KR20190118185A - Antithrombotic or antimicrobial polymer compounds, methods of preparing the same, and medical materials comprising the same - Google Patents

Abstract

According to one aspect, a polymer compound, a chemical additive composition comprising the same, a medical material including the same, and a method of manufacturing the same are provided. According to this, it can be used to manufacture a medical substance which has antithrombotic or antimicrobial property, and is highly versatile.

Description

Antithrombotic or antimicrobial polymer compounds, methods of preparing the same, and medical materials comprising the same

An antithrombotic or antimicrobial polymer compound, a method for preparing the same, and a medical material including the same.

In the case of medical devices in various fields including the cardiovascular system which comes into contact with conventional blood, techniques for coating antimicrobial and antithrombotic substances have been developed to suppress infection and thrombus formation. Problems such as process difficulties and toxicity in the body have been raised and are still unresolved. Therefore, there is a very high need for the development of antimicrobial and antimicrobial polymer compounds having high versatility, and chemical additive compositions using the same.

In general, protein adsorption occurs spontaneously on the surface of the medical material in contact with blood. As a result, cells and various other components in the blood slowly disperse and adhere to the surface of the medical material already adsorbed as protein. Protein adsorption not only reduces the function of medical materials, but also causes side effects such as blood clot formation and inflammation. In addition, protein adsorption may reduce the sensitivity of the inserted medical instrument sensor to check the health of the patient, thereby reducing the diagnostic efficiency. Therefore, the strategy of inhibiting protein adsorption, which is a primary phenomenon, is very effective in blood contact-type medical devices inserted into the body from the viewpoint of research and development.

Zwitterionic polymers can be defined as polymers having an equal number of anion and cationic groups evenly distributed along the polymer chain. The combination of these oppositely charged functional groups (zwitter in German) makes the polymer superhydrophilic, while at the same time maintaining the overall neutral charge. Polymers containing ionic groups are one of the most important types of polymers. These polymers range from naturally occurring biopolymers such as proteins and nucleic acids to synthetic thickeners and soaps. Ionic polymers can be classified into polyelectrolytes and zwitterionic polymers. Ionic polymers are polymers containing anionic or cationic functional groups, while zwitterionic polymers are polymers containing both cations and anionic functional groups. Zwitterionic polymers have a wide range of applications, such as ion exchange, trace metal chelation of drinking water, sewage treatment, soil management, paper reinforcement, pigment residues, shampoos and hair conditioner formulations. Zwitterionic polymers have a charge located in the pendant side chain of the monomer, or in the polymer main chain in the case of polyesters, polyphosphazenes and polyphosphobetaines. You may. In engineering terms, zwitterionic polymers are considered to be a substitute for polyethylene glycol (PEG), which is widely used to prevent nonspecific protein adsorption and to minimize cell adhesion in bacteria, animals or humans. PEG polymers, however, have essentially the same repeating units, whereas zwitterionic polymers can undergo a wide range of structural changes depending on the specific monomer chemistry.

Various and extensive studies have been conducted for a long time regarding the antimicrobial activity of metals. Certain metals such as silver (Ag), mercury (Hg) and tellurium (Te) are known to be extremely toxic to most bacteria and to have antimicrobial effects even at extremely low concentrations. Because of the inherent toxicity of these metals to bacteria and yeast, certain metals have been used as antimicrobials since ancient times. Today, antimicrobial metal compounds such as metal surfaces, coatings, chelating compounds and nanomaterials are used in a wide range of fields such as industry, agriculture and healthcare. These advances have been made through innovative discoveries such as the destruction of certain metals by antimicrobial resistant biofilms, synergistic antimicrobial activity with other antimicrobial agents, inhibition of selective metabolism and the death of multidrug resistant bacteria. However, it is also true that certain metals cause cellular and tissue toxicity when applied to medical devices that are inserted or implanted in the body, or problems such as systemic toxicity in the case of nanomaterials. In addition, the metal contained in the material is often lost or consumed quickly, the effect is often unsatisfactory. Therefore, in order to apply to the medical material that is inserted into the body of the metal, the development of technology and materials that can maintain the body safety for a long time is urgently required.

It provides a high molecular compound having antithrombogenic or antimicrobial properties.

It provides a composition for chemical addition comprising the polymer compound.

It provides a medical material comprising the polymer compound or a chemical addition composition.

It provides a method for producing the polymer compound.

One aspect provides a polymer compound comprising a copolymer comprising two or more repeating units selected from the group consisting of Formulas 1-3:

[Formula 1]

,

,

[Formula 2]

, 및

, And

[Formula 3]

.

.

