the hybrid solution; and (c) divalent metal in the hybrid solution. Mixing with an ionic solution; comprising, a method for producing a polymer-ceramic hybrid film, cross-linking between the hydroxyl group of the alginate and the calcium phosphate and the carboxyl group of the alginate and the 2 It comprises a double crosslink comprising crosslinks between metal ions and has pH dependent drug release.

According to one side, the step of inducing the arrangement of the mouth of step (b), more specifically the step of inducing the arrangement of particles by pushing the hybrid solution with a glass rod, the screening rate is 5 cm 2 / s to 10 cm 2 can be / s The screening speed means a speed of pushing using a cover, if the speed is less than 5 cm 2 / s may not be sufficient particle induction, if more than 10 cm 2 / s cross-linking between the biocompatible polymer and calcium phosphate The bond can be broken.

According to an embodiment of the present invention, the pH-dependent drug release polymer-ceramic hybrid film may have a sustained release drug release in acidic conditions, and may have a rapid release drug release in basic conditions.

Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are described for the purpose of illustrating the present invention, but the scope of the present invention is not limited thereto.

Preparation Example 1 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A1)

α-calcium phosphate (α-TCP) powder was prepared according to a known method (Kim HW. et al., J Mater Sci Mater Med, 2010, 21, 3019-27). First, commercial calcium carbonate (Sigma Aldrich) and anhydrous dibasic calcium phosphate (Sigma Aldrich) are mixed, reacted by heating at about 1400 ° C. for about 3 hours, and then quenched in air to form the α-TCP phase in powder form. Formed. The formed α-TCP powder was milled by a ball and then dropped into a sieve of about 150 μm, and then stored separately in a vacuum.

Further, 0.3 g of sodium alginate was dissolved in 5 ml of distilled deionized water (D.D.W) to prepare a 6% sodium alginate solution.

The calcium phosphate powder separately stored in the prepared alginate solution was mixed at a weight ratio of 1: 2, and then ultrasonic waves were applied (Sonics, Vibra Cell) to prepare a polymer-ceramic mixed suspension (A1).

Preparation Example 2 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A2)

A polymer-ceramic mixed suspension (A2) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1: 3.

Preparation Example 3 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A3)

A polymer-ceramic mixed suspension (A3) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1: 4.

Preparation Example 4 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A4)

A polymer-ceramic mixed suspension (A4) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1: 6.

Preparation Example 5 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A5)

A polymer-ceramic mixed suspension (A5) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1: 8.

Preparation Example 6 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A6)

A polymer-ceramic mixed suspension (A6) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1:10.

Preparation Example 7 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A7)

A polymer-ceramic mixed suspension (A7) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1:12.

Preparation Example 8 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A8)

A polymer-ceramic mixed suspension (A8) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1:14.

Preparation Example 9 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A9)

A polymer-ceramic mixed suspension (A9) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1:16.

Preparation Example 10 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A10)

A polymer-ceramic mixed suspension (A10) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1:20.

Preparation Example 11 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (B1)

A polymer-ceramic mixed suspension (B1) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 1: 1.

Preparation Example 12 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (B2)

A polymer-ceramic mixed suspension (B2) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 2: 1.

Preparation Example 13 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (B3)

A polymer-ceramic mixed suspension (B3) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 3: 1.

Preparation Example 14 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (B4)

A polymer-ceramic mixed suspension (B4) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 5: 1.

Preparation Example 15 Preparation of Biocompatible Polymer-Ceramic Mix Suspension (B5)

A polymer-ceramic mixed suspension (B5) was prepared in the same manner as in Preparation Example 1, except that the alginate solution and the calcium phosphate powder were mixed at a weight ratio of 10: 1.

Example 1 Preparation of Biocompatible Polymer-Ceramic Hybrid Films

First, the polymer-ceramic mixed suspension (A1) prepared in Preparation Example 1 was applied to a slide glass (7.5 × 2.5 cm 2), and then subjected to a screening process at a speed of 7.4 ± 0.5 cm 2 / s to arrange the particles. Induced. Thereafter, the slide glass was immersed in 0.1 M aqueous calcium chloride (CaCl ₂ ) solution for 30 minutes to form an ion crosslink, thereby preparing a hydrogel. Thereafter, the hydrogel was separated from the slide glass, washed three times with distilled water, and then dried in a vacuum oven for 48 hours on a separate slide glass to prepare a biocompatible polymer-ceramic hybrid film.

