KR102062700B1 - Magnetic nanoparticles coated stent and preparation method thereof - Google Patents

Abstract

The present invention provides a surface modified stent substrate; And a coating layer comprising a coating agent and magnetic nanoparticles. The stent and a method of manufacturing the same, wherein the stent coated with the magnetic nanoparticles uniformly throughout the stent substrate exhibits an exothermic effect by an external magnetic field. Can be applied.

Description

MAGNETIC NANOPARTICLES COATED STENT AND PREPARATION METHOD THEREOF}

The present invention relates to a stent applicable to thermal treatment using an external magnetic field, and to a stent coated with magnetic nanoparticles uniformly over the surface-modified stent substrate and a method of manufacturing the same.

As medical technology advances, the average life expectancy of humans increases, and as the population of older people increases, vascular and non-vascular stenting procedures increase.

In general, the stent is mainly inserted into blood vessels or non-vessels in order to solve the narrowing problem in which blood vessels or non-vessels are blocked by blood clots or cancerous tissues. Inserted stents expand the internal diameter of the constriction to ensure patency, allowing blood, food or metabolism to flow.

Recently, studies have been actively conducted on the development of a functional stent for local treatment of cancer tissues and suppression of tissue hyperproliferation in addition to the basic functions of the stent fixed inside the human body.

Korean Unexamined Patent Publication No. 2016-0100057 (published Aug. 23, 2016) Korean Unexamined Patent Publication No. 2011-0123973 (published Nov. 16, 2011)

 BOCK, N. et al., ACTA BIOMATERIALIA (2010) Vol. 6, pp.786-796  KIM, S. et al., ADVANCED MATERIALS (2013) Vol. 25, pp.5863-5868

It is an object of the present invention to provide a stent and a method of manufacturing the same stably coated magnetic nanoparticles on a stent substrate.

In addition, the stent which is inserted into the narrowed blood vessels and non-vascular vessels and supports the inner wall to secure the patency of the stenosis, as well as the local heating effect by the external magnetic field as well as the original function of the stent and the method of manufacturing the same To provide.

One embodiment to achieve the above object,

Surface modified stent substrates; And

It provides a stent, comprising; a coating layer comprising a coating agent and magnetic nanoparticles.

In addition, one embodiment,

Surface modifying the stent substrate; And

It provides a stent manufacturing method comprising a; coating a coating agent and magnetic nanoparticles on the surface-modified stent substrate to form a coating layer.

According to the present invention, by using a surface modified stent substrate, the magnetic nanoparticles can be uniformly coated over the stent substrate.

In addition, the stent coated with the magnetic nanoparticles is exothermic by the external magnetic field and thus may be applied to magnetic thermal therapy.

Furthermore, the stent coated with the magnetic nanoparticles may be inserted into narrowed blood vessels and non-vascular vessels to support the inner wall to secure the patency of the constriction.

1 is a schematic diagram of a dopamine oxidation polymerization.
2 is a photograph showing the exothermic effect of the magnetic nanoparticles.
3 is a graph showing the exothermic effect of the concentration of the magnetic nanoparticles.
Figure 4 is a photograph showing the stent of the Comparative Example and Example of the present invention.

The present invention provides a surface modified stent substrate; And a coating layer comprising a coating agent and magnetic nanoparticles.

In one embodiment, a stent includes a surface modified stent substrate; And a coating layer comprising a coating agent and magnetic nanoparticles.

The stent substrate may be a stent substrate that is commonly used, and is not particularly limited.

According to one embodiment, the stent substrate may include a non-degradable polymer or biodegradable polymer.

Specifically, the stent substrate is a non-degradable polymer; Or polyglycolide, polylactide (PLLA), poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoate polyhydroxyalkanoates, polypropylene fumarate, polyortho esters, polyesters, other polyesters, polyanhydrides, polyphosphazenes, polyalkylcyanoacrylates, At least one member selected from the group consisting of poloxamers, polyamino L-tyrosine, modified polysaccharrides, oxidized cellulose, gelatin and collagen It may include a biodegradable polymer comprising.

