KR20210068245A - Implant coated with polyphenol-based metal-organic framework - Google Patents

Abstract

One embodiment of the present invention provides an implant comprising: an implant base material; and a functional coating layer provided on the implant base material and comprising a polyphenol-based metal-organic structure. With the implant, therapeutic effects can be improved as polyphenol and metal ions are released together while controlling the release of drug supported on the polyphenol-based metal-organic structure.

Description

Implant coated with polyphenol-based metal-organic framework

The present invention relates to implants coated with polyphenolic metal-organic structures.

A porous metal-organic framework (MOF) can be defined as a porous organic-inorganic polymer compound formed by combining a central metal ion with an organic ligand. It means a crystalline compound having a pore structure. The porous metal-organic structure is used without much distinction between porous organic-inorganic hybrid materials and porous coordination polymers in a broader sense, and a lot of research has been done recently.

Since such a porous metal-organic structure contains organic components in addition to inorganic materials, although thermal stability is weaker than that of inorganic materials, it has structural stability and high specific surface area and thus has various application possibilities. In particular, the porous metal-organic structure has been actively applied to gas-adsorption and catalysts.

An implant is a medical device for implantation that is implanted in a living body and exhibits a desired function, and there are subperiosteal implants, penetrating bone implants, and intraosseous implants. Implants should be manufactured using bio-friendly and stable materials to have no side effects and not to induce chemical and biochemical reactions. Bone bonding strength should be high. For this reason, pure titanium is mainly used for implants, but titanium alloys with superior strength are used in orthopedic fields such as artificial joints.

That is, it is known that titanium and titanium alloys have excellent biocompatibility and exhibit good biocompatibility with surrounding tissues, are chemically and biochemically stable, and have almost no toxicity to the living body. The biocompatibility of titanium is due to the stable passivation film, and it is reported that the interface between the passivation film and the living body is important for osseointegration, and titanium and titanium alloy are known as the most suitable material for implants having a large area.

Cell adhesion, proliferation, and differentiation are important processes for the fixation of the bone and implant interface, and since this process is the key to the success of the implant procedure, the implant surface characteristics are very important. For the above reasons, various types of surface treatment methods are being researched and developed, and a considerable number of methods have already been put into practical use, such as coating gold nanoparticles, hydroxyapatite (HAP), etc. on the implant surface or plasma treatment.

On the other hand, if an infection occurs around an implant placed in the body, it is very difficult to treat, and surgery such as removing an artificial joint and inserting bone cement containing antibiotics or long-term administration of antibiotics is a great burden for the patient. becomes this In addition, complications such as pneumonia and urinary tract infection occur, and in severe cases, death. Accordingly, there is an increasing demand for implants capable of releasing drugs such as antibiotics, but the development thereof is insufficient.

Korean Patent Publication No. 10-2019-0042182

One object of the present invention is to provide an implant coated with a polyphenol-based metal-organic structure capable of controlling the release of a drug, thereby controlling the release of a drug supported on the polyphenol-based metal-organic structure and at the same time polyphenol and metal ions It is to improve the therapeutic effect by being released together.

The technical problems to be achieved by the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned can be clearly understood by those of ordinary skill in the art to which the present invention belongs from the description below. There will be.

The present inventors have found that the drug and polyphenol release control ability of the implant is improved by coating the polyphenol-based metal-organic structure on the porous titanium implant, and completed the present invention.

One aspect of the present invention is an implant base material; And provided on the implant base material, polyphenol-based metal-functional coating layer comprising an organic structure and a drug; provides an implant comprising a.

According to an embodiment of the present invention, the implant base material may be a porous material.

According to an embodiment of the present invention, the implant base material may include any one of titanium, magnesium, iron, aluminum, copper, and alloys thereof.

According to an embodiment of the present invention, the polyphenol-based metal-organic structure may include a polyphenol-based organic ligand and a metal ion coordinated to the ligand.

According to an embodiment of the present invention, the polyphenol-based organic ligand is gallic acid, ferulic acid, ellagic acid, vanillic acid, syringic acid, It may be at least one selected from the group consisting of p-coumaric acid, caffeic acid, sinapinic acid, tannic acid, and curcumin.