The polymer compound may be, for example, a polymer compound including a repeating unit of Formula 1 and a repeating unit of Formula 2, or a polymer compound including a repeating unit of Formula 1, a repeating unit of Formula 2, and a repeating unit of Formula 3 have.

R ₁ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkenyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkynyl group, a substituted or unsubstituted C ₆ to C ₃₀ aryl group, substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, substituted or unsubstituted aromatic ring having 5 to 20 carbon atoms, substituted or unsubstituted cyclic having 3 to 30 carbon atoms It may be a ring group, a substituted or unsubstituted heterocyclic ring group having 3 to 20 carbon atoms, or a combination thereof. R ₁ is substituted or unsubstituted C ₁ to C ₃₀ , C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ alkyl group (eg methyl), substituted or unsubstituted C ₆ to C Aryl groups of ₃₀ , C ₆ to C ₂₀ , C ₆ to C ₁₀ , or C ₆ to C ₈ , substituted or unsubstituted cyclic rings of 3 to 30, 3 to 20, 3 to 10, or 3 to 6 carbon atoms Groups, substituted or unsubstituted C3-20, 3-10, or 3-6 heterocyclic ring groups, or a combination thereof. R ₁ may be an alkylene diphenyl group. For example, R ₁ is methylene diphenyl.

The repeating unit of Formula 1 is methylene diphenyl diisocyanate (MDI), 4,4'-diisocyanato dicyclohexylmethane (hydrogenated MDI or HMDI), hexamethylene diisocyanate : HDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), and methyl isocyanate (MIC).

The x may be an integer of 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 20, 1 to 10, or 1 to 5.

R ₂ and R ₃ are each independently a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkenyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkynyl group , Substituted or unsubstituted C ₆ to C ₃₀ aryl group, substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, substituted or unsubstituted C 5 -C 20 aromatic ring group, substituted or unsubstituted carbon number It may be a cyclic ring group of 3 to 30, a substituted or unsubstituted heterocyclic ring group having 3 to 20 carbon atoms, or a combination thereof.

R ₂ is substituted or unsubstituted C ₁ to C ₃₀ , C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ alkyl group, substituted or unsubstituted C ₆ to C ₃₀ , C ₆ to C ₂₀ , C ₆ to C ₁₀ , or C ₆ to C ₈ aryl groups, substituted or unsubstituted cyclic ring groups having 3 to 30, 3 to 20, 3 to 10, or 3 to 6 carbon atoms, or their May be a combination. For example, R ₂ is a methyl group.

R ₃ may be a substituted or unsubstituted C ₁ to C ₃₀ , C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ alkyl group. For example, R ₃ is a propyl group.

A is —CO ₂ , —SO ₃ , —PO ₃ , a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, or a combination thereof, and the alkyl group may be substituted with a halogen atom.

M may be a metal atom. M is, for example, silver (Ag), cerium (Ce), zinc (Zn), copper (Cu), mercury (Hg), arsenic (As), antimony (Sb), tin (Sn), barium (Ba) ), Iron (Fe), titanium (Ti), palladium (Pd), gold (Au), gallium (Ga), lead (Pb), and bismuth (Bi).

The y may be an integer of 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 20, 1 to 10, or 1 to 5.

R ₄ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₆ to C ₃₀ aryl group, a substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, a substituted or unsubstituted Cyclic ring groups having 3 to 30 carbon atoms, substituted or unsubstituted heterocyclic ring groups having 3 to 20 carbon atoms, or a combination thereof. The heteroaryl group or heterocyclic ring group may include one or more hetero atoms selected from the group consisting of N, O and S. R ₄ is substituted or unsubstituted C ₁ to C ₃₀ , C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ alkyl group, substituted or unsubstituted C ₂ to C ₃₀ , C ₂ to C ₂₀ , C ₂ to C ₁₀ , or C ₂ to C ₆ alkenyl group, substituted or unsubstituted C ₂ to C ₃₀ , C ₂ to C ₂₀ , C ₂ to C ₁₀ , or C ₂ to C ₆ alky Aryl group, substituted or unsubstituted C ₆ to C ₃₀ , C ₆ to C ₂₀ , C ₆ to C ₁₀ , or C ₆ to C ₈ aryl group, substituted or unsubstituted C ₆ to C ₃₀ , C ₆ to C ₂₀ , C ₆ to C ₁₀ , or C ₆ to C ₈ heteroaryl group, a substituted or unsubstituted cyclic ring group having 1 to 30, 3 to 20, 3 to 10, or 3 to 6 carbon atoms, substituted or unsubstituted Ring heterocyclic ring having 3 to 20, 3 to 10, or 3 to 6 carbon atoms, or a combination thereof. R ₄ may be a substituted or unsubstituted C ₁ to C ₂₀ alkyl group, dimethylene oxide, trimethylene oxide, tetramethylene oxide, butadiene, isobutylene, isosorbide, or a combination thereof. R ₄ may be a C ₁ to C ₃₀ alkyl group substituted with a halogen atom. R ₄ may be a perfluorinated C ₁ to C ₃₀ alkyl group. For example, R ₄ is isosorbide.

