KR20180038355A - Elastic polymer-ceramic hybrid film having excellent flexibility and mechanical property and method for preparation thereof - Google Patents

Abstract

The present invention relates to an elastic polymer-ceramic hybrid film with excellent elastic and mechanical properties and a manufacturing method thereof. A polymer-ceramic hybrid material according to the present invention is the elastic polymer-ceramic hybrid film, which can maintain a film foam for a long time while implementing excellent elastic and mechanical properties at the same time, thereby being applied as a medical material. Also, a hydrogel used in a film manufacturing process can be very helpfully used as a 3D printing material. The polymer-ceramic hybrid film according to the present invention can improve mechanical strength by differently arranging ceramic particles in a hybrid material. Also, the method for manufacturing an elastic polymer-ceramic hybrid film according to the present invention includes only the manufacturing process which is simple and easy and can manufacture a polymer-ceramic material at room temperature. The elastic polymer-ceramic hybrid film includes: a biocompatible polymer including a carboxyl group and a hydroxyl group; calcium phosphate; and a divalent metal ion.

Description

TECHNICAL FIELD [0001] The present invention relates to an elastic polymer-ceramic hybrid film excellent in elasticity and mechanical properties, and a method for producing the same. [0002]

The present invention relates to an elastic polymer-ceramic hybrid film excellent in elasticity and mechanical properties, and a method for producing the same.

Researches are actively being conducted to create hybrid materials for ceramics (inorganic materials), metals and polymer materials that have been classified as traditional materials at present. A hybrid in a material means that two or more materials considered to be heterogeneous, such as inorganic, metal, and polymer, are implemented in one system and have a synergy effect for new performance while maintaining their performance .

One of the most interesting hybrid materials is hybrid materials of polymers and ceramics. Polymers are materials composed mainly of carbon chain reaction and can be classified into one kind of organic materials. Ceramic materials include oxides, hydroxides, carbonates, phosphates (for example, titanium oxide And the like. Organic and inorganic materials can be considered not to mix well because they have various aspects such as bonding properties and physical properties. However, in fact, so-called "polymer-ceramic hybrid materials" Found. The skeleton that maintains the skeleton of the human body is an inorganic material of hydroxyapatite (HAP). Since the muscle and soft tissues are composed of organic materials of collagen and polysaccharide, the human body can be regarded as a huge hybrid of organic matter and inorganic matter . In addition, most of the substances forming the egg shell of algae are calcium carbonate (calcium carbonate), which is a hybrid material in which a polymer membrane is attached to the inner surface.

Polymer materials and ceramics that can be used as hybrid materials are very diverse. However, when focusing on the field of medical materials in terms of field, both polymers and ceramics should have biostability and compatibility. For this purpose, biocompatible polymers or easily decomposable polymers are suitable. It is also desirable that the ceramic material is also easily degraded in living organisms or in vivo, and that the degradation products do not have toxicity to the living body. Representative medical natural polymer materials include agarose, pectin, carrageenan, chitosan, alginate, gelatin, collagen and chondroitin sulfate. This is representative. In addition, ceramic materials are compounds that are highly likely to be used as medical materials or biological applications. Hydroxyapatite is an important component that constitutes the skeleton of the human body and is an important material in research on tissue engineering and artificial biomaterials , Clay and layered metal hydroxides have recently been actively studied for drug delivery.

On the other hand, in the case of the polymer-ceramic hybrid material, as described above, in order to be applied to a damaged area where a certain load is required for a predetermined period when used for medical treatment, or to a field such as 3D bio- Possible mechanical properties are required. A film having flexibility (e.g., elasticity) that can be applied to cover a complicated tissue and organ of a patient is required. In the case of a polymer-ceramic hybrid material, it is generally manufactured in gel form or in particle form All. However, hydrogels, films and various forms with flexibility and strength are required in order to be able to be applied throughout the aforementioned medical or complex types of tissues and organs.

In addition, when a polymer-ceramic hybrid material is produced, since it involves processes such as induction of a chemical reaction, high temperatures, high pressures, or crosslinking agents and initiators have to be added.

