KR20170060262A

KR20170060262A - 3-layer blood filter module for plasmapheresis and preparation method thereof

Info

Publication number: KR20170060262A
Application number: KR1020150164415A
Authority: KR
Inventors: 한영아; 서영민; 정용일; 김환국; 박대규; 이재원
Original assignee: (재)한국섬유기계연구원
Priority date: 2015-11-24
Filing date: 2015-11-24
Publication date: 2017-06-01

Abstract

The present invention relates to a three-stage plasma-isolated blood filter module and a method of manufacturing the same. The filter media module of the present invention and the system including the same showed the effect of effectively reducing lipid-related components under specific operating conditions while maintaining the amount of albumin and protein in blood. From this, it is expected that the filter media module through the present invention can be utilized as a high-performance module that can effectively replace existing medical membranes.

Description

[0001] The present invention relates to a three-stage blood separation blood filter module and a preparation method thereof,

The present invention relates to a three-stage plasma-isolated blood filter module and a method of manufacturing the same.

Medical textile refers to fibers used for the prevention or treatment of diseases such as examination, optometry, prescription, medication or surgical operation, and is used as a core part or material of medical devices and quasi-drugs. Medical fibers can be classified into five types according to the type of material: fiber yarn, textile fabric, fiber structure, nonwoven fabric, and composite material.

Among these, nonwoven fabric is used for nonwoven fabric such as wound dressing, cartilage, white blood cell filter, blood / plasma exchange filter, hemodialysis material, suture material, maternity material, drug delivery system and blood transplantation.

In the medical industry, the demand for medical fibers is continuously increasing. In particular, the demand for the first and second blood filters (hemocyte separation blood filter, plasma membrane) and shielding membranes used in hospitals is rapidly increasing .

However, the global medical textile industry is dominated by Johnson & Johnson, Smith & Nephew, and 3M through global branding, technology exclusivity, and brand portfolio strategies based on industry recognition. At the same time, research and development of a production system that has optimal functions for each production stage process is underway in developed countries such as the US, Germany, and Japan, and localization technology development and commercialization that are comparable to domestic ones are in urgent need.

Korean Published Patent Application No. 2015-0022701 A1 (Apr. Korean Patent Publication No. 2015-0039051 A1 (Apr. Korean Registered Patent No. 1361452 B1 (Apr.

In order to solve the above problems, the present invention proposes a module comprising a blood filter for a high-performance plasma membrane and constructs a system including the same. Further, the manufacturing technology of the blood filter module is supplemented through feedback based on evaluation of performance, , A high-performance blood filter module with high biological stability, and a system including the same.

The present invention relates to a method for producing a polyurethane-based polyurethane foam, Electrospinning the spinning solution on one side or both sides of the nonwoven fabric to obtain a polymer nanofiber composite web; And polymer nanofiber composite webs in a three-tiered structure. The present invention also relates to a method of manufacturing a three-stage plasma-isolated blood filter module.

The present invention also relates to a nonwoven fabric comprising a non-woven fabric layer and a polyether polyurethane nano-fiber composite layer having pores having an average pore size of 0.3 μm to 0.9 μm superimposed on one or both surfaces of the nonwoven fabric layer in three layers / RTI > The present invention relates to a three-stage plasma-isolated blood filter module.

The present invention also relates to a filter system comprising the three-stage plasma separation blood filter module.

The present invention relates to a three-stage plasma-isolated blood filter module and a method of manufacturing the same. The filter media module and the system including the filter module of the present invention reduce the amount of serum albumin and protein, .

From this, it is expected that the filter media module through the present invention can be utilized as a high-performance module that can effectively replace existing medical membranes.

1 is an SEM image of the filter media prepared in Example 1. Fig.
2 is an SEM image of the filter media prepared in Example 2. Fig.
Figure 3 is a numerical measurement of the three-stage plasma-isolated hemocyte filter module.
Fig. 4 is a photograph of the filter cartridge used in the three-stage plasma separation blood filter module.
5 is a lab-scale system for applying a circulatory blood filter module.
6 shows the results of the plasma component separation performance evaluation according to the module-flow rate-RPM.
7 shows the results of the plasma component separation performance evaluation according to the module 3-flow rate.
8 shows the results of the plasma component separation performance evaluation according to the module 2 flow rate.
9 shows the results of the plasma component separation performance evaluation according to the system operation time.
FIG. 10 shows the results of the blood component separation performance evaluation according to the BAA 200 module-flow rate.
11 shows the results of the plasma component separation performance evaluation according to the BBA 100 module-flow rate.