Z may be an integer of 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 20, 1 to 10, or 1 to 5.

The polymer compound may include a C ₁ to C ₃₀ alkyl group, a carboxyl group, or a combination thereof substituted with a halogen atom at one or more terminals. The polymer compound may include C ₁ to C ₃₀ , C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ alkyl groups, citric acid, or a combination thereof substituted with halogen atoms at one or more terminals thereof. . The alkyl group of C ₁ to C ₃₀ substituted with the halogen atom may be a perfluorinated C ₁ to C ₃₀ alkyl group. For example, the polymer compound is a compound polymerized with citric acid at either or both ends.

The polymer compound may be a metal composite. The metal complex may be a complex of the polymer compound and the metal ion described above.

The term "substituent" refers to the introduction of an atom group instead of a hydrogen atom when one or more hydrogen atoms in the organic compound are substituted with another atom group to form a derivative.

The "substituted" of the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aromatic ring group, cyclic ring group, heterocyclic ring group used in the formula (1) to (3) is substituted with a halogen atom, a halogen atom Alkyl group of C ₁ to C ₅ (e.g., CCF ₃ , CHCF ₂ , CH ₂ F, CCl _3, etc.), hydroxy group, nitro group, cyano group, amino group, amidino group, acetamino group, hydrazine, hydrazone, carboxyl group or its Salts, sulfonic acid groups or salts thereof, phosphoric acid or salts thereof, C ₁ to C ₅ alkyl groups, C ₂ to C ₅ alkenyl groups, C ₂ to C ₅ alkynyl groups, C ₃ to C ₁₀ cycloalkyl groups, C ₆ To C ₁₀ to aryl group, C ₆ to C ₁₀ heteroaryl group, C ₆ to C ₂₀ arylalkyl group, C ₆ to C ₂₀ heteroarylalkyl group, or a combination thereof.

Another aspect provides a chemical addition composition comprising a polymer compound according to one aspect.

The chemical addition composition may be a composition for adding to the manufacturing step of the medical material or for coating, dipping, or applying the medical material.

The composition may be for antifouling, antithrombotic, antibacterial, or a combination thereof. The composition may be for preventing adsorption of proteins. When the polymer compound or a composition including the same is in contact with blood, it may inhibit the adhesion or adsorption of proteins in the blood to the polymer compound or the composition including the same, and inhibit the formation of a thrombus. The composition may inhibit the attachment or adsorption of microorganisms (eg, bacteria) to the polymer compound or a composition including the same or may cause the microorganisms to die.

Another aspect may be a medical material comprising a polymer compound or a chemical additive composition according to one aspect.

The medical material may be combined with or coated with the polymer compound or the composition. The high molecular compound can be combined with polyvinyl chloride, for example.

The medical material may be a film, tube, sheet, stent, catheter, implant, suture, hydrogel, or a combination thereof.

Another aspect includes polymerizing a substituted or unsubstituted diethanol amine with either propane sultone or butane sultone to produce a zwitterionic diol compound; And

It provides a method for producing a high molecular compound comprising the step of polymerizing the obtained zwitterionic diol compound and diisocyanate compound to produce a zwitterionic polyurethane polymer.

The method includes polymerizing a substituted or unsubstituted diethanol amine with either propane sultone or butane sultone to produce a zwitterionic diol compound.

The diethanol amine may be substituted with an alkyl group of C ₁ to C ₂₀ , C ₁ to C ₁₀ , or C ₁ to C ₅ . For example, the diethanol amine is methyl diethanol amine (MDEA).

The method includes polymerizing the obtained zwitterionic diol compound with a diisocyanate compound to produce a zwitterionic polyurethane polymer.

The diisocyanate compound is for example methylene diphenyl diisocyanate (MDI), 4,4'-diisocyanato dicyclohexylmethane (HMDI), hexamethylene diisocyanate (HDI), isophorone diisocinate (IPDI) , Toluene diisocyanate (TDI), and methyl isocyanate (MIC).

The method may further comprise adding a plasticizer to the zwitterionic diol compound and the diisocyanate compound. The plasticizer may be a substituted or unsubstituted C ₁ to C ₂₀ alkyl group, dimethylene oxide, trimethylene oxide, tetramethylene oxide, butadiene, isobutylene, isosorbide, or a combination thereof.

