WO2018066780A2 - Polymer-ceramic hybrid film having mechanical properties and elasticity, and method for manufacturing same - Google Patents

Abstract

The present invention relates to a polymer-ceramic hybrid film and a method for manufacturing same. The polymer-ceramic hybrid material according to the present invention, which is an elastic polymer-ceramic hybrid film, can maintain a film form for a long time while realizing excellent elasticity and mechanical properties at the same time, and thus can be applied as a medical material such as a patch. Also, a hydrogel used in the manufacturing process of the film can be very usefully utilized as a material for 3D printing. The mechanical strength and elasticity of the polymer-ceramic hybrid film according to the present invention can be improved by varying the arrangement of ceramic particles within the hybrid material by varying the processing process of a hybrid solution. Further, the method for manufacturing an elastic polymer-ceramic hybrid film according to the present invention only includes simple and easy manufacturing steps and allows for the manufacture of a polymer-ceramic material even at room temperature.

Description

Polymer-ceramic hybrid film having mechanical properties and elasticity and preparation method thereof

The present invention relates to a polymer-ceramic hybrid film having mechanical properties and elasticity 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. Polymers refer to materials consisting mainly of a chain reaction of carbon, and may be classified as organic materials. 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, so the human body can be regarded as a huge hybrid of organic matter and inorganic matter. . 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, different shapes and surface properties are required for hybrid materials to be applied to the above-mentioned fields such as medical or complex tissues and organs. For example, hydrogels, films, and various other forms having flexibility and strength are required, and biocompatibility for interacting with a patient's surrounding tissue when applied for medical purposes is required.

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. In relation to this, research is being conducted to control physical properties of a film by controlling process conditions in a film manufacturing process.

Therefore, research and manufacturing methods for various physical properties and forms of polymer-ceramic hybrid materials have been actively conducted (Syntheses and Characterizations of Polymer-Ceramic Composites Having Increased Hydrophilicity, Air-Permeability, and Anti-Fungal Property (Journal) of the Korean Chemical Society, 2010), Korean Patent Publication Nos. 10-1360942 and 10-1328645 have proposed a related technology.

Korean Patent Publication No. 10-1360942, (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 biocompatible polymer struts side by side in a direction crossing with the direction of the distributed biocompatible polymer strut; (c) Distributing struts of one or more natural biocompatible materials 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.

Korean Patent Publication No. 10-1328645, a) preparing two solutions by dissolving two different biodegradable polymers in an organic solvent; 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 materials prepared by the Korean Patent Publication Nos. 10-1360942 and 10-1328645 are achieved to some extent, the manufacturing process cannot be achieved at room temperature, There was a problem that the mechanical properties can not be produced in a controlled film form and the like.

Therefore, it is necessary to develop a technology for producing polymer-ceramic hybrid materials in a film form through a simple manufacturing method while having elasticity and flexibility, and a process technology for producing a film without using a crosslinking agent or an initiator at room temperature. Do.

The present inventors have attempted to develop a new elastic polymer-ceramic hybrid material to solve the above-mentioned problems of the prior art. As a result of this research effort, the mixing ratio of the polymer and the ceramic is controlled in a specific range or the process conditions are adjusted. When adjusted, it was confirmed through data that flexibility and mechanical properties (physical properties) required for the polymer-ceramic hybrid material can be controlled, and in particular, in preparing the polymer-ceramic hybrid material, calcium chloride When curing the aqueous solution containing a specific ion as shown in the specific process conditions it was confirmed that the film form excellent in elasticity and / or mechanical properties is prepared, by confirming the chemical mechanism and process conditions, the present invention was completed.

The present invention provides a polymer-ceramic hybrid film and a method of manufacturing the same.

According to one embodiment of the present invention, a biocompatible polymer including a carboxyl group and a hydroxyl group; Calcium phosphate; And divalent metal ions. A polymer-ceramic hybrid film is provided.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 20: 1 to 8: 1.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 5: 1 to 1: 1.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 1: 2 to 1:20.

According to one side, the biocompatible polymer may be alginate.

According to one side, a hydroxyl group of the alginate may be crosslinked with the calcium phosphate.

According to one side, the calcium phosphate may be calcium triphosphate (TCP, tricalcium phosphate).