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

Patent Literature 1 discloses a method for producing a biodegradable polymer, comprising the steps of: (a) distributing two or more biocompatible polymer struts on a plate side by side to form a stratum layer; (b) distributing the biocompatible polymeric struts side by side in the direction of the distributed biocompatible polymeric struts on the distributed biocompatible polymeric stratum; (c) a strand of at least one natural biocompatible material selected from the group consisting of gelatin, fucoidan, collagen, alginate, chitosan and hyaluronic acid bearing cells is distributed between the biocompatible polymer strands distributed in step (b) Forming crosslinks on the biocompatible natural material to be dispensed, while distributing the biocompatible polymeric material strands so that they do not come in contact with the biocompatible polymeric struts; And (d) repeating steps (b) and (c) sequentially to form a hybrid structure. The present invention also provides a method for producing a cell-supported biocompatible polymer-biocompatible natural material hybrid structure.

Patent Document 2 discloses a method for producing a biodegradable polymer, comprising the steps of: a) dissolving two different biodegradable polymers in an organic solvent to prepare respective solutions; b) preparing a nano / micro hybrid fiber sheet by spinning nanofibers and microfibers of biodegradable polymers simultaneously in both directions by using the electrospinning method for each solution prepared above; c) removing the residual solvent of the hybrid fiber sheet so as to obtain a nano / micro hybrid fiber nonwoven fabric.

However, although the physical properties required for the polymer-ceramic hybrid material produced by each of the above proposed Patent Documents 1 and 2 have been achieved to a certain extent, the manufacturing process can not be performed at room temperature, and in particular, a film type in which flexibility and mechanical properties are controlled It can not be manufactured by a conventional method.

Therefore, it is necessary to develop a technique that can be produced by a simple production method in film form while satisfying physical properties of a polymer-ceramic hybrid material, and a technique for producing a film at room temperature without using a crosslinking agent or an initiator.

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

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

As a result of these research efforts, the present inventors have made efforts to develop a new polymer-ceramic hybrid material for solving the problems of the above-mentioned prior arts. As a result of such research efforts, when the mixing ratio of the polymer and the ceramic is controlled within a specific range, In particular, it has been found through the data that flexibility and mechanical properties, which are required physical properties, can be controlled. In particular, in the production of the polymer-ceramic hybrid material, the arrangement of ceramic particles is induced, The present inventors have completed the present invention by confirming that the film form having elasticity is maintained for a long period of time when cured in an aqueous solution containing the water-soluble polymer.

The present invention provides an elastic polymer-ceramic hybrid film excellent in elasticity and mechanical properties and a method for producing the same.

According to one embodiment of the present invention, a biocompatible polymer comprising a carboxyl group and a hydroxyl group; Calcium phosphate; Wherein the biocompatible polymer and the calcium phosphate are mixed at a weight ratio of 5: 1 to 1: 1. The present invention also provides an elastic polymer-ceramic hybrid film comprising the biocompatible polymer and calcium phosphate.

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

According to one aspect, the hydroxyl group of the alginate can be crosslinked with the calcium phosphate.

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

According to one aspect, the carboxyl group of the alginate may be cross-linked with the divalent metal ion.

According to one aspect, the divalent metal ion may be calcium ion (Ca ^< ^{2 + &} gt ^; ).

According to one aspect, the hybrid film may exhibit pH dependent drug release.

According to another embodiment of the present invention, there is provided a biocompatible polymer comprising (a) a biocompatible polymer including a carboxyl group and a hydroxyl group, and calcium phosphate in a weight ratio of 5: 1 to 1: 1 Preparing a mixed hybrid solution; (b) inducing an array of particles in the hybrid solution; And (c) mixing the hybrid solution with a divalent metal ion solution. The present invention also provides a method for producing an elastic polymer-ceramic hybrid film.

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

According to one aspect, the hydroxyl group of the alginate can be crosslinked with the calcium phosphate.

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

According to one aspect, the scoring speed may be 5 cm 2 / s to 10 cm 2 / s.

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

According to one aspect, the carboxyl group of the alginate may be cross-linked with the divalent metal ion.

According to one aspect, the divalent metal ion may be calcium ion (Ca ^< ^{2 + &} gt ^; ).