The method may further comprise capping the obtained zwitterionic polyurethane polymer with C ₁ to C ₃₀ alkyl (including perfluorinated alkyl groups), citric acid, or combinations thereof substituted with halogen atoms. . The polymer compound may include a C ₁ to C ₃₀ alkyl group, a carboxyl group, or a combination thereof substituted with a halogen atom at one or more terminals.

The method may further comprise mixing the obtained zwitterionic polyurethane polymer with the metal ions to produce a zwitterionic polyurethane metal polymer.

According to the polymer compound according to one aspect, a chemical additive composition comprising the same, a medical material comprising the same, and a method of preparing the same, it may be used to prepare a medical material having antithrombogenic or antimicrobial properties and having high versatility.

1 is a chemical formula of the structure constituting the zwitterionic polyurethane copolymer.
2 is a schematic diagram of a scheme for synthesizing zwitterionic diols.
3A is a schematic diagram of a scheme for synthesizing zwitterionic polyurethane.
3B is a schematic diagram of a scheme for synthesizing zwitterionic isosorbide polyurethane.
Figure 4a is a schematic diagram of a reaction scheme for synthesizing the antimicrobial polymer compound by attaching citric acid to both ends of the zwitterionic polyurethane, Figure 4b is a polymer compound having antimicrobial properties by attaching citric acid to both ends of the zwitterionic isosorbide polyurethane It is a schematic diagram of the reaction formula which synthesize | combines.
5 is an image of a film processed by mixing a polymer compound synthesized in PVC.
Figure 6a is a graph showing the results of analyzing the structure of the film prepared using the FTIR, Figure 6b is a graph showing the result of measuring the water contact angle of the film according to the content of the polymer compound, Figure 6c is an X-ray photoelectron spectrometer It is a graph showing the binding energy between atoms on the surface of the film produced using.
7A and 7B are graphs showing the amounts of BSA and fibrinogen adsorbed on a film according to the content of the polymer compound, respectively.
8 is a photograph showing bacteria grown in the presence of a polymer compound.

It will be described in more detail through the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1 Preparation of Antimicrobial or Antithrombotic Polymer Compound and Analysis of Physicochemical Properties of the Prepared Polymer Compound

1. Synthesis of Zwitterionic Diols

To a 3-neck round bottom flask was added 30 ml of dimethylformamide anhydrous (DMF) (Sigma-Aldrich).

To DMF was added 0.06 mol (6.9 ml) of methyldiethanolamine (MDEA) (Sigma-Aldrich) and 0.06 mol (7.3 g) of 1,3-propanesultone (Sigma-Aldrich), about 50 Stir in the presence of nitrogen gas for about 5 hours at a temperature of ℃. Thereafter, the reactant was added to the acetone (Sigma-Aldrich) solution and precipitated. The precipitate was centrifuged at about 4000 rpm for about 2 minutes, then the supernatant was removed and a precipitate was obtained. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for one day to obtain zwitterionic diol in powder form.

A schematic diagram showing a chemical reaction for synthesizing zwitterionic diols is shown in FIG. 2.

2. Preparation of Polyurethane Compounds

2.1. Preparation of Zwitterionic Polyurethanes

Zwitterionic diols were prepared as described in 1.

30 ml of DMF was added to a three necked round bottom flask and purged with nitrogen gas to remove moisture. To the filled flask was added 0.018 mol (4.36 g) zwitterionic diol and 0.027 mol (6.8 g) methylene diphenyl diisocyanate (MDI) (Sigma-Aldrich) and 58 μl Tin (catalyst) as catalyst. II) was added.

The reaction was stirred in the presence of nitrogen gas at a temperature of about 80 ° C. for about 20 minutes. Thereafter, the reaction was added to the chloroform (Sigma-Aldrich) solution and precipitated. Filter paper was used to obtain the precipitated reaction. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for 1 day to obtain zwitterionic polyurethane ("SPU") in powder form.

A schematic diagram illustrating a chemical reaction for synthesizing zwitterionic polyurethane (SPU) is shown in FIG. 3A.

2.2. Preparation of Zwitterionic Isosorbide Polyurethane

Zwitterionic diols were prepared as described in 1.

30 ml of DMF was added to a three necked round bottom flask and filled with nitrogen gas to remove moisture. To the filled flask was added 0.009 mol (2.18 g) zwitterionic diol and 0.009 mol (1.32 g) isosorbide (Sigma-Aldrich) to dissolve isosorbide. 0.027 mol (6.8 g) of MDI (Sigma-Aldrich) was added to the reaction, and 58 μl of Tin (II) was added as a catalyst.

