JPS61272057A - Dry serum separator - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a plasma separator that separates blood cell components and plasma components from blood. This invention relates to a novel medical blood clot that does not contain any ingredients and has no wood inside.

(Prior Art) In recent years, porous membranes made of polymer compounds have been widely used in the medical field, and in particular, techniques for separating blood into various components by membrane separation have been put into practical use. Among them, a plasma separator that separates blood into blood cell components and plasma components is used for plasma purification therapy, which separates and discards the plasma of patients with disease-causing plasma components and replenishes it with the plasma of a patient. It has begun to be used for many medical purposes, including plasma purification therapy to return to patients, plasma collection to collect only plasma from healthy individuals, and preserved blood/plasma separation to separate stored blood into blood cell and plasma components.

In order for this plasma separator to be widely used, it is extremely important that it has high separation efficiency and can process in a short time, is easy to operate, can be supplied at low cost, and is highly medically safe. It is.

From this point of view, plasma separators having new porous membranes made of various materials have been proposed.

These plasma separators are roughly divided into the following two types depending on the characteristics of the porous membrane material. The first type is a plasma separator that incorporates a porous membrane made of a hydrophobic polymer, examples of which include polyethylene, polypropylene,
Polysulfone, etc. have been reported. Porous membranes made of hydrophobic polymers have the following characteristics: when treating aqueous liquids such as blood, they do not swell with water, have strong mechanical strength, and have little strength loss due to water, which reduces the possibility of serious accidents such as blood leakage. Examples include having a small gender.

However, a disadvantage of porous membranes made of hydrophobic polymers is that aqueous liquids such as blood do not wet the hydrophobic polymer, making it difficult for them to penetrate into the pores of the porous membrane. A plasma separator with a built-in porous membrane made of 11Q cannot be used as a plasma separator as it has no plasma filtration capacity as it is. Therefore, it is necessary to hydrophilize the porous 11Q made of a hydrophobic polymer in advance. Examples of the hydrophilic treatment include a method in which a hydrophobic porous membrane is treated with a surfactant, and a method in which a low surface tension organic solvent that is miscible with water is permeated into the pores and then replaced with water. However, in a plasma separator treated with a surfactant, the surfactant elutes into the blood and plasma during plasma separation, which poses a safety problem.

Furthermore, in the method using a low surface tension organic solvent, the effect of lignophilization is effective only while the pores are filled with replaced water, and the ability to permeate aqueous solutions such as plasma is lost due to drying. In order to maintain the permeability of aqueous solutions even after drying, it is necessary to use a wetting agent such as glycerin or polyethylene glycol, and like surfactants, these wetting agents have the problem of elution into blood and plasma. has.

The second type of plasma separator is a plasma separator that incorporates a porous membrane made of a hydrophilic polymer, examples of which include regenerated cellulose, cellulose diacetate,
Polyvinyl alcohol, ethylene-vinyl alcohol copolymer, etc. have been reported. Porous membranes made of hydrophilic polymers are characterized by the fact that the surface of the pores in the linear membrane is hydrophilic, allowing aqueous liquids such as blood to penetrate into the pores; Unlike , it does not require parent tree processing. However, a disadvantage of porous membranes made of hydrophilic polymers is that they shrink significantly when changed from a wet state to a dry state, so special drying methods such as freeze-drying or a large amount of glycerin as a wetting agent are required. Such processing is necessary. Examples include large swelling when changing from a dry state to a wet state, and a large decrease in mechanical strength due to water. Porous membranes for plasma separation require large pore diameters and high porosity because they require permeation of plasma components containing high molecular weight proteins, and these drawbacks are further exacerbated.

(Problems to be Solved by the Invention) Plasma separators can be broadly divided into water-filled types and dry types based on their final component form. The water-filled type has the internal space of the plasma separator filled with sterile distilled water, and has the advantage that it can be used immediately by simply replacing distilled water with physiological saline (priming) before use. Sterilization methods that are limited and possible after filling with water include high-pressure steam sterilization and gamma ray sterilization, but both require that the entire plasma separator has heat resistance or gamma ray resistance.

