WO2018056737A1 - Method for manufacturing non-bleeding injection needle having immediate hemostatic capability - Google Patents

Abstract

An injection needle coated with chitosan, in which an oxidized catechol group is introduced into chitosan and crosslinked, according to the present invention, has the ability to immediately suppress bleeding occurring at the time of injection. As such, the present invention is effective for injecting not only patients having low hemostatic ability such as diabetic patients, chemotherapy patients and hemophilia patients, but also for patients showing a blood rejection response and children, and has an effect of immediately suppressing hemorrhage of strong pulsing, blood-rich organs such as a heart.

Description

Manufacturing method of bleeding needle with immediate hemostatic ability

The present invention relates to a non-bleeding needle having immediate hemostatic ability, and more particularly to a method for preparing a non-bleeding needle having immediate hemostatic ability by controlling the degree of crosslinking and chemical structure of chitosan introduced with a catechol group. It is about.

Various types of hemostatic products have been developed for the successful surgery of patients with blood clotting disorders. Fibrin glue, a representative medical hemostatic agent, is biocompatible as a hemostatic agent using blood coagulation proteins in vivo. In addition, the hemostatic catheter, one of the medical devices with hemostatic ability, has a material having elasticity at the distal end of the catheter, and has been designed to have a function of physically preventing bleeding (US Patent US4133303 A). However, most hemostatic materials and devices have a disadvantage in that adhesion is poor in a living body in which a lot of water is present, and the mechanical properties are weak and easily denatured. Therefore, the development of medical products using biomaterials having excellent tissue adhesion and biocompatibility has become an important issue.

Meanwhile, chitosan, in which a catechol group, a functional group contributing to the mussel adhesion ability, is introduced, has been applied as a biomaterial showing excellent adhesion to tissues and mucous membranes even in an aqueous environment. International Publication No. WO2013 / 077476 discloses an adhesive hydrogel composition comprising chitosan having a catechol group introduced therein and a pluronic bond with a thiol group at the end thereof, and specifically, of a chitosan having a catechol group introduced therein. Disclosed are excellent hemostatic ability and bioadhesiveness.

)에 의해 가교된 키토산을 코팅하여 제조한 무출혈 주사바늘을 개시하고 있다. 그러나, 무출혈 주사바늘은 안정적인 지혈능을 나타내기까지, ~20초 정도의 시간이 걸리며, 그 시간은 가교된 키토산 필름이 팽윤되어 하이드로겔 형태로 전이되는 시간을 나타낸다.In addition, the catechol group (partially oxidized recently in Korean Patent No. 10-1576503)

Disclosed is a bleeding-free needle prepared by coating a chitosan crosslinked by the). However, the bleeding-free needle takes about 20 seconds to show stable hemostatic ability, which indicates the time when the crosslinked chitosan film is swollen and transferred to hydrogel form.

Accordingly, the present inventors produce a bleeding needle having immediate hemostatic ability by coating a chitosan film having improved crosslinking by maximizing the degree of oxidation of the catechol group in order to shorten the hemostatic time of the existing bleeding injection needle. The present invention was completed by confirming that the bleeding-free needle can suppress bleeding generated at the time of injection in about 2 seconds.

Summary of the Invention

It is an object of the present invention to provide a method for producing an injection needle which prevents bleeding immediately after removing a needle after injection.

Another object of the present invention is to provide a bleeding-free needle in which the needle coating film is introduced to the surface.

Another object of the present invention is to provide a shortened hemostatic time of the bleeding needle.

In order to achieve the above object, the present invention comprises the steps of (a) leaving the catechol group introduced chitosan-catechol solution at a temperature of 50 ~ 70 ℃ for 1 to 5 days to induce oxidation and crosslinking of the catechol group; And (b) coating the surface of the needle with the chitosan-catechol solution.

1 is an image showing the results of ultraviolet-visible spectroscopic spectra and X-ray photoelectron spectra of chitosan-catechol solution used for the preparation of short-bleed-free bleeding needles.