The reaction was stirred in the presence of nitrogen gas at a temperature of about 80 ° C. for about 20 minutes. Thereafter, the reaction was added to the chloroform (Sigma-Aldrich) solution and precipitated. Filter paper was used to obtain the precipitated reaction. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for 1 day to obtain zwitterionic isosorbide polyurethane ("SIPU") in powder form.

A schematic diagram showing the chemical reaction for synthesizing zwitterionic isosorbide polyurethane (SIPU) is shown in FIG. 3B.

3. End capping of polyurethane

3.1. Preparation of Citric Acid Zwitterionic Polyurethane

Zwitterionic polyurethane (SPU) was prepared as described in 2.1.

30 ml of DMF was added to a three necked round bottom flask and filled with nitrogen gas to remove moisture. To the filled flask was added 0.0045 mol (0.75 g) of citric acid (Sigma-Aldrich) to dissolve citric acid. 0.015 mol (1.5 g) of SPU was added to the reaction and the reaction was stirred at a temperature of about 90 ° C. for about 12 hours. Thereafter, the reaction was added to the chloroform (Sigma-Aldrich) solution and precipitated. Filter paper was used to obtain the precipitated reaction. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for one day to give a citric acid-endcapped zwitterionic polyurethane ("CSPU") in powder form.

A schematic diagram illustrating the chemical reaction for synthesizing citric acid terminal zwitterionic polyurethane (CSPU) is shown in FIG. 4A.

3.2. Preparation of Citric Acid Zwitterionic Isosorbide Polyurethane

Zwitterionic isosorbide polyurethane (SIPU) was synthesized as described in 2.2.

30 ml of DMF was added to a three necked round bottom flask and filled with nitrogen gas to remove moisture. To the filled flask was added 0.0036 mol (0.6 g) of citric acid (Sigma-Aldrich) to dissolve citric acid. 0.0012 mol (1.5 g) of SIPU was added to the reaction and the reaction was stirred at a temperature of about 90 ° C. for about 12 hours. Thereafter, the reaction was added to the chloroform (Sigma-Aldrich) solution and precipitated. Filter paper was used to obtain the precipitated reaction. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for 1 day to give a citric-endcapped zwitterionic isosorbide polyurethane ("CSIPU") in powder form.

A schematic diagram showing the chemical reaction for synthesizing citric acid terminal zwitterionic isosorbide polyurethane (CSIPU) is shown in FIG. 4B.

4. Films containing zwitterionic polyurethanes and their surface properties

4.1. Preparation of Films Containing Zwitterionic Polyurethanes

As additives, zwitterionic polyurethane compounds were synthesized as described in 2.1, 2.2, 3.1, and 3.2.

Polyvinyl chloride (PVC), a basic polymer component, was mixed with a final content of 0% (w / w), 3% (w / w), or 10% (w / w) zwitterionic polyurethane compound. . Using a heat press, the mixture was heated at a temperature of about 170 ° C. for about 1 minute holding time and about 4 minutes pressing time to prepare a film.

The composition ratio of the composition for film manufacture is shown in Table 1 below.

Number Name additive  Final content (% (w / w)) One PVC none 0 2 SPU3 SPU 3 3 SPU10 SPU 10 4 SIPU3 SIPU 3 5 SIPU10 SIPU 10 6 CSPU3 CSPU 3 7 CSPU10 CSPU 10 8 CSIPU3 CSIPU 3 9 CSIPU10 CSIPU 10

An image of the prepared film is shown in FIG. 5.

4.2. Surface properties of film

A film containing zwitterionic polyurethane was prepared as described in 4.1.

Fourier transform infrared spectroscopy (FTIR) was used to confirm the structural characteristics of the prepared film surface. The film was irradiated with infrared light using FT / IR-4100 (Jasco Analytical Instruments, USA), and a graph of transmittance against wavenumber is shown in FIG. 6A. As shown in Fig. 6a, a carbonyl group appears to peak at a wavenumber 1730cm ^-1 CN groups since appeared in the wave number 1528cm ^-1 as a peak, it was confirmed that the urethane bond in the polyurethane compound. In addition, since SO ₃ ⁻ in sulfobetain appeared as a peak at wavenumber 1730 cm ⁻¹ and quaternary amine appeared as a peak at 960 cm ⁻¹ , it was confirmed that the produced film contained a zwitterionic functional group.