In addition, since the product is shipped in the presence of water, it is heavy and, in the unlikely event that it is contaminated with bacteria, there is a possibility of large numbers of bacteria multiplying. On the other hand, dry type plasma separators can use ethylene oxide gas sterilization, which is a safe and reliable sterilization method that can be used on almost all materials, and the growth rate of bacteria is low in dry conditions. It is highly safe.

However, among known plasma separators incorporating porous membranes, dry type plasma separators are known;
When a hydrophobic polymer is used as a porous membrane material, surfactants, glycerin, or
A wetting agent such as polyethylene glycol is attached.

In addition, those using hydrophilic polymers have glycerin attached to them to prevent shrinkage during drying, and there are no known dry type plasma separators with built-in porous membranes that do not contain blood-eluting substances. Even if a porous membrane made of a hydrophilic polymer such as ethylene-vinyl alcohol copolymer can be dried without a wetting agent such as glycerin, the porous membrane will be wetted by aqueous liquids such as blood. It has the disadvantages of dimensional changes due to swelling when exposed to water, a decrease in mechanical strength, and strong water absorption. In the case of a plasma separator with a built-in hollow fiber-like porous membrane, dimensional changes due to moisture can cause filamentous turbulence, resulting in uneven blood flow and residual blood that cannot be returned sufficiently after use. cause problems.

(Means for Solving the Problems) The present inventors have made extensive studies to improve the shortcomings of these known plasma separators incorporating porous membranes and to obtain a plasma separator with excellent safety. We have arrived at the present invention. That is, the gist of the present invention is a dried plasma separator that includes a porous membrane and is characterized by having the following requirements (a), (b), and (c).

(a) The porous membrane is a composite porous membrane formed by a porous structured matrix made of a hydrophobic polymer and a coating layer made of a water-insoluble hydrophilic polymer that substantially covers the pore surface of the matrix. be.

(b) The porous membrane does not substantially contain blood-eluting organic or inorganic compounds such as surfactants and wetting agents.

(c) There is no water anywhere in the internal space of the plasma separator.

The absence of water anywhere in the internal space refers to the pore space of the porous membrane constituting the plasma separator, the internal space of the hollow fiber membrane, the space surrounded by the membrane and the container, etc.
謔I+ Naka-eki ↓ Kotk-No! -1-□ 1%
-L4hi, happy vomit↓ru.

(Operations and Embodiments) The dried plasma separator of the present invention has a built-in porous membrane having a porous structured matrix made of a hydrophobic polymer,
This is a composite porous membrane formed by a coating layer made of a water-insoluble hydrophilic polymer that substantially covers the pore surface of the pores, so like a hydrophobic porous membrane, it is susceptible to water damage upon contact with blood. There is almost no swelling or decrease in strength due to water, and since the surface is made of a hydrophilic polymer, it has good water wettability and can be used as a plasma separator without any pretreatment to make it hydrophilic. In addition, the composite porous membrane built into the plasma separator shows almost no change in dimensions or performance even after repeated drying and wetting, so it can be easily dried without using a wetting agent such as glycerin. Furthermore, since no surfactant is required for parentification, the porous membrane is highly safe and contains virtually no solution-eluting components. In addition, since the plasma separator is a dry plasma separator whose internal space is not filled with ice, it is lightweight and has low transportation costs, and there are no particular restrictions on the sterilization method.The sterilization method is ethylene oxide gas sterilization. , high-pressure steam sterilization, and gamma ray sterilization can be used, and has the advantage that ethylene oxide gas sterilization can be performed without any limitations on the material constituting the plasma separator. Additionally, since it is a dry plasma separator, sterility is ensured during storage after sterilization.

In the present invention, a plasma separator incorporating a porous membrane includes at least one porous membrane that separates blood into blood cells and plasma, a blood inlet for introducing the separated blood, and a blood inlet for introducing blood with concentrated blood cells. A plasma separator is a plasma separator that has a blood outlet for extracting blood and a plasma outlet for extracting separated plasma, and its shape, size, etc. are not particularly limited.

