KR20190073916A - Method for manufacturing device of temporary vascular closure - Google Patents

Abstract

The present invention relates to a method for manufacturing a device for temporary vascular closure. The method for manufacturing a device for temporary vascular closure comprises a first vascular closure device manufacturing step of manufacturing a first vascular closure device by dissolving a temperature-sensitive polymer in a solvent. Accordingly, the present invention can provide a technique for a device for temporary vascular closure which can temporarily block blood flow during surgery.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for manufacturing a temporary vessel closure device,

The present invention relates to a method of manufacturing a temporary vessel closure device.

Conventionally, surgical procedures requiring incision of the body tissue or organ have a possibility of causing a large amount of hemorrhage, so that medical attempts have been made in the past to control hemorrhage occurring during surgery.

Especially, in the case of vascular anastomosis, if the blood flow can not be blocked quickly, the operator 's workability is lowered and the operation time is delayed more than necessary and the operation success rate is decreased.

In this regard, Korean Patent Laid-Open Publication No. 2013-0118668 discloses a technique of securing a stent inside a blood vessel and inserting a blood vessel blocking member into a stent fixed to the inner wall of the blood vessel to block blood flow.

However, in the method of inserting the blood vessel blocking member into the inside of the stent, the process of fixing the stent to the desired position must be preceded. In order to reopen the blocked blood flow, the blocking member must be removed, There was also the possibility of additional vessel damage during the procedure for blocking blood flow.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a technique for temporarily closing a blood vessel that can temporarily block blood flow during an operation.

The present invention has been made in view of the above problems, and it is an object of the present invention to provide an apparatus and method for controlling the same.

According to an aspect of the present invention, there is provided a method for manufacturing a temporary vascular closure device, comprising the steps of: preparing a first vascular closure device by dissolving a temperature sensitive polymer in a solvent, The temperature responsive polymer may be 20 to 30 wt% and the solvent may be 70 to 80 wt% in the manufacturing step of a vascular closure device.

According to another aspect of the present invention, there is provided a method for manufacturing a temporary vessel closure device, comprising: preparing a polymer solution by dissolving a thermosensitive polymer in a solvent; And a second vessel closing device for preparing a second vessel closing device by injecting a first biodegradation adjusting agent into the polymer solution so as to control the biodegradation rate of the temperature responsive polymer.

Also, in the step of preparing the polymer solution, the thermosensible polymer is mixed at 19 to 20 wt% and the solvent is mixed at 78 to 80.9 wt%. In the second vessel closure device manufacturing step, the first biodegradation agent is mixed with 0.1 to 2 Can be added to the polymer solution in weight%.

The method of manufacturing a temporary vessel closure device may further include a step of injecting a second biodegradability adjusting agent into the second vessel closure device and stirring the second biodegradation rate adjusting agent. In the adjusting agent injecting step, 1 biodegradability modifier may be added in an amount of 0.1 to 9 parts by weight per 100 parts by weight of the biodegradability regulator.

In the method for manufacturing a temporary vessel closure device, the solution prepared in the step of injecting the modifier is heated to 70 to 90 ° C for 15 to 24 hours to control the degree of biodegradation of the second vessel closure device, And a third vessel closure device manufacturing step of manufacturing a third vessel closure device having a slower biodegradation rate.

The thermosensitive polymer may be selected from the group consisting of polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer, polyethylene glycol-poly (lactic-co-glycolic acid) -polyethylene glycol copolymer, polyethylene glycol-polycaprolactone-polyethylene glycol copolymer, Methoxypolyethylene glycol-polyester copolymer, poly (N-isopropylacrylamide), and combinations thereof.

The first biodegradation modifier may be at least one selected from the group consisting of carboxymethylcellulose, alginate, hyaluronic acid, hydroxyethylcellulose, pullulan, and combinations thereof.

The second biodegradation regulator may be at least one selected from the group consisting of citric acid, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide, and combinations thereof .

The solution of the above-mentioned problems is merely illustrative and should not be construed as limiting the present invention. In addition to the exemplary embodiments described above, there may be additional embodiments described in the drawings and the detailed description of the invention.

As described above, according to various embodiments of the present invention, since the biodegradation rate of a temporary vessel closure device can be controlled, it is possible to provide an optimal vessel closure technique at a variable operation time.

That is, the present invention improves the workability of a practitioner when used in an operation requiring interruption of blood flow, such as an anastomosis, and can adjust the biodegradation time of the vessel closure apparatus considering the time required for the operation, It can flexibly respond to the operation time which is variable according to the degree of difficulty.

In addition, since the transient vascular closure device according to the present invention is biodegraded in the body in a short time after the operation is completed, the vascular closure device has an effect of preventing the inflammatory reaction that may occur when the components of the vascular closure device remain in the body.

In addition, since the present invention exists in a liquid form at room temperature, it is convenient to perform a procedure of injecting blood into the blood vessel requiring interception of the blood flow, and it is unnecessary to perform a separate procedure to remove the vessel closing apparatus, .

Furthermore, since the present invention is maintained in a hydrogel state due to body temperature after being injected into a blood vessel, it functions as a physical barrier for blocking blood flow, thereby blocking blood flow rapidly.