In addition, the water contact angle of the film was measured to measure the hydrophilicity of the film. The prepared film was prepared under dry conditions or hydrated conditions for about 1 day. The prepared film was loaded on a water contact angle measuring device OCA40 (Dataphysics, Germany), and 3 mL of distilled water was dropped on the film surface to measure the water contact angle. Five replicate experiments were performed to calculate the average value of the water contact angle. The graph of the calculated water contact angle according to the sample is shown in FIG. 6B. As shown in FIG. 6B, the water contact angle decreased as the content of the additive increased. Therefore, it was confirmed that the hydrophilicity of the prepared film increases as the content of the additive increases. In addition, when comparing the water contact angle of the dried film and the hydrated film, the water contact angle of the hydrated film was further reduced. Therefore, it was confirmed that the hydrophilicity of the film increases as the content of the additive increases under the conditions of hydrating the film. This indicates that many zwitterionic functional groups with functionality are present on the surface of the film.

In addition, the surface characteristics of the film prepared by x-ray photoelectron spectroscopy (XPS) was confirmed. The film was loaded into PHI 5000 VersaProbe (Physical Electronics, USA) and the surface properties, structural analysis, and binding energy (eV) between atoms at the surface of the prepared films were measured. A graph of the peak intensity (c / s) against the measured binding energy (eV) is shown in Figure 6c. As shown in FIG. 6C, since S _2p (2p orbital of sulfur atom) shows a peak of 166 eV and N _1s (1s orbital of nitrogen atom) has a peak of 402 eV, a zwitterionic functional group having a functional film It was confirmed that a lot exists on the surface of. In addition, the peak intensity of the dried film and the hydrated film was compared, and the peak intensity of the hydrated film was higher. Thus, it was confirmed that more zwitterionic functional groups were present on the surface of the hydrated film than the dry film, and the zwitterionic functional groups were exposed to the surface of the film under hydration conditions to make it more hydrophilic.

As a result of comparing the peak intensities of the films in the dry and hydrated states, the surface of the hydrated films exhibited more zwitterionic functional groups. This can be seen that the zwitterionic portion is exposed to the surface under the hydration conditions to show more hydrophilicity.

5. Formation of Zwitterionic Polyurethane / Metal Composites

5.1. Formation of Zwitterionic Polyurethane / Metal Composites

Zwitterionic polyurethane (SPU) was prepared as described in 2.1.

50 ml of distilled water was added to a round flask wrapped in foil to block light. The flask contains 0.0075 mol of AgNO ₃ (Sigma-Aldrich), 0.0075 mol of ZnSO ₄ (Sigma-Aldrich), 0.0075 mol of CuSO ₄ (Sigma-Aldrich), and 0.0075 mol of Ce (NH ₄ ) ₂ (NO ₃ ) ₆ (Sigma-Aldrich) was added to dissolve. 0.0025 mol of SPU was added to the reaction and stirred at room temperature for about 2 hours.

Thereafter, the reactants were placed in a beaker containing acetone (Sigma-Aldrich) solution and precipitated. The centrifuge was run at 4000 rpm for 2 minutes. The supernatant was removed and precipitated and washed three times with the settled precipitate. The precipitate was dried in vacuo for 1 day to give the final product in powder form.

Thereafter, the reactant was added to the acetone (Sigma-Aldrich) solution and precipitated. The precipitate was centrifuged at about 4000 rpm for about 2 minutes, then the supernatant was removed and a precipitate was obtained. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for one day to obtain a zwitterionic polyurethane metal composite in powder form.

5.2. Metal complex formation of zwitterionic isosorbide polyurethane

Zwitterionic isosorbide polyurethane (SIPU) was prepared as described in 2.2.

50 ml of distilled water was added to a round flask wrapped in foil to block light. The flask contains 0.0075 mol of AgNO ₃ (Sigma-Aldrich), 0.0075 mol of ZnSO ₄ (Sigma-Aldrich), 0.0075 mol of CuSO ₄ (Sigma-Aldrich), and 0.0075 mol of Ce (NH ₄ ) ₂ (NO ₃ ) ₆ (Sigma-Aldrich) was added to dissolve. 0.0025 mol SIPU was added to the reaction and stirred at room temperature for about 2 hours.

Thereafter, the reactants were placed in a beaker containing acetone (Sigma-Aldrich) solution and precipitated. The centrifuge was run at 4000 rpm for 2 minutes. The supernatant was removed and precipitated and washed three times with the settled precipitate. The precipitate was dried in vacuo for 1 day to give the final product in powder form.

Thereafter, the reactant was added to the acetone (Sigma-Aldrich) solution and precipitated. The precipitate was centrifuged at about 4000 rpm for about 2 minutes, then the supernatant was removed and a precipitate was obtained. This process was repeated three times to precipitate and wash the reaction. The precipitate was dried in vacuo for 1 day to obtain a zwitterionic isosorbide polyurethane / metal complex in powder form.