When the diameter of the fiber is manufactured in the nanometer range, it has a unique characteristic that is physically distinguishable from the conventional fiber, so that it can be used as a filter having a function of separating an extremely small material or a use of a catalyst carrier having a large surface area. Respectively. Electrospinning and melt-blown (MB) methods can be used to produce such nanometer-sized fibers. Nanofiber fabrication technology by electrospinning and meltblown method can produce nanofibers with various functions by combining various polymers and solvents and controlling process parameters. Therefore, it is possible to manufacture nanofibers using high-performance filter materials, polymer batteries and electronic materials There is an advantage that it can be widely used. In particular, there is a growing need for artificial tissues such as blood filters, artificial blood vessels, tissue regeneration, drug delivery in the body, wound healing, anti-adhesion shielding films, nonwoven fabrics for wound healing, and cosmetics.

Electro-spinning is a process in which a very high voltage is applied between a nozzle and a collector and a polymer is sprayed from a nozzle. Since the product is generally obtained in the form of a web or a nonwoven fabric, It can be said that it is the optimum spinning method for manufacturing.

A melt-blown (MB) process involves spinning a low-viscosity melt base polymer through a small nozzle, drawing the molten resin by high-temperature, high-pressure air, It can be said to be a manufacturing method having a tabular form. The characteristics of the nonwoven fabric obtained through the meltblown process can be varied depending on the size of the nozzle, the discharge amount and the process conditions, and it is possible to produce various nonwoven webs of 10 to several hundred (gsm) Thus, it is an optimal material for a filter medium such as a filter. It is a manufacturing method having excellent price competitiveness compared to other nonwoven fabrication methods by relatively simple process control.

In the present invention, the polyether-based polyurethane is excellent in tensile strength and blood compatibility, has excellent radiation stability in the production of a filter through electrospinning, and does not cause loss of albumin when used as a blood filter, and selectively separates IgG and LDL can do.

In the present invention, the polymeric nanofiber composite web was prepared by electrospinning the spinning solution containing the polyether-based polyurethane on a nonwoven fabric, and thus the tensile strength was further improved and the ability to selectively separate IgG and LDL was remarkably improved.

In the present invention, the average pore size of the nanofiber composite web is not limited to a line capable of achieving the object of the present invention. For example, the average pore size may be 0.3 to 0.9 μm, And can range from 0.4 μm to 0.8 μm. There is little loss of albumin in this range, and IgG and LDL can be selectively separated. If the average diameter of the pores exceeds 0.9 m, the efficiency of collection of the plasma protein decreases. If the average diameter of the pores is less than 0.3 m, the pores may be easily blocked by the collected plasma proteins.

In the present invention, the polyether-based polyurethane nanofiber composite web layer may be composed of nanofibers having an average diameter of 100 nm to 500 nm. The nanofiber composing the nanofiber composite web layer may be formed of a polyether polyurethane. The polyether polyurethane may have a weight average molecular weight of 10,000 to 500,000, preferably 25,000 to 300,000. Tensile strength and tear strength can be excellent. Commercial examples of the polyether-based polyurethane include, but are not limited to, Elastollan 1195A from BASF. It is also preferred that the tensile strength measured by the ASTM D 412 method is between 5500 psi and 6000 psi.

In the present invention, the nonwoven fabric layer may be selected from the group consisting of polyethylene terephthalate (PET), polyethylene (PE) and polypropylene (PP), and more preferably, Polyethylene terephthalate having excellent stiffness and atmosphere corrosion resistance can be used.

The nonwoven fabric is preferably, but not limited to, a thickness of 1 μm to 50 μm, an air permeability of 200 to 400 cm 3 / cm 3 / sec according to ASTM D 737, a tensile strength of 10 to 30 MPa according to ASTM D 882 Is preferably used.