The polymer-ceramic hybrid material according to the present invention is an elastic polymer-ceramic hybrid film and can be applied as a medical material because it can maintain a film shape for a long time while simultaneously realizing excellent elasticity and mechanical properties. In addition, the hydrogel used in the production process of the film can be very usefully used as a material for 3D printing.

The polymer-ceramic hybrid film according to the present invention can improve the mechanical strength by changing the arrangement of the ceramic particles in the hybrid material by varying the hybrid solution in the above-mentioned hybrid solution. In addition, the method for producing an elastic 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 should be understood that the effects of the present invention are not limited to the effects described above, but include all effects that can be deduced from the description of the invention or the composition of the invention set forth in the claims.

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

In the following, embodiments will be described in detail with reference to the accompanying drawings.

Various modifications may be made to the embodiments described below. It is to be understood that the embodiments described below are not intended to limit the embodiments, but include all modifications, equivalents, and alternatives to them.

The terms used in the examples are used only to illustrate specific embodiments and are not intended to limit the embodiments. The singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, the terms "comprises" or "having" and the like refer to the presence of stated features, integers, steps, operations, elements, components, or combinations thereof, But do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or combinations 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 to which this embodiment belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the contextual meaning of the related art and are to be interpreted as either ideal or overly formal in the sense of the present application Do not.

In the following description of the embodiments, detailed description of related arts will be omitted if it is determined that the gist of the embodiment may be unnecessarily blurred.

One embodiment of the present invention is a biocompatible polymer comprising a carboxyl group and a hydroxyl group; Calcium phosphate; Wherein the biocompatible polymer and calcium phosphate are mixed in a weight ratio of 5: 1 to 1: 1. The present invention also provides an elastic polymer-ceramic hybrid film comprising the biocompatible polymer and calcium phosphate.

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

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

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

The hybrid film may contain the biocompatible polymer and calcium phosphate at the same time. In this case, the hybrid film may preferably be mixed such that the weight ratio of the biocompatible polymer is greater than or equal to that of the ceramic.

Specifically, the biocompatible polymer and ceramic may be mixed in a weight ratio of 5: 1 to 1: 1. When the biocompatible polymer and ceramic are mixed in the mixing ratios of the ranges described above, the polymer-ceramic hybrid film containing the biocompatible polymer and the ceramic can exhibit excellent elasticity and mechanical properties at the same time while maintaining the film form. .

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 +)} Lt; / RTI > The crosslinking between the carboxyl group of the alginate and the divalent metal ion may be an ionic bond.

That is, a crosslinking between the hydroxy group of the alginate and calcium phosphate and a double crosslinking of the 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 carrying a drug therein. At this time, the hybrid film may exhibit pH-dependent drug releasability.

Specifically, the hybrid film may exhibit slow drug release under acidic conditions with low pH, while it may exhibit rapid drug release under basic conditions with high pH. That is, since the drug releasability can be controlled according to the pH environment to which the hybrid film is applied, a hybrid film can be selected and applied according to the pH of the application site.

FIG. 8 shows a process of manufacturing an elastic polymer-ceramic hybrid film according to an embodiment of the present invention and a particle arrangement inside the film.

Referring to FIG. 8, another embodiment of the present invention is a method for preparing a biocompatible polymer, comprising: (a) mixing a biocompatible polymer containing a carboxyl group and a hydroxyl group with calcium phosphate in a ratio of 5: 1 to 1: 1 to prepare a mixed hybrid solution; (b) inducing an array of particles in the hybrid solution; And (c) mixing the hybrid solution with a divalent metal ion solution. The present invention also provides a method for producing an elastic polymer-ceramic hybrid film.

In the step (a), the weight ratio of the biocompatible polymer may be greater than or equal to that of the ceramic. The specific mixing ratio and the effect thereof 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 alginate, but is not limited thereto.

In the step (a), the alginate may be mixed in a solution state, and the concentration of the alginate may be, for example, 1% to 10%, 2.5% to 8.5%, or 5% to 7% May have a concentration of about 6%. In order to increase the elasticity of the molecular weight, it may be preferable to use alginate having a high molecular weight, but the present invention is not limited thereto.

The biocompatible polymers and ceramics may be prepared in the form of a solution, respectively, and then mixed by mixing the two solutions. The suspension may be prepared by mixing.