6. Characterization of zwitterionic polyurethane

6.1. Antithrombotic Effect of Zwitterionic Polyurethane Film

A film was prepared as described in 4.1, and the sample was prepared by cutting the prepared film into a size of 1 cm x 1 cm.

The prepared film was added to each well of a 24-well plate. The film was immersed in phosphate-buffered saline (PBS) and maintained at a temperature of about 37 ° C. for about 2 hours. PBS was removed and 1 ml of bovine serum albumin (BSA) (Sigma-Aldrich) or 0.1 mg / ml of fibrinogen (Sigma-Aldrich) was added to each well. The plate was held for about 1 hour with stirring at a speed of about 30 rpm. Thereafter, the BSA or fibrinogen solution was removed and the film was washed 4-5 times with PBS. To each well was added 1 ml of 2 w% sodium dodecyl sulfate (SDS) solution and stirred at room temperature at a rate of about 30 rpm for about 1 hour. Thereafter, the micro BCA solution and the SDS reaction were mixed in a 1: 1 ratio and maintained for about 2 hours with stirring at a speed of about 30 rpm at a temperature of about 37 ° C. in a 96-well plate. The absorbance of the reactants was measured at a wavelength of 562 nm using a UV detector and the protein was quantified from the measured absorbance. The amount of protein scratched on the film is shown in FIGS. 7A and 7B (FIG. 7A: BSA, FIG. 7B: fibrinogen).

As shown in FIGS. 7A and 7B, the amount of protein adsorbed on the film was decreased in the film having a higher content of zwitterionic polyurethane compared to the film having a lower content of zwitterionic polyurethane. Therefore, it was confirmed that the film having a high content of zwitterionic polyurethane has a protein adsorption inhibitory effect, thereby having an antithrombotic effect as well as an antifouling effect.

6.2. Antimicrobial Effect of Zwitterionic Polyurethanes

Zwitterionic polyurethane / metal composites were prepared as described in 5.1 and 5.2.

Gram-positive bacteria Staphylococcus aureus (ATCC 14458), Staphylococcus epidermidis (ATCC 12228) and Gram-negative bacteria Escherichia coli (ATCC 11775), Pseudomonas ae Luginosa ( Pseudomonas aeruginosa , ATCC 9027) was prepared. For each bacterium, a bacterial solution was made in the saline solution and each bacterium was plated in an agar solid medium. Thereafter, the zwitterionic polyurethane / metal complex was placed in a fresh water spoon in a solid medium stained with bacteria and incubated at 37 ° C. for about 18 hours.

The degree of inhibition of zone formation of bacteria was visually observed and the image is shown in FIG. 8. As shown in FIG. 8, zone formation of bacteria was observed in citric acid terminated zwitterionic polyurethane (CSPU) and citric acid terminated zwitterionic isosorbide polyurethane (CSIPU). Therefore, CSPU and CSIPU was confirmed to have an antimicrobial effect by inhibiting or sterilizing the growth of microorganisms.

Claims (22)

A polymer compound comprising a copolymer comprising two or more repeating units selected from the group consisting of Formulas 1 to 3:
[Formula 1]

In Formula 1, R ₁ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkenyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkynyl group, substituted or Unsubstituted C ₆ to C ₃₀ aryl group, substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, substituted or unsubstituted aromatic ring of 5 to 20 carbon atoms, substituted or unsubstituted C 3 to 30 A cyclic ring group, a substituted or unsubstituted heterocyclic ring group having 3 to 20 carbon atoms, or a combination thereof,
x is an integer from 1 to 100.
[Formula 2]

In Formula 2, R ₂ and R ₃ are each independently a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkenyl group, a substituted or unsubstituted C ₂ to C ₃₀ An alkynyl group, substituted or unsubstituted C ₆ to C ₃₀ aryl group, substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, substituted or unsubstituted C 5 -C 20 aromatic ring group, substituted or unsubstituted A cyclic ring group having 3 to 30 carbon atoms, a substituted or unsubstituted heterocyclic ring group having 3 to 20 carbon atoms, or a combination thereof,
A is —CO ₂ , —SO ₃ , —PO ₃ , a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, or a combination thereof, the alkyl group may be substituted with a halogen atom,
M is a metal atom,
y is an integer from 1 to 100.
[Formula 3]