According to an embodiment of the present invention, the metal ions are Zn ²⁺ , Mg ²⁺ , Ca ²⁺ , Fe ³⁺ , Ti ⁴⁺ and Mn ²⁺ may be at least one selected from the group consisting of.

According to an embodiment of the present invention, the polyphenol-based metal-organic structure may contain 0.1 to 2.0 moles of metal ions with respect to 1 mole of the polyphenol-based organic ligand.

According to an embodiment of the present invention, the average pore size of the polyphenol-based metal-organic structure may be 5 Å to 50 Å.

According to an embodiment of the present invention, the functional coating layer may further include a drug contained in the pores of the polyphenol-based metal-organic structure.

According to an embodiment of the present invention, the drug may be included in an amount of 10 to 70 parts by weight based on 100 parts by weight of the polyphenol-based metal-organic structure.

Another aspect of the present invention comprises the steps of alternately precipitating the implant base material in a first polyphenol-based organic ligand solution and a first metal ion solution to obtain a seed-coated implant base material; and precipitating the seed-coated implant base material in a mixed solution of a second polyphenol-based organic ligand solution and a second metal ion solution to obtain a metal-organic structure-coated implant; It provides a method of manufacturing an implant comprising a.

According to an embodiment of the present invention, the metal-organic structure may further include the step of impregnating in a solution containing a coated implant drug.

Another aspect of the present invention provides a metal-organic structure-coated implant prepared by the above method.

The implant including a functional coating layer including a polyphenol-based metal-organic structure according to an embodiment of the present invention can effectively control the initial mass release of the drug by supporting the drug in the pores of the metal-organic structure. In addition, in the implant according to an embodiment of the present invention, the polyphenol-based organic ligand acts as an additional drug, and a synergistic effect can be realized with the drug contained in the pore.

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

1 shows a schematic diagram of a manufacturing process of an implant including an implant base material and a functional coating layer according to an embodiment of the present invention.
Figure 2 shows an SEM image confirming the surface structure of the implant according to an embodiment of the present invention.
Figure 3 shows the drug release test results in the implant according to the embodiment of the present invention.

Hereinafter, the present invention will be described with reference to the accompanying drawings. However, the present invention may be embodied in several different forms, and thus is not limited to the embodiments described herein.

The terms used herein are used only to describe specific embodiments, and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise. In this specification, terms such as "comprises" or "have" are intended to designate that the features, numbers, steps, operations, components, parts, or combinations thereof described in the specification exist unless otherwise stated. However, it is to be understood that this does not preclude the possibility of the presence or addition of one or more other features or numbers, steps, operations, components, parts, or combinations thereof.

One aspect of the present invention is an implant base material; And provided on the implant base material, polyphenol-based metal-functional coating layer comprising an organic structure; provides an implant comprising a.

The implant includes an implant base material and a functional coating layer provided on the implant base material.

The implant base material may be a porous material, and when the porosity of the implant base material is low, the specific surface area is too small and the drug loading amount is not sufficient, and thus there may be a problem in which the drug effect does not appear or only a temporary effect appears.

The implant base material may include any one of titanium, magnesium, iron, aluminum, copper, and alloys thereof. Preferably, the implant base material may be porous titanium or a titanium alloy.

The functional coating layer is provided on the implant base material, and may include a polyphenol-based metal-organic structure. Furthermore, the functional coating layer may further include a drug supported in the pores of the polyphenol-based metal-organic structure.

The polyphenol-based metal-organic structure may include a polyphenol-based organic ligand and a metal ion coordinated to the ligand. The metal-organic structure is an organic/inorganic high molecular compound in which a polyphenol-based organic ligand forms a crystalline structure by forming a coordination bond with a metal ion, and has a regular and connected pore structure at the molecular level and a high specific surface area. The structure can effectively suppress the initial mass release, and the regular and connected pore structure enables stable and predictable release of functional substances. In addition, the high specific surface area can increase the content of the functional material to prolong the release time.

The metal-organic structure may have an average pore size of 5 Å to 50 Å, for example, 10 Å to 40 Å, for example, 15 Å to 35 Å. The pore size in the above range corresponds to the size of a general drug molecule, and accordingly, the functional material can be impregnated in a tight state in the pores, and can be effectively released to the action target. The average pore size of the metal-organic structure may be measured by measuring the nitrogen adsorption/desorption isotherm of the porous metal-organic structure, and applying the BJH model thereto.