The hydroxyl group of the alginate may be cross-linked with the calcium phosphate in the hybrid solution prepared in the step (a). At this time, the calcium phosphate may be TCP (tricalcium phosphate). The types of ceramics that can be used in addition to calcium phosphate are as described above.

The calcium phosphate mixed in the step (a) may have a particle size ranging from nano-size to micro-size, and may be specifically from 0.5 탆 to 10 탆, but is not limited thereto.

In the step (b), the arrangement of the particles, specifically, the biocompatible polymer and the calcium phosphate particles existing in the hybrid solution may be induced to improve the crystallinity. At this time, the arrangement of the inner particles can be induced by screeding the hybrid solution on the support.

As used herein, the term "screeding" is a process for inducing the arrangement of ceramic particles and smoothing the surface, wherein the hybrid solution is applied on a support such as a slide glass and then a cover such as a cover glass is used Thereby physically pushing it.

When the arrangement of the particles is induced through the scription process, a certain space is secured in the biocompatible polymer chain forming a bond with calcium phosphate, so that penetration of the divalent metal ion to be described later and further cross-linking through the biocompatible polymer chain proceed easily .

In this case, the scoring speed may be 5 cm 2 / s to 10 cm 2 / s. If the velocity is less than 5 cm 2 / s, the particle array may not be sufficiently induced. If the velocity is more than 10 cm 2 / s, the crosslinking between the biocompatible polymer and calcium phosphate The bond can be destroyed.

In the step (c), the concentration of the divalent metal ion solution may be 0.05M to 5M, preferably 0.075M to 1M, and more preferably 0.1M. The calcium ions can be gelated by curing the biocompatible polymer-ceramic hybrid solution, and a film-like biocompatible polymer-ceramic hybrid film can be prepared through a sufficient gelation process more quickly than when the concentration is in the above range .

The carboxyl group of the alginate in the gel produced in the step (c) 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 +)} Lt; / RTI > The crosslinking between the carboxy group of the alginate and the divalent metal ion may be an ionic bond, through which the hybrid solution can be gelled.

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

After the step (c), the gel is dried and then separated from the support to finally obtain an elastic polymer-ceramic hybrid film. Specifically, the drying can 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 provided for the purpose of illustrating the present invention, and the scope of the present invention is not limited thereto.

Manufacturing example  1: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (A1)

α-trisodium phosphate (α-TCP) The 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 calcium phosphate (Sigma Aldrich) were mixed and heated for about 3 hours at about 1400 ° C to quench in air to form α-TCP phase in powder form / RTI > The thus-formed α-TCP powder was milled by a ball, dropped to a size of about 150 μm, and stored separately in a vacuum state.

In addition, 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 prepared alginate solution was mixed with calcium phosphate powder separately stored at a weight ratio of 5: 1 and sonicated to vibra cell to prepare a polymer-ceramic mixed suspension (A1).

Manufacturing example  2: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (A2)

Polymer blend 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 3: 1.

Manufacturing example  3: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (A3)

Polymer blend 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 2: 1.

Manufacturing example  4: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (A4)

Polymer blend 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: 1.

Manufacturing example  5: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (B1)

Polymer blend 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 10: 1.

Manufacturing example  6: Preparation of Biocompatible Polymer-Ceramic Mixed Suspension (B2)

Polymer blend 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 8: 1.

Manufacturing example  7: Preparation of Biocompatible Polymer-Ceramic Mixed 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 6: 1.

Manufacturing example  8: Preparation of Biocompatible Polymer-Ceramic Mixed 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 1: 2.

Manufacturing example  9: Preparation of Biocompatible Polymer-Ceramic Mixed 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 1: 3.

Manufacturing example  10: Preparation of Biocompatible Polymer Suspension (B6)

Polymer blend 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 1:10.

Example  1: Biocompatible polymer-ceramic hybrid  Production of film

First, the polymer-ceramic mixed suspension (A1) prepared in Preparation Example 1 was applied to a slide glass (7.5 x 2.5 cm 2), followed by a scouring process at a rate of 7.4 ± 0.5 cm 2 / s, Respectively. Thereafter, the slide glass was immersed in a 0.1 M aqueous solution of calcium chloride (CaCl ₂ ) for 30 minutes to form ionic crosslinking to prepare a hydrogel. Thereafter, the hydrogel was separated from the slide glass, washed three times with distilled water, and dried on a separate slide glass for 48 hours in a vacuum oven to prepare a biocompatible polymer-ceramic hybrid film.