According to one side, the carboxyl group of the alginate may be crosslinked with the divalent metal ion.

According to one side, the divalent metal ions may be calcium ions (Ca ^{2 +} ).

According to one side, the polymer-ceramic hybrid film may exhibit a pH-dependent drug release.

According to another embodiment of the present invention, (a) preparing a hybrid solution in which a biocompatible polymer including a carboxyl group and a hydroxyl group and a calcium phosphate are mixed; (b) inducing an arrangement of particles in the hybrid solution; And (c) mixing the hybrid solution with a divalent metal ion solution. A method of manufacturing a polymer-ceramic hybrid film is provided.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 20: 1 to 8: 1.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 5: 1 to 1: 1.

According to one side, the biocompatible polymer and calcium phosphate may be mixed in a weight ratio of 1: 2 to 1:20.

According to one side, the biocompatible polymer may be alginate.

According to one side, a hydroxyl group of the alginate may be crosslinked with the calcium phosphate.

According to one side, step (b) may be to screed the hybrid solution on a support (screeding).

According to one side, the screening speed may be 5 cm 2 / s to 10 cm 2 / s.

According to one side, the concentration of the divalent metal ion solution may be 0.05M to 5M.

According to one side, the carboxyl group of the alginate may be crosslinked with the divalent metal ion.

The polymer-ceramic hybrid material according to the present invention is a polymer-ceramic hybrid film, 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 elastic and / or 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 can control elasticity and mechanical properties by controlling the arrangement of ceramic particles in the hybrid material according to the processing of the hybrid solution. 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.

It is to be understood that the effects of the present invention are not limited to the above effects, and include all effects deduced from the configuration of the invention described in the detailed description or claims of the present invention.

1 is a photograph showing a method for elastic evaluation in an embodiment of the present invention.

2 is a photograph showing a method for evaluating mechanical properties in an embodiment of the present invention.

3 is a photograph showing a hybrid film according to an embodiment and a comparative example of the present invention.

4 is a photograph showing a hybrid film according to an embodiment of the present invention.

5 is a photograph showing a hybrid film according to an embodiment of the present invention.

6 is a photograph showing a hybrid film according to an embodiment of the present invention.

7 is a photograph showing that the hybrid film according to an embodiment of the present invention maintains the film form even after 12 days have elapsed.

8 illustrates a process of preparing a hybrid film and an arrangement of particles in a film according to an embodiment of the present invention.

Figure 9 shows the results of the ATR-FTIR analysis of the hybrid film according to an embodiment of the present invention.

10 shows ¹³ C NMR analysis results of the hybrid film according to the embodiment of the present invention.

Figure 11 shows the XRD analysis of the hybrid film according to an embodiment of the present invention.

12 shows the results of TGA analysis of a hybrid film according to an embodiment of the present invention.

13A, 13B and 13C show SEM images of a hybrid film according to an embodiment of the present invention, and FIGS. 13D, 13E and 13F show their FESEM images.

14 is a graph showing a correlation between tensile strength and elongation of a hybrid film according to an embodiment of the present invention.

15a, 15b and 15c show the water content, swelling degree and water resistance of the hybrid film according to the embodiment of the present invention, respectively.

Figure 16a is a graph showing the relationship between UV-Vis absorbance and transmittance of the hybrid film according to the Examples and Comparative Examples of the present invention, Figure 16b is a UV-Vis absorbance of the hybrid film according to the Examples and Comparative Examples of the present invention Is a graph showing the relationship between and wavelength.

Figure 17a, 17b and 17c shows the swelling degree according to the pH conditions of the hybrid film according to an embodiment of the present invention.

18a, 18b and 18c are graphs showing the drug release properties of bovine serum albumin (BSA) according to pH conditions of a hybrid film according to an embodiment of the present invention.

19a, 19b and 19c are graphs showing TCN (tetracycline) drug release property according to pH conditions of a hybrid film according to an embodiment of the present invention.

20A, 20B, and 20C are graphs showing DMOG (dimethyloxaloylglycine) drug release property according to pH conditions of a hybrid film according to an embodiment 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.

Polymer-Ceramic hybrid  film

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; provides a polymer-ceramic hybrid film.