Furthermore, the plasma separator referred to in the present invention is a device whose main purpose is to separate blood cells and plasma from blood, and is used not only for therapeutic purposes such as plasma exchange and plasma purification, but also for plasma collection from healthy people, It is used for purposes such as separating stored blood, and can also be used to separate body fluids into solid and liquid components.1 For example, as an ascites treatment device to remove cancer cells from cancerous ascites. can also be used.

The form of the porous membrane used in the plasma separator of the present invention is not particularly limited, and for example, a flat membrane or a hollow fiber may be used, but a hollow fiber is preferable because it is small and allows efficient separation.

Further, the average pore diameter and porosity of the porous membrane are within the range normally used for plasma separation membranes, and are subject to the present invention, and the preferred range of the average pore diameter is 0.1 to 2.
0 pm, and the porosity ranges from 50 to 30% by volume.

The hydrophobic polymer used in the present invention is a polymer that does not get wet with water and exhibits a contact angle with pure water of about 70 degrees or more. Such hydrophobic polymers hardly swell with water and have almost no decrease in mechanical strength. Typical examples of hydrophobic polymers include polyolefins such as polyethylene and polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, Polystyrene, polysulfone, polydimethylsiloxane, polyethylene terephthalate.

Examples include polyacetal. Among these, polyolefins are preferred to which the principle of the stretching pore method, which can be manufactured without adding solvents or other additives, can be applied in producing the porous structure matrix, and in particular, a porous structure matrix with a sufficiently large pore size can be obtained. Polyethylene is preferred.

The water-insoluble hydrophilic polymer used in the present invention is a water-insoluble and water-wettable polymer that exhibits a contact angle with pure water of about 60 degrees or less. Examples of such hydrophilic polymers include cellulose, cellulose derivatives such as cellulose diacetate, natural polymers such as collagen, and their derivatives, as well as hydrophilic monomer units and hydrophobic monomer units. Examples include various synthetic copolymers. The type of copolymer may be a random copolymer, block copolymer, or graft copolymer. The M aqueous monomer unit has functional groups such as hydroxyl group, carboxyl group, amide group, ami7 group, and sulfonic acid group. Preferably, those having a 1@ group such as a group, an oxyethylene group, or an oxyethylene group include a 7-unit unit such as vinyl alcohol, hydroxyethyl methacrylate, acrylic acid, acrylamide, vinylpyrrolidone, and oxyethylene. The hydrophobic monomer unit preferably has a hydrophobic functional group such as an alkyl group, an alkylene group, a halogen group, a phenyl group, a dimethylsiloxane group, and examples thereof include ethylene, propylene, vinylidene fluoride, etc. Tetrafluoroethylene, vinyl chloride, vinylidene chloride, styrene, dimethylsiloxane,
Examples include seven units such as ethylene terephthalate, bisphenol A carbonate, aminoundecanoic acid, and aromatic urethane.

Among the above hydrophilic polymers, a copolymer consisting of one hydrophilic seven-piece unit and one hydrophobic seven-piece unit is a copolymer that can easily adjust the balance between hydrophilicity and hydrophobicity, and is a porous polymer made of hydrophobic polymers. The proportion of hydrophilic monomer units used in the copolymer is preferably from 40 to 85 to control the adhesion with the structural matrix. I! If the amount of the hydrophilic monomer unit is less than 40%, the hydrophilicity of the copolymer is insufficient, and if it exceeds 85%, the adhesion with the porous structured matrix made of hydrophobic polymers is poor. is weakened. The most preferred example of the hydrophobic monomer unit is ethylene. The seven-piece unit has the same chemical structure as polyethylene, which is the material of a typical hydrophobic porous structure matrix, so it has excellent adhesion to the matrix, and is also extremely chemically stable, making it an excellent material for medical devices. As such, it is highly safe. The most preferred example of hydrophilic monomer units is vinyl alcohol. The monomer unit is the simplest vinyl monomer unit with a hydroxyl group, and is chemically stable and has good compatibility with living organisms.
Furthermore, since it is highly hydrophilic, the copolymer exhibits hydrophilicity even in a relatively small proportion.