The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned can be clearly understood by those skilled in the art from the description of the claims.

1 is a flow chart showing a method for manufacturing a temporary vessel closure device according to a first embodiment of the present invention.
2 is a flow chart showing a method of manufacturing a temporary vessel closure device according to a second embodiment of the present invention.
3 is a flowchart showing a method of manufacturing a temporary vessel closure device according to a third embodiment of the present invention.
Fig. 4 shows the results of the time-series biodegradability test of Production Example 1 of the present invention.
Fig. 5 shows the results of the time-series biodegradability test of Production Example 2 of the present invention.
6 shows the results of the time-series biodegradability test of Production Example 3 of the present invention.
7 shows the results of the time-series biodegradability test of Production Example 4 of the present invention.
Fig. 8 shows the results of the time-course biodegradability test of Production Example 5 of the present invention.
Fig. 9 shows the results of the time-series biodegradability test of Production Example 6 of the present invention.
Fig. 10 shows the results of the time-series biodegradability test of Production Example 7 of the present invention.
Fig. 11 shows the results of the time-series biodegradability test of Comparative Example 2. Fig.
Fig. 12 shows the results of the time-series biodegradability test of Production Example 8 of the present invention.
Fig. 13 shows the results of the time-course biodegradability test of Production Example 9 of the present invention.
Fig. 14 shows the results of the time-series biodegradability test of Production Example 10 of the present invention.
Fig. 15 shows the results of the time-series biodegradability test of Production Example 11 of the present invention.
Fig. 16 shows the results of the time-series biodegradability test of Production Example 12 of the present invention.
17 shows the results of the time-series biodegradability test of Production Example 13 of the present invention.
18 shows the results of the time-series biodegradability test of Production Example 14 of the present invention.
Fig. 19 shows the results of the time-series biodegradability test of Comparative Example 4. Fig.
Fig. 20 shows the results of the time-series biodegradability test of Comparative Example 5. Fig.
Fig. 21 shows the results of the time-series biodegradability test of Comparative Example 6. Fig.
Fig. 22 shows the results of the time-series biodegradability test of Production Example 15 of the present invention.
23 shows the results of the time-series biodegradability test of Production Example 16 of the present invention.
24 shows the results of the time-series biodegradability test of Production Example 17 of the present invention.
25 shows the results of the time-series biodegradability test of Production Example 18 of the present invention.
Fig. 26 shows the results of the time-series biodegradability test of Comparative Example 7. Fig.

The preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings, in which the technical parts already known will be omitted or compressed for simplicity of explanation.

In the following embodiments, the terms first, second, and the like are used for the purpose of distinguishing one element from another element, not the limitative meaning.

In the following examples, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

In the following embodiments, terms such as inclusive or having mean that a feature or element described in the specification is present, and do not exclude the possibility that one or more other features or elements are added in advance.

If certain embodiments are otherwise feasible, the particular process sequence may be performed differently from the sequence described. For example, two processes that are described in succession may be performed substantially concurrently, and may proceed in the reverse order of the described order. That is, each step of the methods described herein may be suitably practiced in any order unless otherwise stated or clearly contradicted by context.

The term "about," as used in reference to figures throughout the specification, when used in the figures or in close proximity to the numerical values when both manufacturing and material tolerances inherent in the stated sense are presented, Absolute numbers are used to prevent unauthorized exploitation by unauthorized intruders of the mentioned disclosure. In certain embodiments, the term " about "means a standard deviation within 1, 2, 3 or 4. In another embodiment, the term "about" is used to refer to any of the following: 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% Respectively.

A method for manufacturing a temporary vessel closure device according to a first embodiment of the present invention will be described with reference to the flowchart shown in FIG.

1. First Vascular Obstacle Preparation Step <S101>

In this step, the process of preparing the first vessel closure device by dissolving the thermosensitive polymer in a solvent may be performed. In the first embodiment, the thermosensitive polymer is a polymer whose physical properties are changed by temperature. The thermosensitive polymer maintains a liquid form at room temperature (for example, 20 ± 5 ° C) and is maintained at a temperature condition such as body temperature (for example, ), The physical properties may be changed in the form of a gel.

The temperature responsive polymer according to the first embodiment may be mixed with a solvent in an amount of 20 to 30% by weight. As a specific example, the content of the thermosensitive polymer may be about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt% About 28% by weight, about 29% by weight, or about 30% by weight. In addition, the content of the thermosensitive polymer may be in a range of at least one of the above values and one or less of the above values.

For example, the content range of the thermosensitive polymer may be in the range of about 20 wt% to about 24 wt%, about 25 wt% to about 30 wt%, or about 20 wt% to about 30 wt%. The temperature responsive polymer according to the first embodiment can maintain the temperature responsiveness according to the room temperature and body temperature conditions within the above range.

If the thermosensitive polymer is less than 20% by weight, the thermosensitive polymer is poor in temperature sensitivity and gelation does not occur at the body temperature. Even if gelation occurs, the gel state may not be maintained for a long time and may return to the liquid phase. When the thermosensitive polymer is more than 30% by weight, gelation occurs at a temperature lower than the body temperature, which is inconvenient to inject into the blood vessel. Therefore, the content of the thermosensitive polymer is preferably within the above-mentioned range.