The hybrid film may have different elasticity and mechanical properties depending on the ratio of the biocompatible polymer and calcium phosphate and the film formation induction process (film manufacturing process speed, film thickness, etc.). Specifically, when the biocompatible polymer and the calcium phosphate are mixed in a weight ratio of 20: 1 to 8: 1, the hybrid film may exhibit excellent elasticity, while they are mixed in a weight ratio of 1: 2 to 1:20. In this case, the hybrid film may exhibit excellent physical properties. Furthermore, when the biocompatible polymer and the calcium phosphate are mixed in a weight ratio of 5: 1 to 1: 1, a balance between elasticity and mechanical properties of the hybrid film may be maintained.

In addition, when the biocompatible polymer and the calcium phosphate are mixed at a weight ratio of 20: 1 to 1:20, the hybrid film including the same may maintain the shape of the film for a long time.

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.

Meanwhile, the carboxyl group of the alginate may be crosslinked with the divalent metal ion. Here, the divalent metal ion is ^{+ 2,} Ca, Be ^{+ 2,} Mg ^{+ 2,} Sr ^{+ 2,} Ba ^{+ 2,} Ra ^2+, or a combination thereof, but 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.

Polymer-Ceramic hybrid  Method of manufacturing film

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 FIG. 9, another embodiment of the present invention provides a hybrid solution in which (a) a biocompatible polymer including a carboxyl group and a hydroxyl group and a calcium phosphate are mixed. Doing; (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.

The mixing ratio of the biocompatible polymer and the calcium phosphate in step (a) is 20: 1 to 8: 1, 5: 1 to 1: 1, or 1 depending on the amount of hybrid film, that is, the desired elastic and mechanical properties. : 2 to 1:20. The effects of the respective mixing ratios are 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%. To increase the elasticity, it may be preferable to use a high molecular weight alginate, but is not limited thereto.

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 in the hybrid film 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 It can be done easily.

At this time, the screening speed may be 5 cm 2 / s to 10 cm 2 / s. The screed speed means a speed that is pushed using a cover, and if the screed speed is less than 5 cm 2 / s under the above-described concentration condition of the hybrid solution, particle array induction may not be sufficiently achieved, and more than 10 cm 2 / s. If the cross-linking between the biocompatible polymer and calcium phosphate is not induced to an optimal state, the elasticity and strength of the film may be insufficient.

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, the 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. Here, the divalent metal ion is Ca ^{2 +,} Be ^{2 +,} Mg ^{2 +,} Sr ^{2 +,} Ba ^{2 +,} Ra ^{2 +,} or a combination thereof, but 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 an elastomeric polymer-ceramic hybrid film. Specifically, the drying may be performed in a vacuum oven for about 48 hours.

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.

Production Example  1: Preparation of biocompatible polymer-ceramic mixed suspension (A1)

Calcium triphosphate (

TCP) Powders were prepared according to known methods (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.

The TCP phase was formed into a powder form. Formed

The TCP powder was milled by ball and then poured into a sieve of about 150 μm and stored separately in 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 stored separately in the prepared alginate solution was mixed in a weight ratio of 20: 1, and then ultrasonic waves were applied (Sonics, Vibra Cell) to prepare a polymer-ceramic mixed suspension (A1).

Production 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 in a weight ratio of 15: 1.

Production 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 12: 1.

Production 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 10: 1.

Production 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 8: 1.

Production 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 5: 1.

Production Example  7: Preparation of biocompatible polymer-ceramic mixed 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 3: 1.

Production 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 2: 1.

Production 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: 1.

Production Example  10: Preparation of biocompatible polymer-ceramic mixed 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: 2.

Production Example  11: Preparation of biocompatible polymer-ceramic mixed suspension (A11)

A polymer-ceramic mixed suspension (A11) 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.

Production Example  12: Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A12)

A polymer-ceramic mixed suspension (A12) 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.

Production Example  13: Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A13)

A polymer-ceramic mixed suspension (A13) 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.

Production Example  14: Preparation of biocompatible polymer-ceramic mixed suspension (A14)

A polymer-ceramic mixed suspension (A14) 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.

Production Example  15: Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A15)

A polymer-ceramic mixed suspension (A15) 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.