Figure 2 shows the result of comparing the physical properties of the film formed on the short-term bleeding needle prepared in Example 1 through a scanning electron microscope.

Figure 3 is an image showing the results of the experiment in vivo on the short bleeding needle prepared in Example 1.

Detailed description and specifics of the invention Embodiment

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

In the present invention, in the chitosan (catechol) group introduced (chitosan), the -OH group contained in the catechol group is mostly oxidized to = O group, and then through the dehydration condensation reaction with -NH ₂ group contained in the chitosan It was confirmed that the bleeding-free needle prepared by coating the surface of the needle with the crosslinked chitosan-catechol solution had no effect of bleeding immediately even if the needle was removed after the injection.

Therefore, one aspect of the present invention (a) leaving the catechol group introduced chitosan-catechol solution at a temperature of 50 ~ 70 ℃ for 1 to 5 days to induce oxidation and crosslinking of the catechol group; And (b) coating the surface of the needle with the chitosan-catechol solution.

On the molar basis of the catechol group, 2 to 10%, preferably 2 to 6%, most preferably 3 to 5% may be crosslinked in the form of a Schiff base.

Preferably the chitosan-catechol may be a compound of Formula 3 or Formula 4.

Formula 3

In formula (3), L is a single bond, C _2-8 straight or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene.

Formula 4

In Formula 4, L is a single bond, C _2-8 linear or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene.

In addition, in the preparation method of the bleeding-free needle of the present invention, after placing the crosslinked chitosan-catechol solution on the needle, it is preferable to coat the needle by rotating the needle at a constant speed.

The coating thickness can be adjusted according to the amount of crosslinked chitosan-catechol solution.

In addition, before placing the crosslinked chitosan-catechol solution on the needle, the step of performing an oxygen plasma treatment may be added, and after the step (b), a drying step may be further performed. It may be dried for up to 30 days, and as a result, the more the oxidation of the catechol proceeds has the effect of improving the strength of the film.

Hereinafter, the present invention will be described in detail.

Needle coating film according to the present invention is characterized in that in the chitosan (chitosan) catechol (catechol) group is introduced, the majority of the catechol group is oxidized and crosslinked, even after removing the needle immediately after injection You can prevent bleeding.

When the degree of oxidation of the catechol group is analyzed by the ultraviolet-visible spectrum, it is preferable that the peak at 500 nm, which is a characteristic of the Schiff base, which is evidence of the crosslinking formed, has an absorbance of 0.02 or more. Here, when the absorbance is 0 or more and 0.02 or less, the degree of oxidation of the catechol group is partially present, and it is confirmed that it takes 15 to 20 seconds or more to show the hemostatic effect (the same as the result of the prior patent No. 10-157603). ).

The present invention relates to a needle coating film composed of a compound of Formula 3 or Formula 4 having a crosslinking rate of 3 to 5% on a molar basis of a catechol group.

Formula 3

In formula (3), L is a single bond, C _2-8 straight or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene.

Formula 4

In Formula 4, L is a single bond, C _2-8 linear or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene.

In the present invention, in the chitosan to which the catechol group is introduced, the -OH group may be oxidized to = O group, and then the catechol group may be crosslinked through a dehydration condensation reaction with the -NH ₂ group included in the chitosan. have. The degree of oxidation of the catechol group may be 5 to 10% oxidized on a molar basis of the catechol group.

)의 옥소(=O) 기가, 적절한 배향으로 위치된 키토산에 포함되어 있는 아민(-NH₂) 기와 반응하여 결합이 형성되는 것을 나타낸다.In addition, the cross-linking through the dehydration condensation reaction, as shown in Scheme 1, oxidized catechol group (

The oxo (= O) group of) reacts with the amine (-NH ₂ ) group contained in the chitosan located in the proper orientation to form a bond.