As the thermosensitive polymer which can be used in the first embodiment, polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer (PEG-PPG-PEG), polyethyleneglycol-poly Polyethylene glycol-poly (lactic-co-glycolic acid) -polyethylene glycol copolymer, PEG-PLGA-PEG), polyethylene glycol-polycaprolactone-polyethylene glycol copolymer (polyethylene glycol-polycaprolactone PEG-PCL-PEG), methoxy polyethylene glycol-polyester copolymer (mPEG-polyester), poly (N-isopropylacrylamide) And at least one selected from the group consisting of combinations thereof.

In the first embodiment, the solvent may be water, distilled water, ion-exchanged water or ultra pure water as an aqueous solvent, but is not limited thereto, and any solvent other than the above-mentioned solvents may be used as long as it is a solvent capable of dissolving the thermosensitive polymer.

In this step, the solvent is 70 to 80% by weight and may be mixed with the thermosensitive polymer. In a specific example, the content of solvent is about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt% %, About 79% by weight, or about 80% by weight. And, the content of the solvent may be in the range of at least one of the above values and one or less of the above values.

For example, the solvent may range from about 70 wt% to about 74 wt%, from about 75 wt% to about 80 wt%, or from about 70 wt% to about 80 wt%. When the solvent according to the first embodiment is mixed with the thermosensitive polymer in the above range, the temperature responsiveness of the thermosensitive polymer can be appropriately maintained.

If the amount of the solvent is less than 70% by weight, the content of the thermosensitive polymer in the whole blood vessel closure component relatively increases, and the gelation of the thermosensitive polymer may occur at a temperature lower than the body temperature. The content of the thermosensitive polymer is relatively decreased to lower the temperature responsiveness of the thermosensitive polymer, so that the content of the solvent is preferably within the above-mentioned range.

A method for manufacturing a temporary vessel closure device according to a second embodiment of the present invention will be described with reference to the flowchart shown in FIG.

1. Polymer solution preparation step < S201 >

In this step, a process of preparing a polymer solution by dissolving the thermosensitive polymer in a solvent may be performed. In the second embodiment, the temperature responsive polymer is mixed at 19 to 20 wt% and the solvent is mixed at 78 to 80.9 wt% to prepare a polymer solution. The types of the thermosensitive polymer and the solvent that can be applied in this step can be applied in the same manner as in the first embodiment described above, so duplicate explanation is omitted.

The temperature responsive polymer according to the second embodiment may be mixed with a solvent in an amount of 19 to 20% by weight. As a specific example, the content of thermosensitive polymer is about 19% by weight, about 19.1% by weight, about 19.2% by weight, about 19.3% by weight, about 19.4% by weight, about 19.5% by weight, about 19.6% by weight, about 19.7% by weight, About 19.8% by weight, about 19.9% by weight, or about 20% by weight. In addition, the content of the thermosensitive polymer may be in a range of at least one of the above values and one or less of the above values.

For example, the content range of the thermosensitive polymer may be in the range of about 19 wt% to about 19.4 wt%, about 19.5 wt% to about 20 wt%, or about 19 wt% to about 20 wt%. The temperature responsive polymer according to the second embodiment can maintain the temperature responsiveness according to the room temperature and body temperature conditions within the above range.

If the temperature responsive polymer is less than 19% by weight, the temperature sensitivity is poor and gelation does not occur at the body temperature condition. Even if gelation occurs, the gel state may not be maintained for a long time and may return to the liquid phase. If the temperature responsive polymer is more than 20% by weight, gelation may occur at a temperature lower than the body temperature, and it is difficult to control the biodegradation rate of the thermosensitive polymer to a level intended by the user. Therefore, Is preferably carried out within the above-mentioned range.

In this step, the solvent is 78 to 80.9% by weight and may be mixed with the thermosensitive polymer. As a specific example, the content of solvent may be about 78% by weight, about 79% by weight, about 80% by weight, about 80.1% by weight, about 80.2% by weight, about 80.3% by weight, about 80.4% by weight, about 80.5% %, About 80.7 wt%, about 80.8 wt%, or about 80.9 wt%. And, the content of the solvent may be in the range of at least one of the above values and one or less of the above values.

For example, the range of solvents may range from about 78 wt% to about 79 wt%, from about 79 wt% to about 80 wt%, from about 80.1 wt% to about 80.9 wt%, or from about 78 wt% to about 80.9 wt% . When the solvent according to the second embodiment is mixed with the thermosensitive polymer in the above range, the temperature responsiveness of the thermosensitive polymer can be suitably maintained.

If the amount of the solvent is less than 78 wt%, the content of the thermosensitive polymer in the entire vasoconstrictor component relatively increases, causing gelation of the thermosensitive polymer at a temperature lower than the body temperature. When the solvent exceeds 80.9 wt% The content of the thermosensitive polymer may be relatively decreased to lower the temperature responsiveness of the thermosensitive polymer, so that the content of the solvent is preferably within the range described above.

2. Second Vessel Closure Equipment Manufacturing Step < S202 >

In this step, a process of manufacturing a second vessel closure device may be performed by injecting a first biodegradation agent into the polymer solution prepared in step S201 so as to control the biodegradation rate at which the thermosensitive polymer is biodegraded in the body.