Example  2 to 4 and Comparative Example  1 to 6: Biocompatible polymer-ceramic hybrid  Production of film

A biocompatible polymer-ceramic hybrid film was prepared in the same manner as in Example 1, except that the kinds of the polymer-ceramic mixed suspension prepared in the above Preparation Examples were controlled as shown in Table 1 below.

division Example Comparative Example One 2 3 4 One 2 3 4 5 6 Polymer-ceramic mixing suspension Kinds A1 A2 A3 A4 B1 B2 B3 B4 B5 B6

Experimental Example  One: hybrid  Observation of film appearance and simple evaluation

The biocompatible polymer-ceramic hybrid films prepared in Examples 1 to 5 and Comparative Examples 1 to 6 were observed with naked eyes and the elasticity evaluation was conducted through a simple experiment as shown in Fig. 1, and the mechanical properties evaluation The results are shown in Fig. 2.

The evaluation standards for the elastic properties and the film form retention for each of the above Examples and Comparative Examples are as follows.

<Elasticity Evaluation Standard>

O: observed to exhibit elastic properties

X: observed to show no elastic properties

&Lt; Evaluation Criteria of Mechanical Properties &

O: observed to exhibit mechanical properties (i.e., the film does not tear in a simple experiment)

X: observed to show no mechanical properties (i. E., The film tears in a simple experiment)

<Evaluation Criteria for Film Form Maintenance>

O: Film form observed to be maintained

X: Film shape is not maintained, cracked or torn

The photographs actually observed are shown in Figs. 3 to 6.

More specifically, FIG. 3 is a photograph showing the results of Examples 1 and 2 (the left photograph is the embodiment 1 and the right photograph is the embodiment 2). 4 is a photograph showing the results of Examples 3 and 4 (the left photograph is the example 3 and the right photograph is the example 4). 5 is a photograph showing the results of Comparative Examples 1 to 3 (Comparative Example 1, Comparative Example 2 and Comparative Example 3 in order from left to right). FIG. 6 is a photograph showing the results of Comparative Examples 4 and 5 (the left photograph is Comparative Example 4 and the right photograph is Comparative Example 5).

The results of evaluation according to the above evaluation criteria are shown in Table 2 below.

division Example Comparative Example One 2 3 4 One 2 3 4 5 Elasticity maintenance O O O O O O O X X Mechanical properties O O O O X X X O O Maintain film form O O O O O O O X X

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

As can be seen from Table 2 and FIGS. 3 to 7, the elastic polymer-ceramic hybrid film according to the embodiment of the present invention can maintain the film shape while simultaneously realizing excellent elasticity and mechanical properties, Impression materials, implant materials, and the like. In addition, the hybrid film can be applied to various fields such as a cosmetic container, a biodegradable material for agriculture, and a food packaging container, as well as a drug delivery system and an artificial cartilage. Furthermore, the hydrogel can be very useful as a material for 3D printing.

Experimental Example  2: hybrid  Identification of molecular structure of film

ATR-FTIR, ¹³ C NMR, XRD, and TGA analyzes were performed to confirm the molecular structure characteristics of the hybrid film according to Example 3, Comparative Example 1, and Comparative Example 6. The ATR-FTIR spectra of sodium alginate, calcium triphosphate and each hybrid film were measured at 650 cm ^-1 to 4000 cm ^-1 wavelength region 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) Respectively. Further, 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 [deg.] 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 Figure 9, compared to the sodium alginate Example 3, Comparative Example 1 and Comparative Example 6 In the hybrid film of the acid strength of the signal 1600㎝ 1405㎝ ^-1 and ^-1 see that sharply reduces And it is analyzed that the calcium ion forms a crosslink (ionic bond) with the carboxyl group of the alginate. Further, in Example 3, Comparative Example 1, and Comparative Example 6, the broad signal intensity around the 3245 cm ^-1 indicating the hydroxy group indicates that the hydroxy group of the alginate and the calcium triphosphate formed a cross-link (hydrogen bond).