Scheme 1

Scheme 2

In Scheme 1 and Scheme 2,

) 및 산화된 카테콜기(

)가 도입된 키토산의 아민(-NH₂) 기를 나타낸 것이고;Compound represented by the formula (1) is a catechol group (

) And oxidized catechol groups (

) Represents the introduced amine (-NH ₂ ) group of chitosan;

) 및 산화된 카테콜기(

)가 도입된 키토산의 산화된 카테콜기를 나타낸 것이고;The compound represented by the formula (2) is a catechol group (

) And oxidized catechol groups (

) Represents the oxidized catechol group of chitosan introduced;

The compound represented by the formula (3) represents two compounds formed by crosslinking the compound represented by the formula (1) and the compound represented by the formula (2) through a dehydration condensation reaction; And

L is a single bond, C _1-8 straight or branched chain alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _1-8 straight chain or Branched alkylene.

) 및 산화된 카테콜기(

)가 도입된 키토산의 전구체는 산화된 카테콜기가 도입되지 않은 키토산이며 후술할 실시예에서 사용한 카테콜기가 도입된 키토산의 구체적인 화학구조식으로는 하기 화학식 5와 같다.Specifically, the catechol group (

) And oxidized catechol groups (

The precursor of chitosan to which) is introduced is chitosan to which the oxidized catechol group is not introduced, and specific chemical structural formulas of chitosan to which the catechol group is introduced in the examples to be described later are represented by the following Chemical Formula 5.

Formula 5

In Chemical Formula 5,

It is preferable that x: y: z is 6.5: 0.5: 3-5.5: 1.5: 3.

In addition, the present invention provides a short-bleeding injection needle coated on the surface of the needle coating film. At this time, the thickness of the hydrogel coated on the surface of the bleeding injection needle is preferably 10 ~ 20㎛, at this time can exhibit a hemostatic effect within 5 seconds. If the thickness is less than 10㎛, there is a problem that the bleeding is not effectively suppressed because the film is not enough to prevent the affected area generated during the injection, if the thickness is 20 ~ 30㎛, coated on the injection needle It takes a long time for the film to be converted into hydrogel form, so it is difficult to get immediate hemostatic effect. have.

) 및 대부분이 산화된 카테콜기(

)가 도입되어 최대로 가교된 키토산 용액을 준비하는 단계(단계 1); 및Furthermore, the present invention is a catechol group (

) And most oxidized catechol groups (

) Is introduced to prepare a maximally crosslinked chitosan solution (step 1); And

It provides a method for producing a blood-free needle including a; coating the surface of the needle using the solution of step 1 (step 2).

Hereinafter, the method of manufacturing a bleeding needle according to the present invention will be described in detail step by step.

) 및 대부분이 산화된 카테콜기(

)가 도입되어 가교된 키토산 용액을 준비하는 단계이다.In the method for producing a blood-free bleeding needle according to the present invention, the step 1 is a catechol group (

) And most oxidized catechol groups (

) Is introduced to prepare a crosslinked chitosan solution.

At this time, the solution may induce the partial oxidation and crosslinking of the catechol group by dissolving and storing the catechol group introduced chitosan in a solvent. The storage temperature is preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and most preferably 60 ° C. In addition, the storage time is preferably 1 to 5 days, more preferably 2 to 4 days, most preferably 3 days. Furthermore, the chitosan to which the catechol group is introduced is preferably 1 to 2% by weight, more preferably 1.3 to 1.7% by weight, and most preferably 1.5% by weight based on the total solution.

If the preferred storage temperature, storage time and the catechol group is outside the weight percent range of the chitosan introduced, there is a problem in that the physical properties of the film required for coating the short-bleeding needle are not obtained.

In the method for preparing a bleeding needle according to the present invention, the step 2 is a step of coating the surface of the needle using the solution of the step 1, specifically, after placing the solution on the needle, injection The coating is performed uniformly while rotating the needle at a constant speed.

In the bleeding-free injection method according to the present invention, step 3 is a step of injecting into a human or animal using the bleeding-free needle prepared in step 2.

In this case, the short-term bleeding injection method, after the film coated on the needle surface is injected into the tissue, it is characterized in that the bleeding is immediately suppressed by blocking the affected area as it is. Hemorrhage is suppressed within 1 to 5 seconds after injection.