Production Example  16: Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A16)

A polymer-ceramic mixed suspension (A16) 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.

Production Example  17: Preparation of biocompatible polymer-ceramic mixed suspension (A17)

A polymer-ceramic mixed suspension (A17) 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.

Production Example  18: Preparation of Biocompatible Polymer-Ceramic Mix Suspension (A18)

A polymer-ceramic mixed suspension (A18) 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.

Production Example  19: Preparation of biocompatible polymer-ceramic mixed suspension (A19)

A polymer-ceramic mixed suspension (A19) 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: 120.

Production Example  20: Preparation of Biocompatible Polymer Suspension (B1)

A polymer suspension (B1) was prepared in the same manner as in Preparation Example 1, except that the calcium phosphate powder was not included.

Example  1: Biocompatible Polymer-Ceramic hybrid  Manufacture of film

First, the 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 rate of 7.4 ± 0.5 cm 2 / s to induce particle arrangement. Thereafter, the hydrogel formed by the ion cross-linking the slide glass was immersed for 30 min in the calcium chloride (CaCl ₂₎ solution of 0.1M was prepared. 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.

Example  2 to 19 and Comparative example : Preparation of biocompatible film

A biocompatible film was prepared in the same manner as in Example 1 except that the kind of the suspension prepared according to the Preparation Example was adjusted as shown in Table 1 below.

Experimental Example  One: hybrid  Observation and Simple Evaluation of Film

The biocompatible films prepared in Examples 1 to 19 and Comparative Examples were visually observed, and elasticity evaluation and mechanical properties were evaluated. In the case of the evaluation of elasticity was carried out through a simple experiment in the method that can be confirmed in Figure 1, in the case of mechanical properties evaluation was evaluated in the following criteria through a simple experiment in the manner that can be confirmed in FIG.

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

<Elastic evaluation standard>

O: observed to exhibit elastic properties

X: observed not to exhibit elastic properties

<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. 3 to 6.

More specifically, Figure 3 is a photograph showing the results for the above Examples 1 to 5 and Comparative Examples. 4 is a photograph showing the results of Examples 6 to 9 above. 5 is a photograph showing the results for Examples 10-14. 6 is a photograph showing the results of Examples 15 to 19.

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

In addition, Figure 7 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 FIGS. 3 to 7, the polymer-ceramic hybrid film according to the embodiment of the present invention can control elasticity and mechanical properties by controlling a mixing ratio between alginate and calcium triphosphate, which are biocompatible polymers. It can keep the film form for a long time. Therefore, the hybrid film can be applied not only to medical materials such as medical patches, dental impression materials or implant materials, but also to drug carriers, artificial cartilage, etc., and to be applied to various fields such as cosmetic containers, agricultural biodegradable materials, and food packaging containers. Can be. Furthermore, the hydrogel obtained in the hybrid film manufacturing process may be very useful as a material for 3D printing.

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

ATR-FTIR, ¹³ C NMR, XRD and TGA analysis were performed to confirm molecular structure characteristics of the hybrid films according to Examples 4, 8 and 15. 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. 9 to 12, respectively.

Referring to the ATR-FTIR results of FIG. 9, it can be seen that the carboxylic acid signal strengths of 1600 cm ⁻¹ and 1405 cm ⁻¹ decrease rapidly in the hybrid films of Examples 4, 8, and 15 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 Examples 4, 8 and 15, the broad signal intensity around 3245 cm ⁻¹ representing the hydroxy group indicates that the hydroxy group of the alginate and calcium triphosphate formed a crosslink (hydrogen bond).

Referring to the ¹³ C NMR results of FIG. 10, in the case of the 176.4 ppm signal indicating the presence of carbonyl carbon in sodium alginate, the strength decreases when mixed with calcium triphosphate. It can be seen that a crosslink (ion bond) was formed in the liver.

Referring to the XRD results of FIG. 11, in the case of a signal at 2θ = 13.7 ° indicating the presence of alginate, the strength gradually decreases with mixing and increasing concentration of calcium triphosphate, thereby decreasing the crystallinity of alginate. . These results suggest that there is good miscibility between alginate and calcium triphosphate. In addition, looking at the results of Examples 4, 8 and 15, it can be seen that as the concentration of calcium triphosphate increases, the signal intensity also increases, and these results indicate that calcium triphosphate is maintained in crystallinity. It is analyzed to affect the mechanical properties.