Referring to the ¹³ C NMR results of FIG. 10, it can be seen that, in the case of a 176.4 ppm signal indicating the presence of carbonyl carbon of sodium alginate, the intensity decreases when mixed with calcium triphosphate. From this, it can be seen that the carboxy group and calcium ion (Ionic bond) between them.

Referring to the XRD results in FIG. 11, it can be seen that, in the case of a signal at 2? = 13.7 ° indicating the presence of alginate, the intensity gradually decreases with increasing mixing and concentration with calcium triphosphate, and the crystallinity of the alginate decreases . These results imply that there is a good miscibility between alginate and calcium triphosphate. In addition, the results of Example 3, Comparative Example 1 and Comparative Example 6 show that the signal intensity increases as the concentration of calcium triphosphate increases. These results indicate that calcium triphosphate remains crystalline, It is analyzed that it will affect the mechanical properties.

Referring to the results of TGA in FIG. 12, the second region (186 ° C to 377 ° C) in which chain bonds are lost in the weight loss region of alginate is related to thermal stability, and in the case of hybrid films, ℃ and the weight loss rate was also decreased as the content of calcium triphosphate was increased. From this, it can be seen that calcium triphosphate improves the thermal stability of the alginate.

In order to observe the surface characteristics of the hybrid films of Example 3, Comparative Example 1 and Comparative Example 6, the surface of each film was observed using SEM (TESCAN VEGA 3, TESCAN), and FESEM (JSM-6700F, JEOL) And the cross-sectional area was observed. The results are shown in Fig. (a) to (c) show SEM images of Comparative Example 1, Example 3 and Comparative Example 6, and (d) to (f) respectively show FESEM images thereof.

Referring to FIG. 13, it can be seen that the increase in the content of calcium triphosphate increases the crosslinking with the alginate, so that the calcium triphosphate particles clearly appear on the alginate surface.

Experimental Example  3: hybrid  Evaluation of Mechanical Properties of Film

In order to evaluate the mechanical properties of the hybrid film according to Example 3, Comparative Example 1 and Comparative Example 6, a tensile strength was measured using a fatigue tester (E3000LT, INSTRON) according to the ASTM standard under a humidity of 60-65% And elongation were measured. Specifically, each of the hybrid films was cut into strips (5 x 1 cm 2), and grips were formed thereon to prepare test specimens. The distance between the gage length of the specimen and the grip was 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.

division Specimen thickness (mm) Elongation (%) Tensile Strength (MPa) Comparative Example 1 0.10 ± 0.01 13.23 254.51 Example 3 0.10 ± 0.01 10.50 257.52 Comparative Example 6 0.10 ± 0.01 4.44 38.48

Referring to Table 3 and FIG. 14, the hybrid film of Example 3 showed excellent elongation and tensile strength as compared with that of Comparative Example 6, and showed similar values to those of the hybrid film of Comparative Example 1. [ The hybrid film of Comparative Example 6 was found to have intergranular agglomeration due to excessive calcium trisodium content and thus the specimen was easily broken even under a low load. These results suggest that the hybrid film of Example 3 exhibits excellent elasticity and can be used in various fields as described above such as medical materials such as dental elastic impression materials and food packaging containers.

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

Moisture content, swelling and water resistance were evaluated to confirm the characteristics of the hybrid film according to Example 3, Comparative Example 1 and Comparative Example 6 with respect to moisture. The release characteristics of a substance, e.g., a drug, deposited on the interior of the film may vary depending on the moisture content, swelling degree and water resistance of the hybrid film, and thus can be used as an indirect indicator therefor.

First, each hybrid film was cut and dried, and the dried specimen (4 × 2 cm 2) was weighed and left in the air for 7 days under a relative humidity of 60-65% at 25 ° C. After 24 hours, the respective specimens were weighed and the moisture content (%) was calculated by the following equation (1). The results are shown in FIG. 15 (a).