In order to evaluate the hemostatic capacity of the bleeding needle according to the present invention, the following experiment was performed.

First, in order to check the characteristics of the solution used for the preparation of short-term bleeding injection needle, the polymer solution stored for 3 days at 4 ℃ corresponding to the conditions of the prior patent (patent registration 10-1576503) and 3 days at 60 ℃ Absorbance was measured by ultraviolet-visible spectroscopy of the polymer solution stored for the time, and is shown in Figure 1A. The black graph corresponds to a solution of chitosan catechol which has not been oxidized at all, and the red graph corresponds to a partially oxidized chitosan catechol solution (corresponding to Patent Registration 10-1576503). The blue graph corresponds to the chitosan catechol solution that caused the greatest crosslinking of the chain. It was confirmed that the degree of absorption at 500 nm, which is a characteristic corresponding to the Schiff base resulting from crosslinking of quinone and amine groups, was increased when stored at 60 to 3 days. In addition, the absorbance was measured by ultraviolet-visible spectroscopy of the solution stored at 4 ° C. for 5 days and the solution stored at 60 ° C. for 1 day to confirm the critical range of time and temperature, and are shown in FIGS. 1B and 1C, respectively. . When stored at 4 ° C. for 5 days, the absorbance may be similar to that of the solution stored at 60 ° C. for 3 days, but it takes a long time. When stored at 60 ℃ for one day, the absorption at 500 nm is similar to the case stored for 3 days at 4 ℃, it can be confirmed that similar to the existing conditions. Therefore, the condition of storing for 3 days at 60 ℃ was easy for short-term bleeding needle preparation. In FIGS. 1D and 1E, the chemical structural differences between the solution stored at 4 ° C. (FIG. 1D) and the solution stored at 60 ° C. (FIG. 1E) were analyzed using x-ray photoelectron spectra. The left graphs of FIGS. 1D and 1E are for nitrogen (N, 1s) and the right graphs are for (O, 1s). When the solution was stored at 4 ° C, the peak at 401.9 eV of the Schiffbase's binding energy, as seen in the nitrogen element analysis, was prominent. (Orange region, FIG. 1E, left). On the other hand, the solution stored at 60 ℃ it was confirmed that the peak in the binding energy 533.7 eV of the carbonyl group of the 'quinone' in the elemental oxygen analysis (red region, Figure 1E, right). Accordingly, it was confirmed that compound 3 of Scheme 2 coexisted in the polymer solution.

2A and 2B show the results of comparing the thickness of the film formed on the short-bleeding needle with the thickness of the film formed on the hemostatic-bleeding needle in ~ 15 seconds formed under the prior patent condition. Figure 2C is a mechanical film of the film formed on the short-bleeding needle prepared in Example 1 and the film formed on the bleeding-free needle bleeding in ~ 15 seconds formed under the prior patent conditions, the film further oxidized for about 30 days dried The physical properties are compared. After peeling and observing the film of the short-term bleeding-free needle prepared in Example 1 and the bleeding-free bleeding needle after 15 seconds corresponding to the prior patent condition through a scanning electron microscope, The thickness of the film is formed between 14.1 ± 5.4 ㎛, 15 seconds after the bleeding needle of the bleeding needle was confirmed that the thickness of the film is formed between 22.2 ± 26.0 ㎛ (see Figure 2A and 2B).

In addition, in order to compare the mechanical properties of the film introduced into the short-bleeding needle and the film formed under the prior patent conditions, the tensile properties were confirmed using a universal testing machine (UTM, Instron 3253). The chitosan-catechol solution used in Example 1 and 200 μl of the solution corresponding to the prior patent condition were dried at room temperature for 24 hours, and then a film of 1 × 2 cm was formed. Using a 50N Load cell, while pulling at a speed of 5mm / min, the maximum load value at the moment of tearing the film was measured (see Figure 2C).