Specifically, in this step, the first biodegradability adjusting agent may be added to the polymer solution at 0.1 to 2% by weight. In the second embodiment, the first biodegradation modifier is used to slow the biodegradation rate of the thermosensitive polymer included in the second vascular closure device such that the biodegradation rate of the thermosensitive polymer contained in the first vascular closure device is degraded at a relatively slow rate as compared with the biodegradation rate of the temperature- It plays a role.

In a second embodiment, the content of the first biodegradation modifier is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7% About 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 0.9 wt% By weight, about 1.9% by weight, or about 2% by weight. Also, the content of the first biodegradation modifier may be in the range of at least one of the above values and one or less of the above values.

For example, the first biodegradability modifier may range from about 0.1 wt% to about 0.5 wt%, from about 0.6 wt% to about 1 wt%, from about 1.1 wt% to about 1.5 wt%, from about 1.6 wt% to about 2 wt% By weight or from about 0.1% by weight to about 2% by weight. The first biodegradation modifier according to the second embodiment can control the biodegradation rate of the thermosensitive polymer to a suitable level within the above range and maintain the temperature responsiveness of the thermosensitive polymer according to the room temperature and body temperature conditions.

If the amount of the first biodegradability adjusting agent is less than 0.1% by weight, the viscosity of the second vessel closure device becomes too low, and the temperature sensitive polymer easily sweeps away by the bloodstream in the body and biodegradation may occur. If the content of the second vessel is higher than 2% by weight, the viscosity of the second blood vessel closure device becomes too high and the gel state is maintained even at room temperature. Therefore, the temperature sensitivity of the thermosensitive polymer is visually confirmed And there is a problem that it is inconvenient to inject the second vessel closure device into the treatment site, so that the content of the first biodegradation agent is preferably within the above-mentioned range.

In the second embodiment, the first biodegradation regulator is selected from the group consisting of carboxymethylcellulose (CMC), alginate, hyaluronic acid (HA), hydroxyethylcellulose (HEC), pullulan, And a combination thereof.

In this step, a stirring process may be further performed to stir the second vessel closure device prepared by injecting the first biodegradation agent into the polymer solution. For example, the second vascular closure device may be agitated at 100 to 200 rpm for 10 to 30 minutes, but the agitation speed and time may be adjusted by changing the content of each component contained in the second vascular closure device or other experimental conditions This is possible.

A method for manufacturing a temporary vessel closure device according to a third embodiment of the present invention will be described with reference to the flowchart shown in FIG.

1. Polymer solution preparation step <S301>

In this step, a process of preparing a polymer solution by dissolving the thermosensitive polymer in a solvent may be performed. In the third embodiment, the thermosensitive polymer is mixed with 19 to 20 wt% and the solvent is mixed with 78 to 80.9 wt% to prepare a polymer solution. The temperature sensitive polymer and the type and content of the solvent applicable in this step can be applied in the same manner as in the second embodiment described above, so duplicate explanation is omitted.

2. Second Vessel Closure Equipment Manufacturing Step < S302 >

In this step, the first biodegradability adjusting agent may be added to the polymer solution prepared in step S301 to control the biodegradation rate at which the thermosensitive polymer is biodegraded in the body. The kind and content of the first biodegradability adjusting agent applicable in this step can be applied in the same manner as in the second embodiment described above, so that a duplicated description will be omitted.

3. Adjuster injection step <S303>

In this step, a second biodegradability adjusting agent may be added to the second vessel closure device manufactured in step S302 and stirred. In the third embodiment, the second biodegradation modifier reacts with the first biodegradability modifier in the third vessel closure preparation step to be described later to form an interpenetrating polymer network.

The second biodegradability adjusting agent according to the third embodiment may be added in an amount of 0.1 to 9 parts by weight per 100 parts by weight of the first biodegradability adjusting agent. As a specific example, the content of the second biodegradability modifier may be about 0.1 part by weight, about 0.2 part by weight, about 0.3 part by weight, about 0.4 part by weight, about 0.5 part by weight, about 0.6 part by weight About 3 parts by weight, about 4 parts by weight, about 5 parts by weight, about 6 parts by weight, about 7 parts by weight, about 1 part by weight, about 0.7 part by weight, about 0.8 part by weight, about 0.9 part by weight, about 1 part by weight, about 2 parts by weight, About 8 parts by weight or about 9 parts by weight. In addition, the content of the second biodegradation modifier may be in the range of at least one of the above values and not more than one of the above values.

For example, the content range of the second biodegradability modifier may be in the range of about 0.1 to about 0.5 parts by weight, about 0.6 to about 1 part by weight, about 2 to about 1 part by weight based on 100 parts by weight of the first biodegradability modifier 4 parts by weight, about 5 parts by weight to about 7 parts by weight, about 8 parts by weight to about 9 parts by weight, about 0.1 to about 4 parts by weight, about 5 parts by weight to about 9 parts by weight, 9 parts by weight. The second biodegradation modifier according to the third embodiment can regulate the biodegradation rate of the thermosensitive polymer to an appropriate level within the above range and can maintain the formulation of the third vascular closure device in a liquid state at room temperature.

