KR20040006935A - Preparation of biocompatable film using chitosan and hydroxyapatite - Google Patents

Abstract

PURPOSE: A method for making a biocompatible film using chitosan and hydroxyapatite is provided to obtain a biocompatible film having excellent transparency, physical properties, biocompatibility and anti-bacterial property. CONSTITUTION: The method for making a biocompatible film comprises the steps of: (a) forming a chitosan complex that contains nanoparticles of hydroxyapatite; (b) adding a polycarboxylic acid to the complex obtained from the step (a); and molding hydroxyapatite nanoparticles-containing chitosan film from the mixture obtained from the step (b). If desired, the method further comprises the step of treating the film obtained from the step (c) with an acetic anhydride-containing lower alcohol to provide a hydroxyapatite nanoparticles-containing chitin film.

Description

Preparation method of biocompatible film using chitosan and apatite hydroxide {Preparation of biocompatable film using chitosan and hydroxyapatite}

The present invention relates to a method for producing a film having excellent biocompatibility, antimicrobial activity, transparency, etc. using apatite hydroxide and chitosan.

Apatite hydroxide is a calcium phosphate-based ceramic, and has been used as a bone substitute in orthopedics and dentistry because of its excellent bone conductivity, bioactivity, biocompatibility, protein adsorption, and antibacterial activity as a main component of human bone. However, the hydroxide apatite is too hard and brittle, difficult to form, and has a problem of easily falling away from the implanted portion.

Chitosan can be obtained by deacetylating chitin obtained from the shells of shellfish inhabiting the ocean, and its production is 100 billion tons of infinite biological resources per year. It is a natural polymer that is harmless to human body. It is antibacterial, antifungal, biodegradable, It has many functions such as biocompatibility, coagulation, and heavy metal adsorption, and chitosan is mainly used as a heavy metal adsorbent because one amino group and two hydroxy groups exist per glucosamine pyranose ring.

Therefore, interest in the development of the apatite hydroxide / chitosan composite material that can compensate for the transparency and physical disadvantages of the apatite is expected to be used as a medical film, coating material.

Conventional methods for preparing chitosan composites containing calcium hydroxide, phosphoric acid, chitosan, acetic acid, and the like containing apatite hydroxide nanoparticles, but the ratio of apatite hydroxide and chitosan determined at the manufacturing stage cannot be changed. When the acetic acid was added to the chitosan composite containing the apatite hydroxide nanoparticles prepared as described above, and dried again to prepare a film, the apatite hydroxide particles were not evenly dispersed on the surface of the film and were aggregated to provide transparency. Due to the deterioration and the deterioration of physical properties such as tensile strength, it was not possible to use it as a medical film or coating material.

Therefore, the present invention is to provide a method for producing a bio-compatible film using chitosan and hydroxide apatite that can solve all the problems of the prior art as described above.

In order to solve the above problems, the present inventors prepare a chitosan solution by dissolving chitosan in an acetic acid solution and mixing the chitosan solution with a phosphoric acid solution, and then dropping the mixture into a calcium hydroxide (Ca (OH) ₂ ) suspension and stirring to apatite nanoparticles. A chitosan composite containing particles was prepared, and the chitosan composite containing the apatite hydroxide nanoparticles was dried and dissolved in an aqueous polycarboxylic acid solution.

The polycarboxylic acid added to the chitosan complex containing the apatite hydroxide nanoparticles as described above is ionized on the chitosan complex, and the carboxyl group can form an ionic bond with the ionized amino group of chitosan, and at the same time phosphate to calcium ions on the surface of the apatite hydroxide Ion exchange of carboxylic acid ions with higher affinity than ions occurs, resulting in a monodentate and two forms in which one carboxyl group of polycarboxylic acid ions forms a relatively weak bond with one calcium seat of apatite hydroxide The carboxyl group combines with two calcium seats in a bidentate manner to form a strong chelate to prevent crystal growth of the hydroxyapatite hydroxide nanoparticles on the chitosan support, thereby maintaining an even dispersion of the nanoparticles. The present invention was completed by knowing that a biocompatible film using chitosan and apatite hydroxide having excellent transparency, antimicrobial properties, biocompatibility, and physical properties can be prepared.

FIG. 1 is an image micrograph of apatite hydroxide nanoparticle-containing chitosan film prepared by adding citric acid.