Further, specifically, Figure 3A is to confirm the hemostatic effect using the lower extremity vein model of the rat, Figure 3B is to confirm the hemostatic effect using the ventricular bleeding model of the heart of the rat. Figure 3C shows the chitosan catechol film fixed at the injection site after injection into the heart. Experiments were conducted to evaluate the hemostatic time of the short bleeding needle prepared in Example 1, the result of the bleeding needle prepared in Example 1 is that the film formed of chitosan-catechol solution is fixed to the tissue immediately Accordingly, it was confirmed that excellent hemostatic effect within 5 seconds (see Fig. 3A).

In addition, the mechanical properties of the film coated on the short-term bleeding injection needle prepared in Example 1 was stronger than that of the film formed under the preconditions, so that it was confirmed that hemostasis occurred even after direct injection into the heart tissue (see FIG. 3B). .

Therefore, the short-term bleeding-free needle according to the present invention can immediately suppress the bleeding caused by the injection, diabetic patients, chemotherapy patients, hemophilia patients, patients with hemostatic capacity as well as patients with blood rejection reactions, children It can also be useful for injections, especially for hemostasis in organs with large movements such as the heart.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

Example

Preparation Example 1 Preparation of Chitosan Introduced with Catechol

About 30% acetylated chitosan (chitosan 70/100, 24204, Heppe Medical Chitosan) 3g was dissolved in 292mL HCl solution (pH = 2) for 6 hours. The pH was adjusted to 5.5 by slowly adding 8 mL of 0.5N NaOH solution to the chitosan solution. The prepared 1% chitosan solution was stabilized for 12 hours.

2.37 g of 3- (3,4-dihydroxyphenyl) propanoic acid was added to the prepared chitosan solution. Subsequently, as a reactant for forming an amide bond (-CONH-) between an amine (-NH ₂ ) group of chitosan and a carboxy group (-COOH) of 3- (3,4-dihydroxyphenyl) propanoic acid. 2.02 g of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was dissolved in 50 mL of ethanol and added thereto, and the reaction was performed for 1 hour after adjusting the acidity of the solution to pH 4.5. Chitosan to which catechol was introduced was prepared in this process.

In order to remove unreacted 3- (3,4-dihydroxyphenyl) propanoic acid and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), the solution after the reaction was subjected to a dialysis membrane [ Molecular weight cut-off 12,000-15,000] was dialyzed for 2 days in 4.5 L tertiary distilled water containing sodium chloride, 5N HCl, 3 mL. It was dialyzed for 2 days in 4.5 L tertiary distilled water containing 5N HCl, 3 mL. Finally, after dialysis with tertiary distilled water for 6 hours, lyophilization was performed to prepare chitosan into which catechol was introduced (Formula 5, x: y: z = 6.2: 0.8: 3).

Formula 5

Example 1 Preparation of Short-Gleet Needle (26G)

) 및 산화된 카테콜기(

)가 도입되어 가교된 키토산 용액(이하, '키토산-카테콜 용액'으로 명명)을 준비하였다.6 mg of catechol-introduced chitosan prepared in Preparation Example 1 was dissolved in 400 μl of tertiary distilled water, and then stored at 60 ° C. for 3 days to induce oxidation and crosslinking of catechol groups. Thus, catechol group (

) And oxidized catechol groups (

) Was introduced to prepare a crosslinked chitosan solution (hereinafter referred to as 'chitosan-catechol solution').

The degree of catechol group oxidation of the chitosan-catechol solution was determined by measuring the absorbance at a wavelength of 500 nm through ultraviolet-visible spectroscopic spectra. When crosslinking of the oxidized catechol group and the amine group of chitosan is formed, the absorbance at 500 nm wavelength appears. Therefore, when the storage condition of a chitosan-catechol solution was three days at 60 degreeC, it was confirmed that the absorbance shown at 500 nm becomes 0.02 or more.