Examples 2 to 10 and Comparative Examples 1 to 5: Preparation of Biocompatible Polymer-Ceramic Hybrid Films

A biocompatible polymer-ceramic hybrid film was prepared in the same manner as in Example 1 except that the kind of the polymer-ceramic mixed suspension prepared in Preparation Examples was adjusted as shown in Table 1 below.

TABLE 1

Experimental Example 1: Appearance Observation and Simple Evaluation of Hybrid Film

The biocompatible polymer-ceramic hybrid films prepared in Examples 1 to 10 and Comparative Examples 1 to 5 were visually observed and evaluated in the following criteria through a simple experiment in a method that can be confirmed in FIG. .

Evaluation criteria for maintaining mechanical properties and film form for each of the Examples and Comparative Examples are as follows.

<Mechanical Property Evaluation Criteria>

O: observed to exhibit mechanical properties (ie, the film does not tear in simple experiments)

X: No observed mechanical properties (i.e. film tearing in simple experiments)

<Film Form Retention Evaluation Criteria>

O: observed to retain film morphology

X: Film not retained, cracked or torn

The photos actually observed are shown in FIGS. 2 to 7.

More specifically, Figure 2 is a photograph showing the results for the above Examples 1 to 3 (Example 1, Example 2 and Example 3 in order from the left photograph to the right photograph).

3 is a photograph showing the results of Examples 4 and 5 (the left photograph is Example 4 and the right photograph is Example 5). 4 is a photograph showing the results of Examples 6 and 7 (the left photograph is Example 6 and the right photograph is Example 7). 5 is a photograph showing the results of Examples 8 to 10 (Example 8, Example 9, and Example 10 in order from the left photograph to the right photograph). 6 is a photograph showing the results of Comparative Examples 1 and 2 (the right photograph is Comparative Example 1 and the left photograph is Comparative Example 2). 7 is a photograph showing the results for Comparative Examples 3 and 4 (the right photograph is Comparative Example 3 and the left photograph is Comparative Example 4).

In addition, the results evaluated in accordance with the evaluation criteria are shown in Table 2 below.

TABLE 2

In addition, Figure 8 is a photograph showing that the polymer-ceramic hybrid film according to an embodiment of the present invention maintains the film form after 12 days have elapsed.

As can be seen in Table 2 and Figures 2 to 8, the polymer-ceramic hybrid film according to an embodiment of the present invention can maintain the film form while implementing excellent mechanical properties, such as medical structures, drug carriers, artificial cartilage, etc. Not only can be applied, it can be applied to various fields such as cosmetic containers, agricultural biodegradable materials, food packaging containers. Furthermore, the hydrogel can be very usefully used as a material for 3D printing.

Experimental Example 2: Check the molecular structure of the hybrid film

In order to confirm the molecular structure characteristics of the hybrid films according to Example 6, Comparative Example 2 and Comparative Example 5, ATR-FTIR, ¹³ C NMR, XRD and TGA analysis was performed. Sodium alginate, calcium triphosphate and ATR-FTIR spectra of each hybrid film were measured in the 650 cm ^-1 to 4000 cm ^-1 wavelength range using an ATR-FTIR spectrometer (Travel IR, Smiths Detection). ¹³ C NMR analysis of sodium alginate and each hybrid film was performed using an NMR spectrometer (DD2 700, Agilent technologies), and their XRD analysis was performed using an X-ray diffractometer (Bruker DE / D8 Advance, Bruker). It was. In addition, TGA analysis of sodium alginate and each hybrid film was performed using a thermogravimetric analyzer (DTG-60, Shimadzu). All analyzes were performed at a scan rate of 5 ° C./min under a nitrogen atmosphere. The ATR-FTIR, ¹³ C NMR, XRD and TGA analysis results are shown in FIGS. 10 to 13, respectively.

Referring to the ATR-FTIR results of FIG. 10, it can be seen that the carboxylic acid signal strength of 1600 cm ^-1 and 1405 cm ^-1 is sharply reduced in the hybrid films of Example 6, Comparative Example 2 and Comparative Example 5 compared to sodium alginate. This is due to the fact that the calcium ions formed a crosslink (ion bond) with the carboxyl group of the alginate. Further, in Example 6, Comparative Example 2 and Comparative Example 5, the broad signal intensity around 3245 cm ^-1 representing the hydroxy group indicates that the hydroxyl group and the calcium triphosphate of alginate formed a crosslink (hydrogen bond).