FIG. 2 is a diagram showing an x-ray diffraction curve of an apatite hydroxide nanoparticle-containing chitosan film.

FIG. 3 is a transmission electron microscope photograph of an apatite hydroxide nanoparticle-containing chitosan film prepared by adding citric acid. FIG.

FIG. 4 is an associative microscope photograph of an apatite hydroxide nanoparticle-containing chitosan film prepared without adding citric acid.

FIG. 5 is a diagram showing an x-ray diffraction curve of a chitosan film containing no apatite hydroxide.

Therefore, according to the present invention, in the method for producing a biocompatible film using apatite hydroxide and chitosan, (a) preparing a chitosan composite containing apatite hydroxide nanoparticles, (b) a poly to the composite obtained in step a There is provided a process for producing a biocompatible film comprising the step of adding a carboxylic acid, and (c) molding the apatite hydroxide nanoparticle-containing chitosan film with the mixture obtained in step b.

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

The biocompatible film prepared by the method of preparing a biocompatible film using chitosan and apatite hydroxide is mainly composed of apatite hydroxide (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ) nanoparticles and chitosan. As a preferable method of manufacturing an affinity film, it is as follows.

After dissolving the chitosan in acetic acid solution thereby preparing a chitosan solution, and added dropwise to the thus obtained chitosan / acid mixture solution to the chitosan solution is to mix with the phosphoric acid solution to calcium hydroxide (Ca (OH) ₂₎ suspension to the phosphoric acid and calcium hydroxide reaction hydroxide apatite Is synthesized. The chitosan composite containing the finally obtained apatite hydroxide nanoparticles was stirred and aged, filtered, and washed several times and concentrated. The weight ratio of apatite hydroxide and chitosan can be adjusted by mixing a chitosan solution in which only chitosan is dissolved in acetic acid solution without drying the chitosan complex containing the apatite hydroxide nanoparticles. When the chitosan composite containing the apatite hydroxide nanoparticles prepared by the above method is dried, a very hard molded product can be obtained, but the chitosan present in the dried mixture is not dissolved in an acetic acid aqueous solution, and thus it is impossible to produce a film. Do.

In the present invention, polycarboxylic acid is added to the apatite hydroxide nanoparticle-containing chitosan composite prepared as described above with respect to the weight of the apatite hydroxide and dried to prepare a hydroxideite apatite nanoparticle-containing chitosan film, wherein the polycarboxylic acid is citric acid and butanetetra. Carboxylic acid, malic acid, etc. can be used. In addition, if the chitosan composite containing the apatite hydroxide nanoparticles are lyophilized in a slurry state without drying in a general manner, it can be prepared in a fine powder form so that it is more easily dissolved in the aqueous polycarboxylic acid solution to facilitate the manufacturing process of the film. And the transparency and physical properties of the film to be produced is excellent. In addition, a chitosan composite containing apatite hydroxide nanoparticles is prepared by dissolving chitosan in acetic acid solution and mixing the phosphoric acid solution without dropping the chitosan composite containing apatite hydroxide nanoparticles, and then dropping the mixture into calcium hydroxide. Can be.

The added polycarboxylic acid is ionized on the chitosan complex containing apatite hydroxide nanoparticles. In the aqueous solution of the complex, the carboxyl group may form an ionic bond with the ionized amino group of chitosan, and at the same time, ion exchange of carboxylic acid ions having a higher affinity than phosphate ions occurs for calcium ions on the surface of the apatite hydroxide. Monodentate method, in which one carboxyl group of polycarboxylic acid ions forms a relatively weak bond with one calcium seat of apatite hydroxide, or bidentate, in which two carboxyl groups form two calcium seats and a strong chelate. By binding in at least one of the bidentate method to maintain the evenly dispersed state by preventing the crystal growth of the hydroxyapatite hydroxide nanoparticles on the chitosan support.

In addition, the apatite hydroxide nanoparticles-containing chitosan film prepared above may be treated with a lower alcohol containing acetic anhydride to prepare apatite hydroxide nanoparticles-containing chitin film. As the lower alcohol, methanol, ethanol, propanol, or the like can be used. [0038] The lower alcohol containing anhydrous acetic acid can be treated with the apatite hydroxide nanoparticle-containing film to acetylate the amino group of chitosan, thereby allowing the transformation into chitin.