In the present invention, the average pore size measured by the ASTM F 316 method of the nanofiber composite web is not limited, but may be 0.3 μm to 0.9 μm. In the present invention, the radiation voltage during the electrospinning is not limited but may be 1 kv to 50 kv. In the present invention, the spinning distance between the nozzle and the collector of the spinning solution for electrospinning is not limited, but may be 5 cm to 30 cm. In the present invention, the polyether-based polyurethane may have a tensile strength of 5500 psi to 6000 psi, although the tensile strength measured by the ASTM D 412 method is not limited. Also, the ultimate elongation measured by the ASTM D 412 method is not limited within a conventional range, but may be, for example, 300% to 500%, preferably 350% to 450%, preferably 400% to 430% %. The intended tensile strength is excellent in the above range.

Although the solvent is not limited as being possible, for example, a mixture of dimethylacetamide (DMAc) and methyl ethyl ketone (MEK) or a mixture of dimethylformamide (DMF) and methyl ethyl ketone can be used. At this time, the spinning solution may have a solid content of 10 to 30% by weight, more preferably 12 to 18% by weight.

In one embodiment of the present invention, the electrospinning is performed by supplying a spinning solution to a nozzle having a high voltage and then electrospinning the spinning solution onto a collector with a high voltage applied thereto through the nozzle to form a polymer nanofiber, To thereby produce a nanofiber nonwoven fabric.

In the present invention, the spinning voltage of the spinning solution is not limited to that used in conventional electrospinning but may be, for example, 1 kv to 50 kv, preferably 10 kv to 20 kv, preferably 14 kv to 16 kv And the nanofibers can be uniformly applied to the nonwoven fabric in the above range. In the present invention, the spinning distance between the nozzle-collector of the spinning solution is not limited, but may be, for example, 5 cm to 30 cm, preferably 10 cm to 25 cm, preferably 15 cm to 20 cm. If the distance between the nozzles and the collector is too close or too far away, the nanofibers may not be evenly spread.

The average diameter of the nanofibers coated on the nonwoven fabric by the electrospinning is not limited, but may be, for example, 100 nm to 500 nm, preferably 150 nm to 450 nm, preferably 250 nm to 400 nm. The diameter of the nanofibers can greatly affect the size of the pores formed in the nanofiber composite web layer, the degree of porosity, and the distribution of pores. The smaller the diameter of the nanofiber, the smaller the pore size and the smaller the pore distribution. Also, as the diameter of the nanofiber decreases, the specific surface area of the nanofiber increases, and the leakage of the plasma is reduced.

In the present invention, in the case of the nanofiber composite web layer, the average diameter of the nanofibers is not limited, but may be, for example, 100 nm to 500 nm, preferably 150 nm to 450 nm, and preferably 250 nm to 400 nm. The diameter of the nanofibers can greatly affect the size of the pores formed in the nanofiber composite web layer, the degree of porosity, and the distribution of pores. The smaller the diameter of the nanofiber, the smaller the pore size and the smaller the pore distribution. Also, as the diameter of the nanofiber decreases, the specific surface area of the nanofiber increases, and the leakage of the plasma is reduced.

It was confirmed that when the above-mentioned module was used, it showed remarkable resolution ability for plasma protein (LDL) and the like as in the embodiment of the present invention.

The structure of the filter system is not particularly limited as long as it includes the plasma separation blood filter module. However, according to one embodiment of the present invention, the blood filter module is connected to the blood filter module, A plasma bag on the opposite side of the connected motor, and an albumin bag on the side of the blood filter module, and the connection method of the components is not particularly limited.

The condition for removing the lipid component from the plasma component in the filter system using the blood filter module of the present invention is not particularly limited, but according to one embodiment of the present invention, the removal efficiency is the best when operated at 100 mL / min or less When the filter system was operated for about 9 minutes, no change in other lipid - related factors (TG, HDL and LDL) was observed, but the cholesterol - specific reduction rate was 55.1%, indicating selective lipid elimination.

Hereinafter, the present invention will be described in more detail by way of examples. However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.

The physical properties and plasma protein separation performance of the filter media prepared through the following examples were measured as follows.

(Porosity)

It was measured according to the ISO 15901 method on a Micrometrics AutoPore Ⅳ 9500 porosimeter (Mercury Porosimeters).

(Average pore size)

Was measured according to the ASTM F 316 method using a capillary flow porometer (PMI DFP-1200A).

(Average fiber diameter)

The surface of the electrospun nanofiber was measured at a voltage of 5-15 kV using a SEM (Scanning Electron Microscope) measuring apparatus, and the diameter of each nanofiber was measured.