For example, the stent substrate may include a biodegradable polymer, preferably polylactite (PLLA), but is not limited thereto.

When the stent substrate includes a biodegradable polymer, it may be suitable as a stent inserted into a blood vessel or a non-vascular vessel because it is harmless to the human body.

In addition, the stent substrate is characterized in that the surface modified with a catechol-based compound.

The catechol-based compound is a compound having a catechol group, and includes a catechol and derivatives thereof.

The catechol group refers to a group in which a hydroxyl group (-OH) is substituted at an ortho position of the benzene ring. For example, the catechol group may be 1,2-dihydroxybenzene group.

The catechol-based compound includes a catechol group, and the catechol group is bonded to the stent substrate.

In addition, the catechol-based compound may further include an amine group, but is not limited thereto.

For example, the catechol-based compound may include one or more selected from the group consisting of dopamine, norepinephrine, and dihydroxylphenylalanine, but is not limited thereto.

Specifically, the dihydroxylphenylalanine may be L-3,4-dihydroxylphenylalanine.

As another example, the catechol-based compound may include a compound represented by Formula 1, but is not limited thereto.

[Formula 1]

N in Chemical Formula 1 is an integer of 1 to 10. Specifically, n in Formula 1 may be an integer of 1 to 6, more specifically, an integer of 1 to 4, but is not limited thereto.

The catechol-based compound used for surface modification of the stent substrate may be present in a polymerized form by oxidative polymerization.

For example, when dopamine is used as the catechol-based compound, the surface modified stent substrate may include polydopamine by an oxidative polymerization reaction.

Refer to FIG. 1 for a detailed reaction schematic of the dopamine oxidation polymerization.

The catechol-based compound is bonded to the stent substrate, thereby allowing the coating agent and the magnetic nanoparticles to be uniformly and strongly coated on the stent substrate.

In addition, the catechol-based compound is bonded to the stent substrate in an aqueous solution rather than an organic solvent to the stent substrate, thereby reducing damage to the biodegradable stent.

The coating layer includes a coating agent and magnetic nanoparticles.

The coating layer may be coated on the surface modified stent substrate.

Since the coating agent is covalently bonded to the catechol-based compound and exhibits cationicity, the coating agent may induce coating of the anionic nanoparticles.

The coating agent may include an amine group or a thiol group.

Specifically, the coating agent chitosan, polyethylenimine, cysteamine, aminopropanethiol hydrochloride, (dimethylamino) ethanethiol hydrochloride (dimethylamino) ethanethiol hydrochloride and aminohexanethiol It is at least one selected from the group consisting of aminohexanethiol hydrochloride.

For example, the coating agent may include, but is not limited to, chitosan, a biocompatible natural material.

The unit mass ratio per stent of the coating agent is 0.2 to 0.8 mg / stent (mg). Specifically, the unit mass ratio per stent of the coating agent may be 0.3 to 0.7 mg / stent (mg). More specifically, the unit mass ratio per stent of the coating agent may be 0.43 to 0.57 mg / stent (mg), but is not limited thereto.

The unit mass ratio per stent of the coating agent means a content ratio of the coating agent per mg of the stent base.

When the content of the coating agent is in the above range, it is possible to coat uniform nanoparticles, and is advantageous in showing an excellent magnetic induction heating effect.

The magnetic nanoparticles may be present in a dispersed state in the coating agent. The magnetic nanoparticles are preferably coated evenly dispersed in the coating agent. As the magnetic nanoparticles are uniformly dispersed and coated on the coating agent, they exhibit high exothermic efficiency.

The magnetic nanoparticles are materials that exhibit an exothermic effect by an external magnetic field.