The specific surface area of the metal-organic structure is 100 m ² /g to 1,500 m ² /g, for example, 100 m ² /g to 1,000 m ² /g, for example, 150 m ² /g to 700 m ² It can be /g. Due to the high specific surface area in the above range, it is possible to effectively release the functional substance to the target for a long time. The specific surface area of the metal-organic structure may be measured by measuring the nitrogen adsorption/desorption isotherm of the metal-organic structure, and applying the BET equation thereto.

The metal-organic ligand constituting the organic structure is composed of a polyphenol-based component. The polyphenol is a kind of chemical substance found in plants, and refers to a compound in which one or more hydrogen atoms of benzene in a molecule are substituted with a hydroxyl group. A carboxyl group and a hydroxyl group additionally present in the organic ligand can easily form a coordination bond with a metal ion to be described later, thereby forming a porous metal-organic structure having regular pores.

The polyphenol has an antioxidant effect that converts harmful oxygen in the body into harmless substances, which helps to prevent aging, protects DNA, cellular proteins, enzymes, etc. to lower the risk of various diseases, and has anticancer action and heart disease can prevent Accordingly, in addition to the drug, the polyphenol-based component itself can implement a therapeutic effect based on antibacterial properties, etc., which can be realized by effectively releasing the structure together with the drug when applied to the target site (when dissolved in body fluid).

The polyphenol-based organic ligand is derived from a phenol-based component, for example, gallic acid, ferulic acid, ellagic acid, vanillic acid, syringic acid acid), p-coumaric acid, caffeic acid, sinapinic acid, tannic acid, and curcumin may be at least one selected from the group consisting of.

The metal-metal ion constituting the organic structure is a component that forms a structure by forming a coordination bond with the polyphenol-based organic ligand. The metal ion is not particularly limited as long as it is a component easily coordinated, but is preferably harmless to the human body, and a component capable of enhancing the desired therapeutic effect by implementing a synergistic effect with a functional material and/or polyphenol-based component can be

As the metal ion, Zn ²⁺ , Mg ²⁺ , Ca ²⁺ , Fe ³⁺ , Ti ⁴⁺ and Mn ²⁺ may be at least one selected from the group consisting of. At this time, the release of metal ions such as calcium can exert the effect of promoting the formation of bone tissue into the porous implant base material, and when used simultaneously with a drug such as a bone formation promoter, it can promote healing and recovery.

The metal-organic structure may include 0.1 mol to 2.0 mol, for example, 0.3 mol to 1.5 mol, for example, 0.5 mol to 1.0 mol of the metal ion with respect to 1 mol of the polyphenol-based organic ligand. When included in the above range, it is possible to significantly improve the stability of the structure by implementing the desired molecular level regular and connected pores and specific surface area. In addition, when included in the molar ratio, the functional material can be effectively impregnated inside the structure, so that it is suitable for controlling the release rate. On the other hand, when the amount of the metal ion is less than 0.1 mol, the metal ion and the phenol-based organic ligand do not react, and thus a metal-organic structure may not be formed. There may be a problem in that the functional material cannot be impregnated by forming a crystalline metal salt without any pores without forming a porous structure.

The metal-organic structure may have porosity, and a drug may be included in the pores formed inside the structure.

The drug includes a functional material that implements a therapeutic effect together with the metal-organic structure. The functional material may be contained in the pores of the porous metal-organic structure, and is not easily released in the metal-organic structure by the pore structure connected with the small pore size at the molecular level and maintains stability, and thus the initial release rate is rapidly increased It does not increase rapidly and can be released at an appropriate rate for a long time. In particular, the regular and connected pore structure enables stable and predictable release, and changes in pore size and structure can affect the diffusion of functional materials to control the release rate. Furthermore, the polyphenol-based component, which is an organic ligand, is released together with the release of the drug, thereby remarkably improving the therapeutic effect, for example, the anti-inflammatory effect.

The drug may be appropriately selected depending on the field of application, for example, arthritis drug, hormone, bone metabolism agent, immunosuppressant, angiogenesis inhibitor, vitamin agent, protein or peptide drug, anticancer agent, analgesic, anti-inflammatory agent, anti-ulcer agent and antidiabetic agents, but is not limited thereto. In addition, these may be used alone or in combination.