On the other hand, for the stable coating of the prepared chitosan-catechol solution, a 26G-thick needle was subjected to oxygen plasma treatment for 10 minutes. Thereafter, 6.5 μl of the chitosan-catechol solution was placed on the needle and rotated at 40 rpm for 1 hour at room temperature, and the coating was performed twice to complete the short-bleeding needle and dried for one day for further drying. Further crosslinking may be induced in the course of drying for one day.

Example 2 Preparation of Short-Gleet Needle (30G)

For stable coating of the chitosan-catechol solution used in Example 1, a 30G-thick needle was subjected to oxygen plasma treatment for 10 minutes. Subsequently, 4.2 μl of the chitosan-catechol solution was placed on the needle and rotated at 40 rpm for 45 hours at room temperature, and the coating was performed twice to complete the short-bleeding needle and dried for one day for further drying.

Example 3: Preparation of short-term bleeding injection needle (30G) enclosed with fluorescent protein

In the chitosan catechol solution used in Example 1, 10 µg of albumin protein in which rhodamine was bound was dissolved. Short-term bleeding needles were prepared in the same manner as in Example 2 using the solution.

Experimental Example

Experimental Example 1: Storage time in the manufacturing process of short-term bleeding needle

In order to optimize the storage time in the manufacturing process of the short-term bleeding needle prepared in Example 1, the absorbance at 500nm for the solution stored at 4 ℃ 5 days and the solution stored at 60 ℃ 1 day is shown in Figure 1B and Shown in Figure 1C, respectively. As a result, when stored for 4 to 5 days, it was confirmed that the absorbance appeared similarly when stored for 3 days at 60 ℃. In addition, even when stored at 60 ℃ it was confirmed that when stored for 1 day, it is oxidized to a degree not significantly different from the solution stored for 3 days at 4 ℃. Therefore, the storage time for which the degree of oxidation varies with temperature was set to 3 days. For the subsequent experiments, the characteristics of the polymer solution appearing with temperature were compared.

Experimental Example 2: Observation of the film thickness of the short bleeding needle

In order to analyze the film thickness of the short bleeding needle prepared in Example 1, a scanning electron microscope (Hitachi S-4800) was used, and compared with the film thickness of the needle prepared in the prior patent conditions. The results are shown in Figures 2A and 2B.

Figure 2A shows the form of the film coated on the short-bleeding needle prepared in Example 1, Figure 2B is a graph showing the thickness of the film.

As shown in FIG. 2, the film of the needle prepared with the solution stored at 60 ° C. for 3 days was found to have a reduced thickness than the film prepared with the solution stored at 4 ° C. for 3 days. Specifically, it was confirmed that the 14.1 ± 5.4 ㎛ and 22.2 ± 26.0 ㎛, respectively.

Experimental Example 3: Comparative Evaluation of Mechanical Properties of Film

In order to compare the mechanical properties of the film of the short-term bleeding needle prepared in Example 1, and the mechanical properties of the film prepared under the prior patent conditions, a universal testing machine (UTM, Instron 3253) was used, the results are shown in FIG. Shown in 2C.

Figure 2C is a film of a needle prepared with a solution stored for 3 days at 60 ℃ corresponding to the conditions of the short-term bleedless needle prepared in Example 1, a film and a cateche prepared with a solution stored for 3 days at 4 ℃ This is a result of comparing the mechanical properties of the dry film for 30 days to maximize the oxidation of the call. As a result, as the oxidation of the catechol proceeds more, it was confirmed that the strength of the film was increased, and the maximum load value at the instant of tearing of each film was 3.25 for the film formed of the solution stored at 4 ° C. for 3 days. The film formed from the solution stored at ± 1.22N at 60 ° C. for 3 days was 6.07 ± 3.65N, and the maximum load value increased with more oxidation. In addition, when the oxidation of the film is continued for 30 days, the load value was confirmed to increase to 13.4 ± 4.74N.

Experimental Example 4: Evaluation of in vivo hemostatic capacity

In vivo experiments were performed to evaluate the hemostatic ability of the bleeding-free needles prepared in Example 1.