Specifically, the magnetic nanoparticles include an oxide of a metal, and the metal is lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), beryllium (Be), magnesium ( Mg), calcium (Ca), strontium (Sr), barium (Ba), radium (Ra), germanium (Ge), gallium (Ga), bismuth (Bi), indium (In), silicon (Si), germanium ( Ge), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), yttrium (Y), zirconium ( Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), rhodium (Rh), palladium (Pd), silver (Ag), cadmium (Cd), hafnium (Hf), tantalum (Ta), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), gold (Au) and mercury (Hg) may be one or more selected from the group consisting of, It is not limited. More specifically, the metal may be barium (Ba), zinc (Zn), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni) or permalloy (Ni / Fe alloy), but is not limited thereto. It doesn't happen.

For example, the magnetic nanoparticles may be iron oxide nanoparticles, but is not limited thereto.

The average diameter of the magnetic nanoparticles is 1 to 500 nm. Specifically, the average diameter of the magnetic nanoparticles is 10 to 200 nm. More specifically, the average diameter of the magnetic nanoparticles may be 10 to 100 nm, but is not limited thereto.

The magnetic nanoparticles may be porous magnetic nanoclusters, but are not limited thereto.

The unit mass ratio per stent of the magnetic nanoparticles is 0.18 to 14.56 mg / stent (mg). Specifically, the unit mass ratio per stent of the magnetic nanoparticles may be 5.4 to 7.28 mg / stent (mg), but is not limited thereto.

The unit mass ratio per stent of the magnetic nanoparticles means a content ratio of magnetic nanoparticles per mg of the stent base.

When the content of the magnetic nanoparticles is in the above range, applying an external magnetic field of 297 kHz intensity to the prepared stent for 2 to 20 minutes may increase the ambient temperature to 45 to 95 ℃.

When the content of the magnetic nanoparticles is in the above range, it is advantageous to exhibit a magnetic induction heating effect.

When the magnetic nanoparticles are subjected to an external high frequency magnetic field, Brownian relaxation due to the rotation of the nanoparticles themselves dispersed in the liquid, and Neil relaxation due to the energy barrier of the spin inside the nanoparticles Heat is generated by the magnetic hysteresis phenomenon caused by the movement of the spin domains in the material during the development and magnetization in the direction of the external high frequency magnetic field.

2 is a result showing the exothermic effect for each case before the magnetic field, the magnetic field is applied and the magnetic field is removed after the magnetic field around the magnetic nanoparticles.

2, it can be seen that heat is not generated before and after the magnetic field is applied, but only when the magnetic field is applied.

3 is a result showing the exothermic effect of the concentration of the magnetic nanoparticles.

Through the results of FIG. 3, the higher the concentration of the magnetic nanoparticles is, the more rapidly the temperature increases and the higher the temperature, so it can be seen that the exothermic efficiency is better.

In addition, when the external magnetic field is applied, the temperature is rapidly increased by the exothermic effect of the magnetic nanoparticles, and when the magnetic field is removed, the temperature is rapidly dropped within 7 minutes. Through this, it was confirmed that it is advantageous to exothermic effect exothermic effect by the required time in the target site by applying an external magnetic field.

The stent according to the present invention includes a catechol-based compound and a coating agent bound to the stent substrate, so that the magnetic nanoparticles may be uniformly coated.

The stent according to the present invention is inserted into narrowed blood vessels and non-vascular vessels to support the inner wall to prevent narrowing of blood vessels, and also exothermic by external magnetic fields, thereby changing necrosis and physiological function of surrounding tissues. It can be used to treat a variety of diseases including cancer, such as eradicating targeted tumors. In addition, since the thermal treatment is performed using an external magnetic field that is harmless to the human body during the thermal treatment, it is possible to minimize the fear of burns and destruction of normal tissue. In addition, the stent according to the present invention is physicochemically stable so that the coating can be stably maintained for a long time even when the stent is inserted into the body.

In one embodiment, the method of manufacturing the stent,

Surface modifying the stent substrate; And

And coating a coating agent and magnetic nanoparticles on the surface modified stent substrate to form a coating layer.