Referring to the TGA results of FIG. 12, a second region (186 ° C. to 377 ° C.) in which the chain is broken in the weight loss region of 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 4, Example 8 and Example 15 was observed the surface of each film by using SEM (TESCAN VEGA3, Tescan), FESEM (JSM-6700F, JEOL) The cross-sectional area was observed using, and the results are shown in FIGS. 13A to 13F. 13A, 13B, and 13C show SEM images of Example 4, 8, and 15, respectively, and FIGS. 13D, 13E, and 13F show their FESEM images, respectively.

13A to 13F, 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: hybrid  Evaluation of Mechanical Properties of Films

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 Examples 4, 8 and 15 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. 14.

Referring to Table 3 and FIG. 14, the elongation and tensile strength of the hybrid films of Examples 4 and 8 were found to be at similar levels, indicating that both of the elongation and tensile strength of Example 15 were higher. You can check it. These results indicate that the hybrid films of Examples 4 and 8 exhibit excellent elasticity and can be utilized in medical materials or food packaging containers such as dental elastic impression materials.

On the other hand, the low tensile strength value of the hybrid film according to Example 15 was analyzed due to the fact that the specimen was easily broken due to the low elongation and thus could not be applied to the tensile load. Therefore, the hybrid film of Example 15 may be usefully applied to food packaging containers and the like, which do not require elasticity and require only mechanical properties.

Experimental Example  4: hybrid  Evaluation of water content, swelling degree and water resistance of film

Moisture content, swelling and water resistance were evaluated to confirm the moisture properties of the hybrid films according to Examples 4, 8 and 15. 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 were cut and dried to weigh a 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. 15A.

[Equation 1]

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

Referring to Figure 15a, it can be seen that the water 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 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 15b.

[Equation 2]

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

Referring to Figure 15b, it can be seen that the swelling degree decreases as the content of calcium triphosphate increases. This is due to the fact that 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 stirred at 25 ° C. at a rotational speed of 100 rpm for 7 days. 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 through a weight loss rate (%) calculated through Equation 3 below, and the results are shown in FIG. 15C.

[Equation 3]

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

Referring to Figure 15c, it can be seen that as the content of calcium triphosphate increases, the weight reduction rate is lowered to improve the 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 and exit rate, specifically drug release properties.

Experimental Example  5: hybrid  Evaluation of Optical Properties of Films

Opacity and light transmittance were measured to evaluate the optical properties of the hybrid films according to Examples 4, 8 and 15. Specifically, square specimens (2 × 1 cm 2) were prepared by cutting each hybrid film, and the absorbance and transmittance (%) of each specimen was measured using a UV-Vis spectrophotometer in the wavelength range of 200 nm to 800 nm under an air atmosphere. ) Was measured.

The opacity was calculated through Equation 4 below, and the results are shown in Table 4 and FIGS. 16A and 16B. FIG. 16A shows the relationship between transmittance (%) and wavelength, and FIG. 16B shows the relationship between absorbance and wavelength.

[Equation 4]

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

Referring to Table 4 and FIGS. 16A and 16B, the hybrid films of Examples 8 and 15 exhibited similar levels of light transmittance, and have a higher opacity and a lower level than those of the hybrid film of Example 4 or a film containing only alginate. It was confirmed that the light transmittance is shown.

Accordingly, when the hybrid films of Example 8 and Example 15 are applied to food packaging containers, it is possible to effectively prevent the destruction of nutrients such as fat from ultraviolet rays by blocking the light, especially in the case of Example 15 It can be seen that the effect is more excellent.

Experimental Example  6: according to pH conditions hybrid  Swelling degree evaluation of the film

In order to check whether the swelling degree of the hybrid film varies depending on the pH conditions, the swelling degree (%) was changed in the same manner as in Experiment 4 while varying the pH conditions for the hybrid films of Examples 4, 8 and 15. It was calculated and the results are shown in Figs. 17a, 17b and 17c.