[Equation 1]

Water content (%) = (weight of specimen before leaving / weight of specimen after leaving) × 100 (%)

Referring to FIG. 15 (a), it can be seen that as the content of calcium triphosphate increases, the moisture content of the hybrid film decreases. It is analyzed that as the content of calcium triphosphate increases, not only the space that can accommodate water in chain of alginate decreases but also the content of hydrophilic hydroxyl group decreases.

Each of the above dried specimens (4 x 2 cm 2) was immersed in 50 ml of distilled water and stored at 25 ° C for 24 hours. After one hour, each of the immersed specimens was taken out, the water was removed, and the weight was weighed until it reached equilibrium. The degree of swelling (%) was calculated by the following equation (2), and the result is shown in FIG. 15 (b).

&Quot; (2) &quot;

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

Referring to FIG. 15 (b), it can be seen that as the content of calcium triphosphate increases, the degree of swelling decreases. This is because calcium triphosphate binds to the hydrophilic functional group hydroxy group to lower the hydrophilicity of the molecule and reduce the internal space of the alginate chain.

Finally, each pre-weighed dry sample (4 x 2 cm 2) was immersed in 50 ml of distilled water and stirred at 25 ° C for 7 days at a rotation speed of 100 rpm. After 24 hours, 72 hours and 268 hours, each specimen was taken out of distilled water, dried at 40 DEG C for 48 hours and weighed. The water resistance was measured by a weight reduction ratio (%) calculated by the following equation (3), and the result is shown in FIG. 15 (c).

&Quot; (3) &quot;

Weight reduction rate (%) = [(initial drying sample weight - final dried sample weight) / original dried sample weight] × 100 (%)

Referring to FIG. 15 (c), it can be seen that as the content of calcium triphosphate is increased, the weight reduction rate is lowered and the water resistance is improved. This is because calcium triphosphate present on the alginate surface effectively blocks water permeation.

These results imply that the rate of entry and exit of the substance, specifically drug release, can be controlled by controlling the content of calcium triphosphate in the film.

Experimental Example  5: hybrid  Evaluation of Optical Properties of Film

The opacity and the light transmittance were measured to evaluate the optical characteristics of the hybrid film according to Example 3, Comparative Example 1, and Comparative Example 6. Specifically, each hybrid film was cut to fabricate a square specimen (2 x 1 cm 2), and the absorbance and transmittance (%) of each specimen were measured using a UV-Vis spectrophotometer in a wavelength range of 200 to 800 nm under air atmosphere. ) Were measured.

The opacity was calculated by the following equation (4), and the results are shown in Table 4 and FIG. Fig. 16 (a) shows the relationship between transmittance (%) and wavelength, and Fig. 16 (b) shows the relationship between absorbance and wavelength.

&Quot; (4) &quot;

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

division Specimen thickness (mm) Opacity
(%, at 600 nm) Transmittance
(%, at 254 nm) 6% alginate 0.10 ± 0.01 1.96 + 0.12 48.58 ± 0.73 Comparative Example 1 0.10 ± 0.01 6.61 ± 0.27 16.72 ± 0.59 Example 3 0.10 ± 0.01 14.01 + - 0.33 2.23 ± 0.06 Comparative Example 6 0.10 ± 0.01 28.90 + - 1.72 0.40 0.11

Referring to Table 4 and FIG. 16, the hybrid film of Example 3 exhibited a light transmittance similar to that of Comparative Example 6, and exhibited higher opacity and lower light transmittance than the film containing only alginate or the hybrid film of Comparative Example 1 Respectively.

Accordingly, it can be seen that when the hybrid film of Example 3 is applied as a food packaging container, it is possible to effectively prevent destruction of nutrients such as fat from ultraviolet rays by blocking light.

Experimental Example  6: pH dependent hybrid  Evaluation of film swelling

The hybrid films of Example 3, Comparative Example 1 and Comparative Example 6 were tested for their degree of swelling (%) in the same manner as in Experimental Example 4, except that pH conditions were varied, in order to confirm whether the degree of swelling of the hybrid films varied depending on pH conditions. And the results are shown in Fig.

Referring to FIG. 17, it can be seen that the degree of swelling increases depending on the pH in all the hybrid films. It is analyzed that the increase of calcium ion-base bond due to pH increase destroys the cross-linkage between calcium ion-carboxylic acid, thereby increasing the internal space of the film, and the dissociated hydrophilic carboxylic acid anion forms bond with water molecule.