Surface modification of the stent substrate is a step of binding the catechol-based compound on the stent substrate using a solution containing the catechol-based compound.

The pH of the solution containing the catechol-based compound is 8.5 to 10.0.

When the pH of the solution containing the catechol-based compound is within the above range, the effect of the catechol-based compound is oxidized and uniformly coated on the stent substrate, for example, dopamine is oxidized to form a polymer of polydopamine on the stent substrate. It is advantageous to show the effect of uniform coating.

In the stent manufacturing method, forming the coating layer may form a coating layer on an aqueous solution.

By forming the coating layer on an aqueous solution rather than an organic solvent, damage to the biodegradable stent can be minimized.

In addition, the forming of the coating layer may include coating the coating agent on the surface modified stent substrate; And immediately after coating the coating agent, coating the magnetic nanoparticles.

By coating the magnetic nanoparticles immediately after coating the coating agent, the magnetic nanoparticles are advantageously dispersed evenly and improve adhesion.

In the stent manufacturing method described above, for the description of the stent base, the catechol-based compound, the coating agent, and the magnetic nanoparticles, refer to the description described in the stent.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  One. Polydopamine  Coated PLLA Stent  Chitosan and Magnetic Nanoparticles Coated on Substrate Stent

1.1. Magnetic Nanoparticles Manufacturing

2 g of NaOH (Sodium Hydroxide) and 20 ml of DEG (diethylene glycol) were added to the synthesizer, substituted with nitrogen to remove oxygen, and a reflux apparatus was installed, followed by stirring under reflux at 120 ° C for 1 hour. ) Solution was prepared.

In addition, 288 mg of poly acrylic acid (PAA), 64.7 mg of FeCl3 (Iron (III) chloride anhydrous), and 17 ml of DEG were added to the synthesizer, substituted with nitrogen to remove oxygen, and a reflux unit was installed at 220 ° C. (2) Solution was prepared by stirring under reflux for 30 minutes.

 2 ml (1) solution was added to 2 ml (2) solution, followed by further reflux stirring at 220 ° C for 1 hour. The solution stirred at reflux was cooled at room temperature. After washing the synthesis solution with ethanol and tertiary distilled water, magnetic nanoparticles were obtained using a centrifuge.

1.2. Chitosan Coating

0.5 g of chitosan was dissolved with 5 ml of hydrochloric acid (1N HCl), and then 45 ml of tertiary distilled water was further injected to completely dissolve chitosan. The pH of the aqueous solution was maintained at 5.0 to 5.5. 310 mg of N-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 295 mg of 3,4-Dihydroxyphenylacetic acid were dissolved in 25 ml of a solution of 50:50 distilled water and ethanol. Was added. The pH of the mixture was set to 4.5 and then stirred at room temperature for 12 hours. The solution was then separated using membrane (MWCO: 1,000 Da) for 1 day and lyophilized to finally obtain a chitosan coating.

1.3. Stent  Surface modification

15 mg of dopamine hydrochloride was mixed on a PLLA stent substrate in 15 ml of an aqueous solution of TRIS at pH 8.5, and the PLLA stent substrate was inserted into the mixture and stirred for 8 hours. After 8 hours, the stent substrate coated with the primary polydopamine was naturally dried, and then the secondary polydopamine coating was performed in the same manner to obtain a stent substrate surface-modified with polydopamine.

1.4. Coating layer formation

After the stent substrate surface-modified with polydopamine was washed with tertiary distilled water, 90 mg of lyophilized chitosan was dissolved in 3 ml of tertiary distilled water to coat the magnetic nanoparticles, and the first solution was first coated on the stent. Immediately after the first coating, the magnetic nanoparticles were coated using a solution of magnetic nanoparticles having a concentration of 200 g / l, and then dried at room temperature to finally obtain a stent having a coating layer including magnetic nanoparticles and chitosan.

Comparative example  One. PLLA Stent  Chitosan and Magnetic Nanoparticles Coated on Substrate Stent

The stent was manufactured in the same manner as in Example, except that the surface of the stent was modified.