Referring to the ¹³ C NMR results of FIG. 11, in the case of the 176.4 ppm signal indicating the presence of carbonyl carbon of sodium alginate, the strength of the alginate decreased when mixed with calcium phosphate. It can be seen that a crosslink (ion bond) was formed in the liver.

Referring to the XRD results of FIG. 12, in the case of the signal at 2θ = 13.7 ° indicating the presence of alginate, the strength gradually decreases with mixing with calcium triphosphate, and the concentration of alginate decreases. . These results suggest that there is good miscibility between alginate and calcium triphosphate. In addition, looking at the results of Example 6, Comparative Example 2 and Comparative Example 5, it can be seen that the signal intensity also increases as the concentration of calcium triphosphate increases, these results indicate that calcium triphosphate crystallinity is maintained in the hybrid film It is analyzed to affect the mechanical properties.

Referring to the TGA results of FIG. 13, the second region (186 ° C. to 377 ° C.) in which the chain is broken in the weight loss region of the alginate is associated with thermal stability, and in the case of a hybrid film, the corresponding region is 182 ° C. to 407. It was confirmed that the weight loss rate also decreased as the content of calcium triphosphate was formed at ℃. Through this, it can be seen that calcium triphosphate improves the thermal stability of alginate.

On the other hand, in order to observe the surface properties of the hybrid film of Example 6, Comparative Example 2 and Comparative Example 5 was observed the surface of each film using SEM (TESCAN VEGA3, Tescan), FESEM (JSM-6700F, JEOL) The cross-sectional area was observed using, and the results are shown in FIG. (a) to (c) show SEM images of Comparative Example 5, Comparative Example 2 and Example 6, respectively, and (d) to (f) show their FESEM images, respectively.

Referring to Figure 14, the increase in the content of calcium triphosphate increases the crosslinking with the alginate it can be seen that the calcium triphosphate particles appear clearly on the surface of the alginate.

Experimental Example 3: Evaluation of Mechanical Properties of Hybrid Film

Tensile strength using a fatigue tester (E3000LT, INSTRON) according to ASTM standards under humidity conditions of 25 ℃, 60-65% to evaluate the mechanical properties of the hybrid film according to Example 6, Comparative Example 2 and Comparative Example 5 And elongation were measured. Specifically, each hybrid film was cut into strips (5 × 1 cm 2), and grips were formed to prepare test specimens. The gage length of the specimen and the distance between the grips were set to 15 mm and 20 mm, and the crosshead speed was set to 1 mm / s. The measurement results are shown in Table 3 below, and the relationship between tensile strength and elongation is shown in FIG. 15.

TABLE 3

Referring to Table 3 and FIG. 14, the tensile strength of the hybrid film of Example 6 was measured to be lower than that of Comparative Example 2 and Comparative Example 5, but the specimen was easily broken due to the low elongation, so that the tensile load could be further applied. It is analyzed that it was not possible. Therefore, the hybrid film of Example 6 may be usefully applied to food packaging containers and the like, which do not require elasticity and require only mechanical properties.

Experimental Example 4: Evaluation of Water Content, Swelling Degree and Water Resistance of Hybrid Film

The moisture content, swelling and water resistance of the hybrid films according to Example 6, Comparative Example 2 and Comparative Example 5 were evaluated. Depending on the moisture content, swelling degree and water resistance characteristics of the hybrid film, the release properties of the material, for example, the drug contained in the film may be used as an indirect indicator for this.

First, each of the hybrid films was cut and dried to measure a dry specimen (4 × 2 cm 2), and then left in air for 7 days under a relative humidity of 25 ° C. and 60-65%. After 24 hours, each specimen was weighed, and the moisture content (%) was calculated through Equation 1 below, and the results are shown in FIG. 16 (a).

[Equation 1]

Moisture content (%) = (weight of specimen before standing / weight of specimen after standing) × 100 (%)

Referring to Figure 16 (a), it can be seen that the moisture content of the hybrid film decreases as the content of calcium triphosphate increases. This is because the increase in the content of calcium triphosphate decreases the space for accommodating water in the chain of alginate, and also decreases the content of hydrophilic hydroxyl groups.

Further, each of the dried specimens (4 × 2 cm 2) was immersed in 50 ml distilled water and then stored at 25 ° C. for 24 hours. After 1 hour, each of the immersed specimens was taken out to remove moisture, and weighed until the weight reached equilibrium. Swelling degree (%) was calculated through the following equation (2), the results are shown in Figure 16 (b).