[Example 1]

15% by weight of a polyether polyurethane (Elastollan 1195A from BASF having a tensile strength of 5700 psi) was dissolved in a mixed solution of dimethylformamide and methyl ethyl ketone in a volume ratio of 7: 3 (v / v) A usage solution was prepared.

50 ml of the spinning solution prepared on a polyethylene terephthalate 100% product (thickness 0.10 mm, air flow rate 300 cm3 / cm3 / sec) manufactured by Nanyang Nonwoven Co., Ltd. was injected into the nozzle and electrospun was irradiated at a radiation voltage of 15 kV and a radiation distance of 8 cm A polymeric nanofiber composite web was formed to prepare a plasma separation blood filter (Fig. 1).

The average pore size and the fiber diameter of the polymer nanofiber composite web were measured to be 0.42 μm and 267 nm, respectively.

3 and 4, a three-stage circulation blood filter module was manufactured using the blood filter manufactured above (type 2). In this case, the filter module has a length of 10.7 cm × 8 cm, and the filter material contained therein is processed into pleats. SUS material (SU-405), which can be sterilized in consideration of sterilization, was used in the manufacture of the filter, and it consisted of 2.5 gaskets.

[Example 2]

A new plasma separation blood filter was prepared by the same method as in Example 1 (Fig. 2).

The polymer nanofiber composite web had an average pore size of 0.24 μm and a fiber diameter of 252 nm.

3 and 4, a three-stage circulation blood filter module was manufactured using the blood filter manufactured above (type 3). In this case, the filter module has a length of 10.7 cm × 8 cm, and the filter material contained therein is processed into pleats. SUS material (SU-405), which can be sterilized in consideration of sterilization, was used in the manufacture of the filter, and it consisted of 2.5 gaskets.

[Example 3]

A system to which the lab-scale circulatory system blood filter module was applied was designed using the plasma separation blood filter module manufactured in the above-mentioned Example 1 and Example 2, and constructed in the laboratory animal center of Daegu Kyungbuk Advanced Medical Industry Promotion Foundation (Fig. 5) .

The metering pump used in the system was a 5.6 inch touch screen periplamic pump (Model No. EMP-2000W from EMS-Tech Scientific Co. LTD) and the flow rate, time, volume volume and rotation speed (RPM) of the metering pump can be adjusted. The hardware specifications of the metering pump are shown in Table 1 below.

[Table 1] EMP-2000W

The above-described metering pump was connected to the blood filter module, and a blood bag was connected to the opposite side of the motor connected to the blood filter module, and an albumin bag was connected to the blood filter module. At this time, the tube for connecting each component was sterilized.

[Example 4]

The first-order performance of the blood filter module was evaluated using the lab-scale circulatory system constructed in the third embodiment.

Wet TBA-120FR (Toshiba) equipment was used for biochemical analysis of plasma components. The biochemical analysis components and measurement methods are shown in Table 2 below.

[Table 2] Biochemical analysis Components and measurement methods

The separation performance of plasma proteins and the like of the blood filter module was evaluated by the above-described measurement method under the following experimental conditions. Tables 3 and 4 list experimental conditions and conditions. At this time, the relative decrease rate (%) was calculated using the blood biochemical results. The calculation method was calculated by the formula (I).

&Lt; RTI ID = 0.0 >

[Table 3] First condition

[Table 4] Second condition

Results of the first condition experiment

The results of the primary condition test of Table 3 are shown in FIG. When compared before and after passage through the secondary blood filter, there was no effect on serum albumin (ALB) and protein (PRO). In the case of LDL, the values were not changed in 2-50-50, 2-25-100, and 3-50-50, but in the 2-100-50, 3-100-50, and 3-50-100, 6.8 and 9.8 And 38.2%, respectively. Especially, LDL and LDL decreased by 40.9%, 43.9%, 38.9%, and 38.2%, respectively, of lipid-related indicators such as cholesterol (CHO), triglyceride Reduction rate.

The detailed values for each component are shown in Table 5 below.

[Table 5] Blood biochemical analysis results under experimental condition 1

Secondary condition experiment result

The results of the secondary condition test of Table 4 are shown in FIGS. Compared with the results before and after passage through the secondary blood filter, when Module 3 was used, the lipid-related indicators (CHO, TG, HDL and LDL) decreased more than 20% (FIG. 7), and when Module 2 was used, it was confirmed that the lipid-related indicators were markedly reduced under all conditions (FIG. 8).