Experimental Example  1. Uniformity of Coating

The stent pictures prepared in Example 1 and Comparative Example 1 are shown in FIG. 4, respectively.

As shown in FIG. 4, in the comparative example of the stent coated with chitosan and magnetic nanoparticles on a stent substrate not coated with polydopamine, the chitosan and magnetic nanoparticles were not uniformly coated and the adhesive strength was weak. The coating layer on the substrate was peeled off. In addition, in the case of the stent coated with chitosan and magnetic nanoparticles on the stent substrate coated with polydopamine, the chitosan and magnetic nanoparticles were uniformly coated, and it was confirmed that the peeling phenomenon did not appear due to improved adhesion.

Claims (19)

Stent substrates surface-modified with catechol-based compounds; And
And a coating layer comprising a coating agent including an amine group or a thiol group and magnetic nanoparticles for thermal treatment.
The magnetic nanoparticles include an oxide of a metal, and the metal is at least one selected from the group consisting of iron (Fe), magnesium (Mg), and zinc (Zn).
Stent.
delete The method of claim 1,
The stent substrate,
Non-degradable polymers; or
Polyglycolide, polylactide (PLLA), poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates ), Polypropylene fumarate, polyortho esters, polyesters, other polyesters, polyanhydrides, polyphosphazenes, polyalkylcyanoacrylates, and poloc Contains at least one member selected from the group consisting of poloxamers, polyamino L-tyrosine, modified polysaccharrides, oxidized cellulose, gelatin and collagen Comprising a biodegradable polymer;
Stent.
The method of claim 1,
The catechol-based compound includes a catechol group,
The catechol group is bonded to the stent substrate
Stent.
The method of claim 4, wherein
The catechol-based compound further comprises an amine group
Stent.
The method of claim 1,
The catechol-based compound includes at least one selected from the group consisting of dopamine, norepinephrine and dihydroxylphenylalanine.
Stent.
The method of claim 1,
The coating agent is chitosan, polyethylenimine, cysteamine, aminopropanethiol hydrochloride, (dimethylamino) ethanethiol hydrochloride and aminohexanethiol hydrochloride ( aminohexanethiol hydrochloride) at least one member selected from the group consisting of
Stent.
delete The method of claim 1,
The average diameter of the magnetic nanoparticles is 1 to 500 nm
Stent.
The method of claim 1,
The magnetic nanoparticles are porous magnetic nanoclusters
Stent.
Surface modifying the stent substrate with a catechol based compound; And
And coating a coating agent including an amine group or a thiol group and magnetic nanoparticles for thermal treatment on the surface modified stent substrate to form a coating layer.
The magnetic nanoparticles include an oxide of a metal, and the metal is at least one selected from the group consisting of iron (Fe), magnesium (Mg), and zinc (Zn).
Stent manufacturing method.
The method of claim 11,
Surface modification of the stent substrate is a step of binding the catechol-based compound on the stent substrate using a solution containing a catechol-based compound
Stent manufacturing method.
The method of claim 12,
PH of the solution containing the catechol-based compound is 8.0 to 10.0
Stent manufacturing method.
The method of claim 11,
Forming the coating layer,
Coating the coating on the surface modified stent substrate; And
Immediately after coating the coating agent, coating the magnetic nanoparticles; comprising
Stent manufacturing method.
delete The method of claim 11,
The average diameter of the magnetic nanoparticles is 1 to 500 nm
Stent manufacturing method.
The method of claim 11,
The magnetic nanoparticles are porous magnetic nanoclusters
Stent manufacturing method.

The method of claim 1,
Unit mass ratio per stent of the magnetic nanoparticles is 0.18 to 14.56 mg / stent (mg),
Stent.
The method of claim 11,
Unit mass ratio per stent of the magnetic nanoparticles is 0.18 to 14.56 mg / stent (mg),
Stent manufacturing method.

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