If the second biodegradation modifier is less than 0.1 part by weight based on 100 parts by weight of the first biodegradability modifier, the reaction with the first biodegradability modifier is weak and formation of the interpenetrating polymer network is limited. Therefore, It is difficult to produce a third vessel closure device having a velocity lower than the biodegradation velocity of the vessel.

When the second biodegradation modifier exceeds 9 parts by weight, the degree of reactivity between the first biodegradation modifier and the second biodegradability modifier becomes excessively high, so that the inter-penetration polymer network is excessively formed. Therefore, in the third vessel closure device, Since the reactants of the biodegradation modifiers change to water-insoluble, they are not easily mixed with the thermosensitive polymer, and the gel state is maintained even at room temperature. Therefore, it is troublesome to inject the vessel closure device into the treatment site. Therefore, it is preferable that the content of the second biodegradability modifier is within the above-mentioned range.

In the third embodiment, the second biodegradation regulator is citric acid, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, EDC ), N-hydroxysuccinimide (NHS), and combinations thereof.

The stirring speed and time can be controlled flexibly according to the content of each component contained in the stirring solution and other experimental conditions. The agitation speed and the agitation time can be controlled flexibly at 100 to 200 rpm for 10 to 30 minutes.

4. Third vessel closure tool manufacturing step < S304 >

In this step, the solution prepared in step S303 is heated to 70 to 90 DEG C for 15 to 24 hours to regulate the biodegradation degree of the second vascular closure device, whereby the third vascular closure device having a slower biodegradation rate than the second vascular closure device Can be performed.

That is, the first biodegradation modifier and the second biodegradability modifier stirred in step S303 may react with each other through this step to form an interpenetrating polymer network. In this case, when heating is performed within the time range and the temperature range described above, since the reaction between the first biodegradation degree regulator and the second biodegradation degree regulator is weak, it is difficult to sufficiently form the interpenetrating polymer network. It is difficult to produce a third vascular closure device having a rate lower than the biodegradation rate. When the solution is heated beyond the time range and the temperature range described above, the manufacturing time becomes unnecessarily long or the production efficiency decreases It is preferable to produce the third vessel closure device within the above-described time range and temperature range.

In addition, it is preferable to heat the solution in a state in which the lid is closed so that the solvent contained in the solution prepared in the step S303 upon heating in this step is not evaporated.

Meanwhile, the temporary vessel closure device manufactured according to various embodiments of the present invention may further include 0.1 to 1 part by weight of the anti-thrombogenic agent per 100 parts by weight of the whole vessel closure device. In addition, the antithrombotic agent may be, but not limited to, heparin, streptokinase, urokinase, and the like.

Hereinafter, the present invention will be described in more detail with reference to specific production examples and experimental examples. The following Preparation Examples and Experimental Examples are merely examples for helping understanding of the present invention, and thus the scope of the present invention is not limited thereto or limited.

&Lt; Embodiment 1 >

Preparation of first vessel closure device

Polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer (Poloxamer 407) and Preparation Example 4 were prepared in the same manner as in Examples 1 to 3 and Comparative Examples 1 and 2, except that the temperature-responsive macromolecule (Preparation Example 4: methoxypolyethylene glycol-poly (Lactic-co-glycolic acid) -Polyethylene Glycol Copolymer, Production Example 7 is Poly (N-vinylpyrrolidone) -Polyethylene Glycol Copolymer, Production Example 5 is Polyethylene Glycol-Polycaprolactone-Polyethylene Glycol Copolymer, Production Example 6 is Polyethylene Glycol- Isopropylacrylamide)) and a solvent (water) were mixed to prepare a first vascular closure device. In Table 1, the unit of each value is grams.

ingredient Production Example 1 Production Example 2 Production Example 3 Production Example 4 Production Example 5 Production Example 6 Production Example 7 Comparative Example 1 Comparative Example 2 Temperature-responsive polymer 20 25 30 20 22 25 29 15 45 menstruum 80 75 70 80 78 75 71 85 55

Test and evaluation method of first vessel closure device

1. Biodegradability test

1) The sample is placed in a constant-temperature water bath at 37 ° C for 10 minutes to gel.

2) Add 40 ml of PBS solution to each of 4 tubes.

3) Put tubes in a constant temperature water bath at 37 ℃ for 10 minutes.

4) Put approximately 1 g of gelled reference sample in an aluminum pan and measure initial weight.

 4-1) Measure the initial weight of the aluminum pan.

 4-2) Measure the weight of the reference sample excluding the weight of aluminum pan.

5) Subsequent to measurement After placing the sample in a tube, immerse it in a shaking bath.

(shaking bath temperature: 37 DEG C, rpm: 120)

6) After putting in the shaking bath, take out each tube at intervals of 10 minutes, 25 minutes, 40 minutes and 60 minutes and measure the weight of the aluminum pan. At this time, the PBS solution in the aluminum pan is removed as much as possible, and only the request sample is left.

※ How to Remove PBS: Remove the aluminum pan from the tube, turn it over the resting sheet for 2-3 seconds, turn it over again and remove the PBS solution inside / outside the aluminum pan with tissue paper. At this time, care should be taken not to remove the sample on the inside of the aluminum fan.

7) When the weight of the aluminum pan measured in 6) is removed from the weight of the initial aluminum pan, the weight of the reference sample is calculated.