The drug may be included in an amount of 10 parts by weight to 70 parts by weight, for example, 20 parts by weight to 50 parts by weight, based on 100 parts by weight of the metal-organic structure. When included in the above content, the drug can be effectively impregnated inside the structure, so that it is suitable for suppressing the initial mass release and controlling the release rate, and a sufficient therapeutic effect can be realized. On the other hand, when the amount of the drug is less than 10 parts by weight, the release rate is too low to realize the desired therapeutic effect, and when it exceeds 70 parts by weight, there may be a problem that the initial mass release is slightly increased.

In the implant according to an embodiment of the present invention, the implant base material such as titanium, which has relatively excellent mechanical properties, serves as a skeleton, and the polyphenol-based metal-organic structure is coated only on the wall surface of the implant base material, so the mechanical strength and modulus of elasticity change. It is possible to provide an implant with improved drug release control and therapeutic performance without the need for treatment.

Another aspect of the present invention provides a method for manufacturing an implant. Another aspect of the present invention provides a metal-organic structure-coated implant prepared by the above method.

According to an embodiment of the present invention, a method for manufacturing an implant comprises the steps of seed coating an implant base material, and growing a metal-organic structure on the seed coating to obtain an implant coated with a metal-organic structure. (Fig. 1).

The step of seed coating the implant base material is by a layer-by-layer (LBL) coating method, specifically, seed coating by alternately precipitating the implant base material in a first polyphenol-based organic ligand solution and a first metal ion solution. It can be carried out by obtaining an implanted base material. The step of alternately precipitating the implant base material in the first polyphenol-based organic ligand solution and the first metal ion solution may be repeated 5 or more times, for example, 5 to 20 times, for example, 10 times. can

The step of growing the metal-organic structure on the seed coating to obtain the metal-organic structure-coated implant is by a solvothermal reaction, specifically, the second polyphenol-based organic ligand solution and the second metal. It can be carried out by precipitating the seed-coated implant base material in a mixed solution of an ionic solution to obtain a metal-organic structure-coated implant.

The method of manufacturing the implant may further include impregnating the metal-organic structure in a solution containing a coated implant drug. Through this, the drug may be supported in the pores of the metal-organic structure.

Example

Example 1. Metal-organic structure coating on porous titanium surface (seed growth method)

1.1. Metal-Organic Structure Seed Coating: Layer-by-layer (LBL) coating

After dissolving 10 mmol of ferulic acid in 50 ml of ethanol to prepare a first solution, a porous titanium implant base material was precipitated in the first solution for 1 hour, coated with ferulic acid, and washed with an ethanol solution. On the other hand, a second solution was prepared by dissolving 10 mmol of zinc nitrate in 50 ml of N,N-dimethylformamide (DMF), and a porous titanium implant base material coated with ferulic acid was added to the second solution 1 After precipitation for an hour, it was taken out and washed with DMF.

The above steps were repeated 9 more times to obtain a porous titanium implant base material coated with a seed.

1.2. Growth of metal-organic structures: solvothermal reaction

2 mmol of ferulic acid was dissolved in 30 ml of ethanol to prepare a third solution, and 2 mmol of zinc nitrate was dissolved in 30 ml of DMF to prepare a fourth solution. After slowly mixing the third solution with the fourth solution to make a mixed solution, and putting the mixed solution in a stirring autoclave, the porous titanium implant base material with the seed coating obtained in Example 1.1. The reaction was carried out for 24 hours. After the reaction was completed, the metal-organic structure-coated porous titanium implant was washed with a DMF solution and then dried at 90° C. and vacuum conditions.

The surface structure of the porous titanium implant coated with the metal-organic structure was confirmed through the SEM image (FIG. 2). As a result of observation, the porous titanium implant coated with the metal-organic structure was coated with a zinc-ferulate structure (Zn-ferulate) with a thickness of about 5 μm, and the microstructure formed a structure in which the nanorods were irregularly stacked. Confirmed. On the other hand, it was confirmed that the compressive strength (184 MPa → 184 MPa) and elastic modulus (5.2 GPa → 5.0 GPa) of the porous titanium implant coated with the metal-organic structure hardly changed before and after coating.