First, the rat leg vein model (SD rat, 8 week old male, 250 g) and the rat heart model (SD rat, 8 week old male, 250 g) were prepared. Then, the needle was removed within 5 seconds after the injection to confirm that the film coated on the surface of the short-bleeding needle prepared in Example 1 shows an immediate hemostatic effect. The results are shown in FIG.

Figure 3 is an image showing the results of the experiment in vivo on the bleeding needle prepared in Example 1. Specifically, FIG. 3A shows the hemostatic effect using the rat lower leg vein model prepared in Example 1, and FIG. 3B shows the rat heart model using the needle prepared in Examples 2 and 3 The observed hemostatic effect and the film fixed on the heart were confirmed.

As shown in Figure 3A, the bleeding needle prepared in Example 1 was shown to have a significantly better hemostatic effect compared to the general needle as the film formed of chitosan-catechol solution is immediately fixed to the tissue.

In addition, as shown in FIG. 3B, the general needle showed bleeding when injected into the rat heart, whereas the bleeding did not occur at all when injected with the short-bleeding needle prepared in Example 2. In addition, no bleeding occurred even after injection with the short-bleeding needle prepared in Example 3, and the film fixed to the heart when the needle was removed was replaced with a fluorescence imaging device (Xenogen, IVIS 200, USA). I could confirm it.

)가 키토산에 도입되어 가교된 키토산으로 코팅된 주사바늘은 주사시 발생하는 출혈을 즉각적으로 억제할 수 있어, 당뇨병 환자, 항암치료 환자, 혈우병 환자 등 지혈능력이 떨어지는 환자뿐만 아니라 혈액거부반응을 보이는 환자, 어린이의 주사에도 유용하게 사용할 수 있는 효과가 있으며, 나아가 심장과 같은 박동이 강하고 혈액이 많은 장기의 출혈도 즉각적으로 억제할 수 있는 효과도 있다.As such, the oxidized catechol group according to the present invention (

) Is introduced into chitosan and coated with crosslinked chitosan, which can immediately suppress bleeding caused by injections, resulting in blood rejection as well as patients with low hemostatic ability such as diabetics, chemotherapy patients, and hemophilia patients. It is also useful for the injection of patients and children, and also has the effect of immediately inhibiting bleeding of strong heart-like, bloody organs.

The non-bleeding needle having immediate hemostatic ability according to the present invention can immediately suppress bleeding occurring regardless of the injection time, and thus can be useful for injection of patients with blood coagulation disorder.

As described above in detail specific parts of the present invention, it will be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

Method for preparing a bleeding needle comprising the following steps: (a) leaving the catechol-group introduced chitosan-catechol solution at a temperature of 50-70 ° C. for 1-5 days to induce oxidation and crosslinking of the catechol group; And (b) coating the surface of the needle with the chitosan-catechol solution. The method of claim 1, Method of producing a bleeding injection needle, characterized in that 2 to 10% cross-linked on a molar basis of the catechol group. The method of claim 1, The chitosan-catechol is a method of preparing a bleeding injection needle, characterized in that the compound of Formula 3: Formula 3

In formula (3), L is a single bond, C _2-8 straight or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene. The method of claim 1, The chitosan-catechol is a method of preparing a bleeding injection needle, characterized in that the compound of Formula 4: Formula 4

In Formula 4, L is a single bond, C _2-8 linear or branched alkylene or -C (= 0) -R ^1- , and R ¹ is a single bond or C _2-8 straight or branched alkylene. The method of claim 1, After placing the cross-linked chitosan-catechol solution on the needle, the method of producing a blood-free needle, characterized in that the coating is rotated at a constant speed. The method of claim 1, Method of producing a blood-free needle, characterized in that the coating thickness is adjusted according to the amount of crosslinked chitosan-catechol solution. The method of claim 4, wherein A method of producing a blood-free needle comprising the step of performing an oxygen plasma treatment before placing the crosslinked chitosan-catechol solution on the needle. The method of claim 1, Method of producing a blood-free injection needle, characterized in that for performing the additional drying step after the step (b).

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