8) Compare the weight of 1 g of sample before commissioning with the weight of commissioned sample, and calculate the percentage of decomposition by the test.

9) Repeat steps 1) to 8) several times (three times) to derive the results.

The weight loss rate of each production example and comparative example with time was calculated using the above-described biodegradability test method (using the average weight of four reference samples per hour), and the results are shown in FIG. 4 to FIG. Referring to FIGS. 4 to 10, it can be confirmed that the biodegradation proceeds rapidly in 40 minutes or less in Production Examples 1 to 7. On the other hand, referring to FIG. 11, Comparative Example 2 shows a relatively slow rate It can be seen that biodegradation proceeds. For reference, Comparative Example 1 was not gelled at 37 ° C and maintained a liquid form, so biodegradation experiments based on gelling of the sample were not performed.

2. Viscosity Evaluation

The viscosity at 25 DEG C (spindle 64, 20 rpm) and the viscosity at 37 DEG C (spindle 64, 1 rpm) were measured using a Brookfield viscometer, and the results are shown in Table 2 below. In the following Table 2, the unit of viscosity value is cP (Centi poise).

Viscosity analysis temperature Production Example 1 Production Example 2 Production Example 3 Production Example 4 Production Example 5 Production Example 6 Production Example 7 Comparative Example 1 Comparative Example 2 25 ℃ 60 120 200 450 80 450 150 40 56000 37 ℃ 139200 136400 140500 120000 94600 130600 150000 250 154500

3. Experiment to confirm gelation by temperature

The tube containing each preparation example and comparative example was placed for 10 minutes while keeping the temperature of the water bath at 25 占 폚 and 37 占 폚, respectively, and the form of the composition was visually confirmed, and the results are shown in Table 3 below.

Temperature Production Example 1 Production Example 2 Production Example 3 Production Example 4 Production Example 5 Production Example 6 Production Example 7 Comparative Example 1 Comparative Example 2 25 ℃ Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Gel 37 ℃ Gel Gel Gel Gel Gel Gel Gel Liquid phase Gel

As shown in Table 3, the preparation examples 1 to 7 of the present invention maintain the liquid form at room temperature, so that the injection is convenient during the procedure and changes to gel form at the body temperature condition, so that the blood vessels are temporarily closed, Can be demonstrated. In addition, when the content of each component contained in the first vascular closure device is in excess or less than the input amount range of each component, it can not be gelled at the body temperature and the bleeding performance is poor, And thus it can be confirmed that it is not suitable for injecting the vessel closure device during the procedure.

&Lt; Embodiment 2 >

Preparation of second vessel closure device

Polyethyleneglycol-polypropylene glycol-polyethylene glycol copolymer (Poloxamer 407), Production Example 11 was poly (N-isopropyl (meth) acrylate) as a thermoreactive polymer in Production Examples 8 to 10 and Comparative Examples 3 to 6, Acrylamide), Production Example 12 is methoxy polyethylene glycol-polyester copolymer, Production Example 13 is polyethylene glycol-poly (lactic-co-glycolic acid) -Polyethylene Glycol Copolymer, Production Example 14 is Production of Polyethylene Glycol-Polycaprolactone (Polyethylene glycol copolymer) and a solvent (water) were mixed to prepare a polymer solution. To the polymer solution thus prepared, a first biodegradation regulator (Production Examples 8 to 10, Comparative Examples 3 to 6, Carboxymethylcellulose, Production Example 11 Hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, The content of each component is as shown in Table 4 below, and in the following Table 4, the unit of each value is grams.

ingredient Production Example 8 Production Example 9 Production Example 10 Production Example 11 Production Example 12 Production Example 13 Production Example 14 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Temperature-responsive polymer 19 20 19 19 20 20 19 15 25 19 20 menstruum 79 78 80 79 79 78 79 84 73 76 80 The first biodegradation modifier 2 2 One 2 One 2 2 One 2 5 0

Test and evaluation method of second vessel closure device

1. Biodegradability test

The biodegradability test of the second vascular closure device was carried out in the same manner as described above, and the weight loss rate of each preparation example and the comparative example with time was derived, and the results are shown in Figs. 12 to 21. Fig. 12 to 18, it can be confirmed that the biodegradation is completed within 2 hours in Production Examples 8 to 14. On the other hand, referring to FIGS. 19 to 21, Comparative Examples 4 and 5 are compared with Production Examples 8 to 14 It can be seen that the biodegradation proceeds at a relatively slow rate. In Comparative Example 6, since the first biodegradation level control agent is not included, it can be confirmed that the biodegradation proceeds at a rapid rate within one hour. For reference, Comparative Example 3 was not gelled at 37 占 폚 and maintained a liquid form, so that no biodegradation experiment based on gelling of the sample was performed.

2. Viscosity Evaluation

The viscosity at 25 DEG C (spindle 64, 20 rpm) and the viscosity at 37 DEG C (spindle 64, 1 rpm) were measured using a Brookfield viscometer, and the results are shown in Table 5 below. In the following Table 5, the unit of viscosity value is cP (Centi poise).