The changes in the measurement indices according to the operating time of the system showed a surprising reduction of 55.1% in cholesterol when operated for 9 min, but no changes in other lipid-related factors (TG, HDL and LDL).

The detailed values for each component are shown in Table 6 below.

[Table 6] Blood biochemical analysis results in experimental condition 2

[Example 5]

The secondary performance of the blood filter module was evaluated using the lab-scale circulatory system constructed in Example 3 above.

The prepared filter media type 3 was labeled 'B' and the type 2 was labeled 'A'. Then, the filter media media were stacked in three stages to observe the change of the measured index according to the change of the flow rate.

Module BAA

[Table 7] Third condition

Module BBA

[Table 8] Fourth condition

Biochemical analysis was performed on the two types of modules in the same manner as in Example 4.

The separation performance of plasma proteins and the like of the blood filter module was evaluated by the above-described measurement method under the following experimental conditions. Tables 9 and 10 list experimental conditions and conditions. At this time, a relative decrease rate (%) was calculated using the blood biochemical results, and this calculation method was calculated by the above formula (I).

[Table 9] Blood biochemical analysis results in the third condition

Results of the third condition experiment

The result of the third condition experiment of Table 9 is shown in FIG. In comparison with before and after the passage through the secondary blood filter, it was found that CHA 78.5%, TG 71.3%, HDL 70.2% and LDL 75.2%, which are indicators of lipid in BAA 200 condition,

Results of the fourth condition experiment

The results of the fourth-order condition test of Table 10 are shown in Fig. In comparison with before and after passage through the secondary blood filter, it was found that CHL 51.3%, TG 56.9%, HDL 46.5% and LDL 51.7%, which are indicators of lipid in BBA 100 condition, As a result of evaluating the biological stability of the filter media module manufactured at Daegu Gyeongbuk Advanced Medical Industry Promotion Foundation Experimental Animal Center, the effluent of the test material showed little cytotoxicity, no adverse effect was observed in the intradermal reaction, Sensitization was evaluated as a weak substance. In addition, the acute toxicity test of the test specimens commissioned by the Korea Testing and Research Institute was confirmed to have no systemic toxicity changes within 72 hours after administration.

Further, as has been confirmed from the above-mentioned embodiments, it has been found that the filter media module and the system including the same of the present invention have an effect of effectively reducing lipid-related components under specific operating conditions while maintaining the amounts of albumin and protein in blood.

It has been confirmed that the filter media module through the present invention can be utilized as a high-performance module that can effectively replace existing medical membranes and the like, thereby completing the present invention.

Claims

Preparing a polyether-based polyurethane spinning solution;
Electrospinning the spinning solution on one side or both sides of the nonwoven fabric to obtain a polymer nanofiber composite web; And
Stacking the polymer nanofiber composite web in three stages;
/ RTI > A method for manufacturing a three-stage plasma-isolated blood filter module comprising:

The method according to claim 1,
Wherein the nonwoven fabric is selected from the group consisting of polyethylene terephthalate, polyethylene and polypropylene.

The method according to claim 1,
Wherein the average pore size of the nanofiber composite web measured by an ASTM F 316 method is 0.3 μm to 0.9 μm.

The method according to claim 1,
Wherein the radiation voltage during electrospinning is between 1 kv and 50 kv.

The method according to claim 1,
Wherein the nozzle-to-collector scattering distance of the spinning solution during electrospinning is 5 cm to 30 cm.

The method according to claim 1,
Wherein said polyether-based polyurethane has a tensile strength of 5500 psi to 6000 psi as measured by the ASTM D 412 method.

A non-woven fabric layer, and a three-layered structure comprising a polyether-based polyurethane nano-fiber composite layer having pores having an average pore size of 0.3 μm to 0.9 μm superimposed on one or both surfaces of the nonwoven fabric layer Plasma separation blood filter module.

8. The method of claim 7,
Wherein said polyether-based polyurethane has a tensile strength of 5500 psi to 6000 psi as measured by the ASTM D 412 method.

8. The method of claim 7,
Wherein the nonwoven fabric layer has a thickness of 1 to 50 μm.

8. The method of claim 7,
Wherein the nanofiber composite web layer comprises nanofibers having an average diameter of 100 nm to 500 nm.

A filter system comprising a three-stage plasma separation blood filter module as claimed in any one of claims 7 to 10.