As a result, it can be expected that the drug release rate of the hybrid film increases at a high pH and that the drug release rate decreases at a low pH environment. Considering these characteristics, a selective application of the hybrid film can be expected have.

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

In order to evaluate the drug releasing properties of the hybrid films of Example 3, Comparative Example 1 and Comparative Example 6, hydrogels were obtained in the respective hybrid film production steps and bovine serum albumin (BSA), tetracycline (TCN) and DMOG dimethyloxalyglycine) to prepare a gel bead.

Specifically, each of the hydrogels and the respective drugs (BSA, TCN and DMOG) were put into distilled water, and they were mixed by applying ultrasonic waves at 25 ° C. The BSA, TCN and DMOG were mixed with 0.165 g of hydrogel at a concentration of 4.9 × 10 ^-6 mol, respectively. The mixture was added to a vial containing 0.1 M calcium chloride (CaCl ₂ ), and ultrasonic waves were applied for 30 minutes to crosslink . Then, the content of each vial was lyophilized for 48 hours to obtain gel beads having different kinds of drugs and different contents of alginate and calcium triphosphate.

(BioMate 3S, Thermo Scientific) at 37 ° C with varying pH to evaluate the drug release of gel beads against BSA, TCN and DMOG. Specifically, each gel bead was dissolved in 10 ml of distilled water, and the UV-Vis spectra of the solution was recorded and analyzed spectrophotometrically to determine the drug release (%). The results for BSA, TCN and DMOG were 18 to 20.

18 to 20, it was confirmed that the drug release rate was increased as the pH was increased in all of BSA, TCN, and DMOG, and the drug release rate was decreased as the calcium triphosphate content was increased. In view of this point, it can be seen that the elastic hybrid film of Example 3 is effective in an environment in which drug release at an appropriate rate is required under neutral pH conditions.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. For example, if the techniques described are performed in a different order than the described methods, and / or if the described components are combined or combined in other ways than the described methods, or are replaced or substituted by other components or equivalents Appropriate results can be achieved.

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

Claims (15)

A biocompatible polymer comprising a carboxyl group and a hydroxyl group;
Calcium phosphate; And
A divalent metal ion,
Wherein the biocompatible polymer and calcium phosphate are mixed in a weight ratio of 5: 1 to 1: 1.
The method according to claim 1,
Wherein the biocompatible polymer is alginate. &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt;
3. The method of claim 2,
Wherein the hydroxyl group of the alginate is crosslinked with the calcium phosphate.
The method of claim 3,
Wherein said calcium phosphate is TCP (tricalcium phosphate).
3. The method of claim 2,
Wherein the carboxyl group of the alginate is crosslinked with the divalent metal ion.
6. The method of claim 5,
Wherein the divalent metal ion is calcium ion (Ca ^&lt; ^{2 + &} gt ^; ).
The method according to claim 1,
elastic polymer-ceramic hybrid film exhibiting pH-dependent drug release.
(a) preparing a hybrid solution in which a biocompatible polymer containing a carboxyl group and a hydroxyl group and calcium phosphate are mixed at a weight ratio of 5: 1 to 1: 1;
(b) inducing an array of particles in the hybrid solution; And
(c) mixing the hybrid solution with a divalent metal ion solution. &lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;
9. The method of claim 8,
Wherein the biocompatible polymer is alginate. &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt;
10. The method of claim 9,
Wherein the hydroxyl group of the alginate is crosslinked with the calcium phosphate.
9. The method of claim 8,
Wherein the step (b) comprises screeding the hybrid solution on a support. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;
12. The method of claim 11,
Wherein the scribing speed is 5 cm 2 / s to 10 cm 2 / s.
9. The method of claim 8,
Wherein the concentration of the divalent metal ion solution is 0.05 M to 5 M. 2. The method for producing an elastic polymer-ceramic hybrid film according to claim 1,
10. The method of claim 9,
Wherein the carboxyl group of the alginate is crosslinked with the divalent metal ion.
15. The method of claim 14,
Wherein the divalent metal ion is calcium ion (Ca ^&lt; ^{2 + &} gt ^; ).

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