Viscosity analysis temperature Production Example 8 Production Example 9 Production Example 10 Production Example 11 Production Example 12 Production Example 13 Production Example 14 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 25 ℃ 36 360 24 150 108 36 216 560 150600 228500 60 37 ℃ 417600 577400 220500 499800 1075000 438600 561600 780 680400 890400 139200

3. Experiment to confirm gelation by temperature

The tube containing each preparation example and comparative example was placed for 10 minutes while keeping the temperature of the water bath at 25 占 폚 and 37 占 폚, respectively, and the form of the composition was visually confirmed, and the results are shown in Table 6 below.

Temperature Production Example 8 Production Example 9 Production Example 10 Production Example 11 Production Example 12 Production Example 13 Production Example 14 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 25 ℃ Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Gel Gel Liquid phase 37 ℃ Gel Gel Gel Gel Gel Gel Gel Liquid phase Gel Gel Gel

As shown in Table 6, the production examples 8 to 14 of the present invention maintain the liquid form at room temperature, so that the injection is convenient during the procedure and the gel form changes at the body temperature condition. Thus, the blood flow blocking effect and the hemostatic effect Can be demonstrated. In addition, when the content of the temperature-responsive polymer and the solvent contained in the second vascular closure device exceeds or falls below the input amount range of the component through the test results of Comparative Examples 3 to 6, the gelling ability can not be gelled at the body temperature, It can be confirmed that the gel is not suitable for injecting the vessel closure device during the procedure.

In addition, it can be seen from the experimental results of Comparative Examples 5 and 6 that the temperature responsiveness and biodegradability depend on the content of the first biodegradability modifier even though the content of the temperature-responsive polymer and the solvent is in the optimal range.

&Lt; Third Embodiment >

Preparation of third vessel closure device

The polymer solution was prepared by mixing the temperature-responsive polymer and the solvent in the amounts shown in Table 7 below, and a first biodegradability regulator was added to the prepared polymer solution. After complete dissolution, a second biodegradability modifier was added and stirred at 20 rpm for 30 minutes. Thereafter, the solution with stirring was put in a glass bottle, and the solution was heated in an oven at 80 캜 for 24 hours in a state that the lid was closed to prevent evaporation of the solvent. Thus, a first biodegradability adjusting agent and a second biodegradability adjusting agent To complete the third vessel closure device. The content of each component is as shown in Table 7 below, and the unit of each numerical value in the following Table 7 is grams.

ingredient Production Example 15 Production Example 16 Production Example 17 Production Example 18 Comparative Example 7 Comparative Example 8 Temperature-responsive polymer (Poloxamer 407) 19 19 19 19 19 19 Solvent (water) 79 79 79 79 79 79 The first biodegradation modifier (carboxymethylcellulose) 2 2 2 2 2 2 Second biodegradation degree
Modulator 0.18
(Citric acid) 0.09
(Citric acid) 0.12
(Citric acid) 0.04
(EDC, NHS) 0 0.3
(Citric acid)

Test and evaluation method of third vessel closure device

1. Biodegradability test

The biodegradability test of the third vessel closure device was carried out in the same manner as described above, and the weight loss rate of each preparation example and comparative example with time was derived, and the results are shown in Figs. 22 to 26. Fig. 22 to 25, it can be confirmed that the biodegradation is completed within 3 hours in Production Examples 15 to 18. On the other hand, referring to FIG. 26, in Comparative Example 7, since the second biodegradation level control agent is not included, To 18, the biodegradation proceeds at a relatively high rate.

For reference, in Comparative Example 8, as the second biodegradation modifier was excessively contained, the degree of reactivity between the first biodegradability modifier and the second biodegradability modifier was excessively high, so that the cross-linked polymer network was excessively formed and biodegradation was not progressed at all.

2. Viscosity Evaluation

The viscosity at 25 DEG C (spindle 64, 20 rpm) and the viscosity at 37 DEG C (spindle 64, 0.3 rpm) were measured using a Brookfield viscometer, and the results are shown in Table 8 below. In the following Table 8, the unit of the viscosity value is cP (Centi poise).

For reference, in Comparative Example 8, as the second biodegradation modifier was excessively contained, the reactivity between the first biodegradability modifier and the second biodegradability modifier was excessively high, so that the viscosity of the polymer network was not formed due to excessive formation of the interpenetrating polymer network.

Viscosity analysis temperature Production Example 15 Production Example 16 Production Example 17 Production Example 18 Comparative Example 7 Comparative Example 8 25 ℃ 4000 2000 2000 2500 36 Not measurable 37 ℃ 2000000 1980000 2000000 2000000 417600 Not measurable

3. Experiment to confirm gelation by temperature

The tube containing each preparation example and comparative example was placed for 10 minutes while maintaining the temperature of the water bath at 25 占 폚 and 37 占 폚, respectively, and the form of the composition was visually confirmed, and the results are shown in Table 9 below.