[Equation 2]

Swelling degree (%) = [(weight of specimen after immersion-weight of specimen before immersion) / weight of specimen before immersion] × 100 (%)

Referring to Figure 16 (b), it can be seen that the swelling degree decreases as the content of calcium triphosphate increases. This is because calcium triphosphate binds to the hydroxy group, which is a hydrophilic functional group, thereby lowering the hydrophilicity of the molecule and reducing the internal space of the alginate chain.

Finally, each pre-weighed dry specimen (4 × 2 cm 2) was immersed in 50 ml distilled water and then stirred for 7 days at 25 rpm at 100 rpm. After 24 hours, 72 hours and 268 hours, each specimen was removed from distilled water, dried at 40 ° C. for 48 hours and then weighed. Water resistance was measured by the weight loss rate (%) calculated through the following Equation 3, the results are shown in Figure 16 (c).

[Equation 3]

% Reduction = [(initial dry specimen weight-final dry specimen weight) / initial dry specimen weight] × 100 (%)

Referring to FIG. 16 (c), it can be seen that as the content of calcium triphosphate increases, the weight reduction rate is lowered to improve water resistance. This is because calcium triphosphate present on the alginate surface effectively blocks the penetration of moisture.

The above results suggest that by controlling the calcium triphosphate content in the film it can control the entry rate, specifically drug release properties of the material.

Experimental Example 5: Evaluation of the Optical Properties of the Hybrid Film

Opacity and light transmittance were measured to evaluate the optical properties of the hybrid films according to Example 6, Comparative Example 2 and Comparative Example 5. Specifically, square specimens (2 × 1 cm 2) were prepared by cutting each hybrid film, and the absorbance and transmittance (%) of each specimen using a UV-Vis spectrophotometer in the wavelength range of 200 nm to 800 nm under an air atmosphere. ) Was measured.

Opacity was calculated through Equation 4 below, and the results are shown in Table 4 and FIG. 17. Fig. 17A shows the relationship between the transmittance (%) and the wavelength, and Fig. 17B shows the relationship between the absorbance and the wavelength.

[Equation 4]

Opacity (%) = (absorbance at 600 nm / film thickness) x 100 (%)

TABLE 4

Referring to Table 4 and FIG. 17, the hybrid film of Example 6 exhibited significantly higher opacity than the hybrid films of Comparative Examples 2 and 5, and exhibited a value close to 0 in transmittance, thereby effectively blocking light. Able to know.

Therefore, when the hybrid film of Example 6 is applied to a food packaging container, it can be seen that it is possible to effectively prevent the destruction of nutrients such as fat from ultraviolet rays by effectively blocking the light.

Experimental Example 6: Evaluation of Swelling Degree of Hybrid Film According to pH Conditions

In order to check whether the swelling degree of the hybrid film varies depending on the pH conditions, the swelling degree (%) in the same manner as in Experiment 4 while varying the pH conditions for the hybrid film of Example 6, Comparative Example 2 and Comparative Example 5 Was calculated and the result is shown in FIG.

Referring to FIG. 18, it can be seen that the degree of swelling increases in all hybrid films depending on pH. On the contrary, when the pH decreases, the swelling degree also decreases. This is because an increase in the intercalation between calcium ions and carboxylic acids increases the internal space of the film by increasing the calcium ion-base bond with increasing pH, and the dissociated hydrophilic carboxylic anion forms a bond with the water molecule.

These results suggest that the drug release rate of the hybrid film may be increased at high pH and the drug release rate may be decreased at low pH. In view of these characteristics, the possibility of selective application of the hybrid film may be expected. have.

Experimental Example 7: Evaluation of drug release of the hybrid film

In order to evaluate the drug release properties of the hybrid films of Example 6, Comparative Example 2 and Comparative Example 5, a hydrogel was obtained in each hybrid film manufacturing process to obtain bovine serum albumin (BSA), tetracycline (TCN) and DMOG ( Gel beads were prepared by mixing with dimethyloxalyglycine.

Specifically, each hydrogel and each drug (BSA, TCN and DMOG) was added to distilled water and mixed by applying ultrasonic at 25 ℃. The BSA, TCN, and DMOG were respectively mixed with 0.165 g of hydrogel at a concentration of 4.9 × 10 ⁻⁶ mol, and added to a vial containing 0.1 M calcium chloride (CaCl ₂ ) and crosslinked by applying ultrasonic waves for 30 minutes. I was. Thereafter, the contents of each vial were lyophilized for 48 hours to obtain gel beads having different kinds of drugs and contents of alginate and calcium triphosphate.