Example 2. Impregnation of Hydrophobic Drugs into Porous Titanium Implants

A fifth solution was prepared by dissolving 0.1 g of a hydrophobic drug ibuprofen (IBU) in 50 ml of hexane. In the fifth solution, the metal-organic structure-coated porous titanium implant obtained in Example 1 was precipitated, and dried at room temperature using a rotary vacuum evaporator. The porous titanium implant impregnated with ibuprofen was washed with water and then dried in an oven at 50° C. for 1 hour.

Example 3. Impregnation of Hydrophilic Drugs into Porous Titanium Implants

A sixth solution was prepared by dissolving 0.1 g of hydrophilic drug diclofenac sodium (DS) in 50 ml of distilled water. In the sixth solution, the metal-organic structure-coated porous titanium implant obtained in Example 1 was precipitated, and dried at room temperature using a rotary vacuum evaporator. The porous titanium implant impregnated with diclofenac sodium was washed with water and then dried in an oven at 50° C. for 1 hour.

Experimental Example 1. Confirmation of release behavior of drugs, etc.

The drug-impregnated porous titanium implants obtained in Examples 2 and 3 were precipitated in 1 L distilled water, and then stirred at a speed of 170 rpm using a shaker. Over time, the solution was collected and subjected to UV-vis. and Raman spectrometer to measure the concentrations of ibuprofen, diclofenac sodium and ferulic acid.

As a result of the experiment, it was confirmed that when the porous titanium implant of Example 2 was used, the hydrophobic drug ibuprofen as well as ferulic acid, a polyphenol-based component, were released at a constant rate (FIG. 3(a)). In addition, even when the porous titanium implant of Example 3 was used, it was confirmed that not only diclofenac sodium, a hydrophilic drug, but also ferulic acid were released at a constant rate (FIG. 3 (a)). Also, in both cases, it was confirmed that the drug was released at a constant rate without the initial mass release of the drug.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.

Claims (13)

implant base material; and
a functional coating layer provided on the implant base material and comprising a polyphenol-based metal-organic structure;
An implant comprising a. According to claim 1,
The implant base material is an implant, characterized in that the porous material. According to claim 1,
The implant base material is an implant comprising any one of titanium, magnesium, iron, aluminum, copper, and alloys thereof. According to claim 1,
The polyphenol-based metal-organic structure is an implant comprising a polyphenol-based organic ligand and a metal ion coordinated to the ligand. 5. The method of claim 4,
The polyphenol-based organic ligand is gallic acid, ferulic acid, ellagic acid, vanillic acid, syringic acid, p-coumaric acid ), caffeic acid (caffeic acid), sinapinic acid (sinapinic acid), tannic acid (tannic acid) and curcumin (curcumin), characterized in that at least one selected from the group consisting of implants. . 5. The method of claim 4,
The metal ions are Zn ²⁺ , Mg ²⁺ , Ca ²⁺ , Fe ³⁺ , Ti ⁴⁺ and Mn ²⁺ Implant, characterized in that at least one selected from the group consisting of. 5. The method of claim 4,
The polyphenol-based metal-organic structure is implanted, characterized in that it contains 0.1 to 2.0 moles of metal ions with respect to 1 mole of the polyphenol-based organic ligand. According to claim 1,
The polyphenol-based metal-organic structure has an average pore size of 5 Å to 50 Å. According to claim 1,
The functional coating layer is an implant, characterized in that it further comprises a drug contained in the pores of the polyphenol-based metal-organic structure. 10. The method of claim 9,
The drug is based on 100 parts by weight of the polyphenol-based metal-organic structure, implant, characterized in that included in 10 to 70 parts by weight. obtaining a seed-coated implant base material by alternately precipitating the implant base material in a first polyphenol-based organic ligand solution and a first metal ion solution; and
precipitating the seed-coated implant base material in a mixed solution of a second polyphenol-based organic ligand solution and a second metal ion solution to obtain a metal-organic structure-coated implant;
A method of manufacturing an implant comprising a. 12. The method of claim 11,
Impregnating the metal-organic structure in a solution containing the coated implant drug
Method of manufacturing an implant, characterized in that it further comprises. An implant coated with a metal-organic structure produced by the method of claim 11 or 12.

Images