Temperature Production Example 15 Production Example 16 Production Example 17 Production Example 18 Comparative Example 7 Comparative Example 8 25 ℃ Liquid phase Liquid phase Liquid phase Liquid phase Liquid phase Gel 37 ℃ Gel Gel Gel Gel Gel Gel

As shown in Table 9, the preparation examples 15 to 18 of the present invention maintain the liquid form at room temperature, so that the injection is convenient during the procedure and the gel form changes at the body temperature condition. Thus, the blood flow blocking effect and the hemostatic effect Can be demonstrated. In addition, when the results of Comparative Example 7 are compared, it can be seen that, when the second biodegradation modifier is not included, it is limited to control the biodegradation rate slowly to a certain level or more. Also, the results of the experiment of Comparative Example 8 show that when the second biodegradation modifier is excessively contained, the degree of reactivity between the first biodegradation modifier and the second biodegradability modifier becomes excessively high, resulting in an excessive formation of the interpenetrating polymer network, Therefore, it can be confirmed that the second biodegradability control agent is not suitable for injecting a blood vessel closure device when the amount of the biodegradation agent exceeds the amount of each component.

As a result, according to various embodiments of the present invention, the viscosity of the thermosensible polymer contained in the vaso-occlusive container can be adjusted to an appropriate level by using the first biodegradation modifier and the second biodegradability modifier, and the biodegradation rate of the vaso- Can be adjusted. In other words, since the present invention can produce a temporary vessel closure device by controlling the rate of biodegradation of a vessel closure device, it is possible to provide a vessel closure device optimized for a variable operation time.

For example, the temporary vessel closure device according to the first embodiment can be applied to a vein suture having a diameter of 4 mm or less or a vein suture having an operation time of less than 40 minutes. The temporary vessel closure device according to the second embodiment can be applied to the operation of a blood vessel having a diameter of 4 mm or less or the operation of a blood vessel requiring an operation time of about 40 minutes to 2 hours, Applicable. The temporary vessel closure device according to the third embodiment can be applied to sophisticated vascular suture surgery or large vascular surgery, which requires an operation time of about 3 hours.

In addition, since the present invention is rapidly biodegraded in the body after the end of surgery, it has an effect of preventing the inflammatory reaction that may occur while the vascular closure component remains in the body.

In addition, since the present invention exists in a liquid state at room temperature, it is convenient to perform a procedure for injecting blood into a blood vessel site requiring interruption of blood flow. After injection into a blood vessel site, the blood vessel is closed due to the body temperature, It acts as a physical barrier and can temporarily block blood flow. For example, when a vascular closure device according to the present invention is injected into a blood vessel through a syringe, the vascular closure device is deformed into a hydrogel state by body temperature to block the blood flow in the blood vessel, thereby providing excellent hemostatic effect.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. And the scope of the present invention should be understood as the scope of the following claims and their equivalents.

Claims (8)

And a first vascular closure device manufacturing step of preparing a first vascular closure device by dissolving the thermosensitive polymer in a solvent,
The temperature-sensitive polymer is 20 to 30% by weight and the solvent is 70 to 80% by weight in the first vessel closure device manufacturing step
A method for manufacturing a temporary vessel closure device. Preparing a polymer solution by dissolving the thermosensitive polymer in a solvent to prepare a polymer solution; And
And a second vascular closure device manufacturing step of preparing a second vascular closure device by injecting a first biodegradability adjusting agent into the polymer solution so as to control the biodegradation rate of the thermosensitive polymer,
A method for manufacturing a temporary vessel closure device. 3. The method of claim 2,
In the polymer solution preparation step, the thermosensitive polymer is mixed at 19 to 20 wt% and the solvent is mixed at 78 to 80.9 wt%
And the first biodegradation level adjusting agent is added to the polymer solution in an amount of 0.1 to 2% by weight in the second vessel closure preparation step
A method for manufacturing a temporary vessel closure device. 3. The method of claim 2,
The method of manufacturing the temporary vessel closure device
Further comprising the step of injecting a second biodegradability adjusting agent into the second vessel closure device and stirring the second biodegradation rate adjusting agent,
And the second biodegradability adjusting agent is added in an amount of 0.1 to 9 parts by weight per 100 parts by weight of the first biodegradability adjusting agent in the adjusting agent adding step
A method for manufacturing a temporary vessel closure device. 5. The method of claim 4,
The method of manufacturing the temporary vessel closure device
The solution prepared in the step of adding the modifier is heated to 70 to 90 ° C for 15 to 24 hours to regulate the biodegradation degree of the second vascular closure device so that the third vascular closure having a slower biodegradation rate than the second vascular closure device And a third vessel closure device manufacturing step of manufacturing a vessel
A method for manufacturing a temporary vessel closure device. 3. The method according to claim 1 or 2,
The thermosensitive polymer may be selected from the group consisting of polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer, polyethylene glycol-poly (lactic-co-glycolic acid) -polyethylene glycol copolymer, polyethylene glycol-polycaprolactone-polyethylene glycol copolymer, methoxypolyethylene Glycol-polyester copolymers, poly (N-isopropylacrylamide), and combinations thereof.
A method for manufacturing a temporary vessel closure device. 3. The method of claim 2,
Wherein the first biodegradation modifier is at least one selected from the group consisting of carboxymethylcellulose, alginate, hyaluronic acid, hydroxyethylcellulose, pullulan, and combinations thereof.
A method for manufacturing a temporary vessel closure device. 5. The method of claim 4,
Wherein the second biodegradation modifier is at least one selected from the group consisting of citric acid, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide, and combinations thereof
A method for manufacturing a temporary vessel closure device.

Images