Hereinafter, the present invention will be described in detail through Examples and Comparative Examples to be described below, but the present invention is not limited to the following Examples.

Example 1

2.5 g of chitosan, 1.5 g of acetic acid, and 5.9 g of phosphoric acid were dissolved in 200 ml of water to prepare a mixture, and the mixture was added dropwise to 7.4 g of calcium hydroxide suspension, at which time the pH was 9 ± 0.2 at high speed. Until the reaction temperature is continuously stirred for 24 hours at 25 ℃ to prepare a chitosan composite containing a weight ratio of 80:20 apatite hydroxide nanoparticles, washed with distilled water and then lyophilized to prepare a powder do. 5 g of the prepared powder and 12.3 g of chitosan were dissolved in 650 ml of water containing 6 g of acetic acid to prepare a composite aqueous solution containing nanoparticles in which apatite hydroxide and chitosan were uniformly mixed in a weight ratio of 30:70. 30 parts by weight of citric acid was added to the weight of the contained apatite, poured into a petri dish and dried at 30 ° C. for 24 hours to prepare a film. 5% sodium hydroxide (NaOH) was used to neutralize and remove acetic acid and citric acid contained in the film. The solution was washed with water, and then dried (30 ° C, 24 h). The prepared film was observed in an image microscope and shown in FIG. 1, and measured by X-ray (x-ray) and shown in FIG. 2. In addition, it is shown in Figure 3 by measuring with a transmission electron microscope.

Comparative Example 1

Except that citric acid is not added during film production, the same procedure as in Example 1 was carried out using an image microscope to show in FIG. 4.

Comparative Example 2

A chitosan composite containing 2 parts by weight of acetic acid and 2 parts by weight of chitosan was prepared, poured into a petri dish, dried at 30 ° C. for 24 hours to prepare a film, and to neutralize and remove acetic acid contained in the film. After washing with 5% sodium hydroxide (NaOH) solution, a water-washed dry chitosan film was prepared. The prepared film was measured by x-ray (x-ray) and is shown in FIG. 5.

* The photograph of FIG. 1 shows the shape of the film in which the apatite hydroxide particles are not seen when citric acid is added, but when the citric acid is not added, the apatite hydroxide nanoparticles are aggregated. In Fig. 2, the apatite hydroxide nanoparticle-containing film shows a typical X-ray diffraction curve of apatite hydroxide, unlike a chitosan film containing no apatite hydroxide in Fig. 5. In FIG. 3, it can be seen that the apatite hydroxide nanoparticle-containing film prepared by adding citric acid includes apatite hydroxide particles having a width of 15 to 20 nm and a length of 100 to 150 nm, and the size is 380 to 780 nm, which is a wavelength range of visible light. As it is much smaller, it is possible to produce transparent films.

As described above, when the film is prepared by treating the chitosan composite containing the apatite hydroxide nanoparticles of the present invention with polycarboxylic acid, the nanoparticles having a smaller size than the wavelength range of visible light are prevented by preventing agglomeration of the apatite hydroxide nanoparticles. By uniformly providing a biocompatible film using a transparent chitosan and apatite hydroxide having excellent physical properties, biocompatibility and antibacterial properties, which is a useful invention that can be widely used in the field of medical films and coating materials.

Claims (4)

A method of producing a biocompatible film using apatite hydroxide and chitosan, the method comprising the steps of: (a) preparing a chitosan composite containing apatite hydroxide nanoparticles, (b) adding polycarboxylic acid to the composite obtained in step a, and (c) A step of molding the apatite hydroxide nanoparticle-containing chitosan film from the mixture obtained in step b. The method of claim 1, further comprising a step of lyophilizing the chitosan composite containing the apatite hydroxide nanoparticles and then adding polycarboxylic acid. The process of claim 1, further comprising the step of treating the apatite hydroxide nanoparticle-containing chitosan film obtained in step (c) with anhydrous acetic acid-containing lower alcohol to prepare the apatite hydroxide nanoparticle-containing chitin film. Method of producing a biocompatible film. 2. The biocompatible film according to claim 1, comprising the step of dissolving chitosan in acetic acid solution, mixing with phosphoric acid solution, and then dropping the mixture into calcium hydroxide to produce a chitosan composite containing apatite hydroxide nanoparticles. Manufacturing method.