To evaluate the drug release properties of gel beads against BSA, TCN and DMOG, they were analyzed using a UV-Vis spectrophotometer (BioMate 3S, Thermo Scientific) at 37 ° C. with varying pH. Specifically, after dissolving each gel bead in 10 ml distilled water, the UV-Vis spectra of the solution was recorded and spectroscopically calculated to derive the drug release (%), and the results for BSA, TCN and DMOG, respectively. 19 to 21 are shown.

Referring to Figures 19 to 21, it was confirmed that the drug release rate increases as the pH of all BSA, TCN, DMOG increases, the drug release rate decreases as the calcium triphosphate content increases. In view of this, it can be seen that the hybrid film of Example 6 is effective in an environment in which sustained-release drug release is required in an acidic pH condition such as the stomach.

Although the embodiments have been described by the limited embodiments and the drawings as described above, various modifications and variations are possible to those skilled in the art from the above description. For example, the techniques described may be performed in a different order than the described method, and / or the described components may be combined or combined in a different form than the described method, or replaced or substituted by other components or equivalents. Appropriate results can be achieved.

Therefore, other implementations, other embodiments, and equivalents to the claims are within the scope of the following claims.

Claims (10)

Alginate biocompatible polymers including a carboxyl group and a hydroxyl group;
Calcium phosphate; And
In the polymer-ceramic hybrid film comprising a divalent metal ion,
A double crosslink including a crosslink between a hydroxyl group of the alginate and the calcium phosphate and a crosslink between a carboxyl group of the alginate and the divalent metal ion,
The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 1: 2 to 1:20,
have pH dependent drug release,
The particle size of the calcium phosphate is 0.5 ㎛ to 10 ㎛,
The polymer-ceramic hybrid film,
Opacity calculated by the following formula is 28.90 ± 1.72%, transmittance is 0.40 ± 0.11%,
Polymer-Ceramic Hybrid Films:
[expression]
Opacity (%) = (absorbance at 600 nm / film thickness) x 100 (%). The method of claim 1,
The polymer-ceramic hybrid film having the pH-dependent drug release,
It has a sustained release drug release in acidic conditions, and has a rapid release drug release in basic conditions,
Polymer-ceramic hybrid film. delete The method of claim 1,
The alginate biocompatible polymer has a space between the chains,
Wherein the divalent metal is located in the space to form a crosslink between the carboxyl group of the alginate and the divalent metal ion,
Polymer-ceramic hybrid film. delete The method of claim 1,
The polymer-ceramic hybrid film,
have a pH dependent swelling degree,
The pH-dependent swelling degree is that pH and swelling degree is in proportion,
Polymer-ceramic hybrid film. The method of claim 1,
The calcium phosphate is calcium triphosphate,
Having a drug release rate proportional to the content of the calcium triphosphate,
Polymer-ceramic hybrid film. The method of claim 1,
Wherein the divalent metal ions are calcium ions (Ca ²⁺ ),
Polymer-ceramic hybrid film. (a) preparing a hybrid solution in which an alginate biocompatible polymer including a carboxyl group and a hydroxyl group and calcium phosphate are mixed in a weight ratio of 1: 2 to 1:20 Doing;
(b) inducing an arrangement of particles in the hybrid solution; And
(c) mixing the hybrid solution with a divalent metal ion solution; and a method of manufacturing a polymer-ceramic hybrid film, including
PH-dependent drug release including a crosslinking between the hydroxyl group of the alginate and the calcium phosphate and a crosslinking between the carboxyl group of the alginate and the divalent metal ion Having,
The particle size of the calcium phosphate is 0.5 ㎛ to 10 ㎛,
The polymer-ceramic hybrid film,
Opacity calculated by the following formula is 28.90 ± 1.72%, transmittance is 0.40 ± 0.11%,
Manufacturing method of polymer-ceramic hybrid film:
[expression]
Opacity (%) = (absorbance at 600 nm / film thickness) x 100 (%). The method of claim 9,
The polymer-ceramic hybrid film having the pH-dependent drug release,
It has a sustained release drug release in acidic conditions, and has a rapid release drug release in basic conditions,
Method for producing a polymer-ceramic hybrid film.

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