Referring to Figure 17a, 17b and 17c, it can be seen that the degree of swelling increases depending on the pH in all the hybrid film. 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 in high pH conditions and the drug release rate may be decreased in low pH environments. In view of these characteristics, the possibility of selective application of the hybrid film may be expected. have.

Experimental Example  7: hybrid  Drug release evaluation of film

In order to evaluate the drug release properties of the hybrid films of Examples 4, 8 and 15, hydrogels were 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 of 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 (%).

The results for the BSA of the hybrid film according to Examples 4, 8 and 15 are shown in FIGS. 18A, 18B and 18C, respectively, and the results for TCN are shown in FIGS. 19A, 19B and 19C, respectively, and DMOG. Results for are shown in Figures 20a, 20b and 20c, respectively.

Referring to Figures 18a, 18b, 18c, 19a, 19b, 19c, 20a, 20b and 20c, all of the BSA, TCN, DMOG increases the drug release rate with increasing pH, and decreases the drug release rate with increasing calcium triphosphate content. It confirmed that it became.

In view of this, the hybrid film of Example 4 is effective in an environment in which rapid drug release is required at high pH conditions such as intestine, and the hybrid film of Example 8 is in a neutral pH condition. It is effective in an environment in which drug release is required at an appropriate rate, and the hybrid film of Example 15 may be effective in an environment in which sustained release drug is required in an acidic pH condition such as 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 components described 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 (20)

1. Biocompatible polymers including a carboxyl group and a hydroxyl group;

   Calcium phosphate; And

   Polymer-ceramic hybrid film comprising a divalent metal ion.
2. The method of claim 1,

   The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 20: 1 to 8: 1, polymer-ceramic hybrid film.
3. The method of claim 1,

   The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 5: 1 to 1: 1, polymer-ceramic hybrid film.
4. The method of claim 1,

   The biocompatible polymer and calcium phosphate are mixed at a weight ratio of 1: 2 to 1:20, polymer-ceramic hybrid film.
5. The method of claim 1,

   The biocompatible polymer is alginate, polymer-ceramic hybrid film.
6. The method of claim 5,

   A polymer-ceramic hybrid film, wherein the hydroxyl group of the alginate is crosslinked with the calcium phosphate.
7. The method of claim 6,

   The calcium phosphate is calcium triphosphate (TCP, tricalcium phosphate), polymer-ceramic hybrid film.
8. The method of claim 5,

   The polymer-ceramic hybrid film of which the carboxyl group of the alginate is crosslinked with the divalent metal ion.
9. The method of claim 8,

   The divalent metal ions are calcium ions (Ca ^{2 +),} polymer-ceramic hybrid film.
10. The method of claim 1,

    A polymer-ceramic hybrid film, exhibiting pH dependent drug release.
11. (a) preparing a hybrid solution in which a biocompatible polymer including a carboxyl group and a hydroxyl group and calcium phosphate are mixed;

    (b) inducing an arrangement of particles in the hybrid solution; And

    (c) mixing the hybrid solution with a divalent metal ion solution; comprising a polymer-ceramic hybrid film.
12. The method of claim 11,

    The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 20: 1 to 8: 1, the method of producing a polymer-ceramic hybrid film.
13. The method of claim 11,

    The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 5: 1 to 1: 1, the method of producing a polymer-ceramic hybrid film.
14. The method of claim 11,

    The biocompatible polymer and calcium phosphate are mixed in a weight ratio of 1: 2 to 1:20, a method for producing a polymer-ceramic hybrid film.
15. The method of claim 11,

    The biocompatible polymer is alginate, a method for producing a polymer-ceramic hybrid film.
16. The method of claim 15,

    And a hydroxyl group of the alginate is crosslinked with the calcium phosphate.
17. The method of claim 11,

    The step (b) is to scree the hybrid solution on a support (screeding), a method for producing a polymer-ceramic hybrid film.
18. The method of claim 17,

    The screening speed is 5 cm 2 / s to 10 cm 2 / s, a method for producing a polymer-ceramic hybrid film.
19. The method of claim 11,

    Method for producing a polymer-ceramic hybrid film, the concentration of the divalent metal ion solution is 0.05M to 5M.
20. The method of claim 15,

    The carboxyl group of the alginate is cross-linked with the divalent metal ion, a method for producing a polymer-ceramic hybrid film.

Images