In formula (3), R ₄ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkenyl group, a substituted or unsubstituted C ₂ to C ₃₀ alkynyl group, substituted or Unsubstituted C ₆ to C ₃₀ aryl group, substituted or unsubstituted C ₆ to C ₃₀ heteroaryl group, substituted or unsubstituted cyclic ring of 3 to 30 carbon atoms, substituted or unsubstituted C 3 to 20 heterocyclic ring groups, or a combination thereof,
The heteroaryl group or heterocyclic ring group includes at least one hetero atom selected from the group consisting of N, O and S;
z is an integer from 1 to 100. The method according to claim 1, wherein R ₁ is a substituted or unsubstituted C ₁ to click when the C ₃₀ alkyl group, a substituted or unsubstituted C ₆ to C ₃₀ aryl group, a substituted or unsubstituted C3 to 30 of a ring group , A substituted or unsubstituted heterocyclic ring having 3 to 20 carbon atoms, or a combination thereof. The method of claim 1, wherein the repeating unit of Formula 1 is methylene diphenyl diisocyanate (MDI), 4,4'- diisocyanato dicyclohexylmethane (dihydrogenated MDI or HMDI), hexamethylene A high molecular compound selected from the group consisting of diisocyanate (hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), and methyl isocyanate (MIC). The method according to claim 1, click when the R ₂ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₆ to C ₃₀ aryl group, a substituted or unsubstituted C3 to 30 of a ring group , Or a combination thereof. The polymer compound according to claim 1, wherein R ₃ is a substituted or unsubstituted C ₁ to C ₃₀ alkyl group. The method of claim 1, wherein M is silver (Ag), cerium (Ce), zinc (Zn), copper (Cu), mercury (Hg), arsenic (As), antimony (Sb), tin (Sn), barium (Ba), iron (Fe), titanium (Ti), palladium (Pd), gold (Au), gallium (Ga), lead (Pb), and bismuth (Bi). The method according to claim 1, wherein R ₄ is heteroaryl, substituted or unsubstituted C ₁ to C ₃₀ alkyl group, a substituted or unsubstituted C ₆ to C ₃₀ aryl group, a substituted or unsubstituted C ₆ to C ₃₀ of the group , A substituted or unsubstituted cyclic ring group having 3 to 30 carbon atoms, a substituted or unsubstituted heterocyclic ring group having 3 to 20 carbon atoms, or a combination thereof,
The heteroaryl group or heterocyclic ring group is a polymer compound containing at least one hetero atom selected from the group consisting of N, O and S. The method according to claim 7, wherein R ₄ is a substituted or unsubstituted C ₁ to C ₂₀ alkyl group, dimethylene oxide, trimethylene oxide, tetramethylene oxide, butadiene, isobutylene, isosorbide, or their A high molecular compound that is a combination. The polymer compound according to claim 1, wherein the polymer compound comprises a C ₁ to C ₃₀ alkyl group, a carboxyl group, or a combination thereof substituted with a halogen atom at one or more terminals. The polymer compound according to claim 9, wherein the polymer compound comprises a C ₁ to C ₂₀ alkyl group, citric acid, or a combination thereof substituted with a halogen atom at one or more terminals. The polymer compound of claim 1, wherein the polymer compound is a metal complex. A composition for chemical addition comprising the polymer compound of claim 1. The composition of claim 12, wherein the composition is for antifouling, antithrombotic, antibacterial, or a combination thereof. The composition of claim 13, wherein the composition is for preventing adsorption of proteins. A medical material comprising the polymer compound of claim 1 or the chemical additive composition of claim 12. The medical material of claim 15, wherein the medical material is combined with or coated with the polymer compound or the composition. The medical material of claim 15, wherein the medical material is a film, tube, sheet, stent, catheter, implant, suture, hydrogel, or a combination thereof. Polymerizing a substituted or unsubstituted diethanol amine with either propane sultone or butane sultone to produce a zwitterionic diol compound; And
A method of producing a polymer compound comprising the step of polymerizing the obtained zwitterionic diol compound and diisocyanate compound to produce a zwitterionic polyurethane polymer. The method of claim 18, wherein the method further comprises adding a plasticizer to the zwitterionic diol compound and the diisocyanate compound. The method according to claim 19, wherein the plasticizer is substituted or unsubstituted C ₁ to C ₃₀ alkyl group, dimethylene oxide, trimethylene oxide, tetramethylene oxide, butadiene, isobutylene, isosorbide, or combinations thereof How to be. The method of claim 18, wherein the method further comprises capping the obtained zwitterionic polyurethane polymer with C ₁ to C ₃₀ alkyl, citric acid, or combinations thereof substituted with halogen atoms. The method of claim 18, wherein the method further comprises mixing the obtained zwitterionic polyurethane polymer with the metal ions to produce a zwitterionic polyurethane metal polymer.

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