The porous membrane incorporated in the plasma separator of the present invention includes a porous structured matrix made of the hydrophobic polymer and a coating made of the water-insoluble hydrophilic polymer that substantially covers the pore surface of the matrix. Formed from layers. A porous structure matrix is a porous structure having pores penetrating from one side to the other, and its manufacturing method can use a normal porous membrane manufacturing method, such as a wet phase conversion method, a melt phase separation method, Known methods such as the stretch hole method can be employed. Among them, the stretch-opening method is a method in which a crystalline polymer is formed into a hollow fiber or film, and then the crystal lamellae are cleaved by cold stretching, and the pore diameter is expanded by hot stretching to create a porous membrane.
This is a preferred method because it produces a porous structure by the physical means of stretching without adding any solvent or other additives to the polymeric material, and there are no problems such as residual solvent.

The coating layer is a hydrophilic polymer layer that substantially covers the pore surfaces of the porous structure matrix, and the thickness of the coating layer is preferably about 10 A or more, which is a monomolecular layer, and there is no particular upper limit to the thickness. The amount of coating layer expressed in weight per unit surface area of the porous structure matrix is approximately I x 10 g/1
It is preferably 1f or more and about 2×IQg/m″ or less.

In the present invention, a blood-eluting compound is an organic or inorganic compound that is added to make a porous membrane parent, to prevent drying shrinkage, or to form a porous structure. It is soluble in blood. Examples include ionic or nonionic surfactants,
Examples include glycerin, polyethylene glycol, calcium carbonate, and silica. These compounds are known to elute into blood and cause hemolysis, blood coagulation, and other toxicity to living organisms, and therefore these compounds must not be substantially included in the plasma separator of the present invention. "Not included" means that the amount is below the amount that indicates biological effects.

A plasma separator incorporating a porous membrane of the present invention is manufactured by the following manufacturing example. That is, after a porous structured matrix made of a hydrophobic polymer obtained by a known production method is assembled as it is or in the shape of a plasma separator containing the matrix, the water-insoluble hydrophilic polymer is mixed with an organic solvent. Alternatively, the surface of the pores of the matrix is coated with the hydrophilic polymer by immersion in a solution dissolved in a mixed solvent of an organic solvent and water. Subsequently, the solvent used in the treatment is dried to complete the coating treatment of the hydrophilic polymer. If the porous structure matrix is directly coated, the plasma separator of the present invention is completed by incorporating the hydrophilic composite porous membrane created by the process into the plasma separator.
The organic solvent for dissolving the water-insoluble hydrophilic polymer of the present invention is selected from good solvents for each polymer, but the solvent is preferably a polar organic solvent. By coating the molecular surface with a hydrophilic polymer solution, highly polar hydrophilic residues are exposed on the surface of the coating layer, thereby improving the hydrophilicity of the surface of the coating layer. In order to increase the polarity of the solvent for hydrophilic polymers, it is preferable to use a mixed solvent in which water is added to the solvent within a range that does not inhibit the solubility of the polymer. Preferred polar solvents include methanol, Examples include alcohols such as ethanol and propatool, heloalcohols such as triple oroethanol and hexafluoroisopropanol, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethioformamide, and dimethylacetamide, which have low boiling points and are easy to dry. Ethanol is particularly preferred because of its high safety.The concentration of the hydrophilic polymer to be dissolved can be any concentration suitable for coating, and can be selected, for example, from about 0.1 to 5% by weight. The coating treatment may be performed once, or may be repeated several times at a relatively low concentration. When performing this treatment in the state of porous structure matrix 2,
The matrix cut into a certain size can be processed in a batch manner, but it is also possible to process the matrix continuously by running a continuous flat membrane-like or hollow fiber-like porous structured matrix in the longitudinal direction. Even if the porous structure matrix is hollow fiber-like, the structure is porous, so a solution of a hydrophilic polymer can easily penetrate into the interior of the matrix, and coating treatment can be performed. After coating with the hydrophilic polymer solution, the processing solvent is dried to produce a hydrophilic composite porous membrane or a plasma separator incorporating the layer. The 0M aqueous composite porous membrane is assembled into a plasma separator. The solvent can be dried by conventional vacuum drying, hot air drying, or the like, and it is also possible to dry the continuous hydrophilic composite porous membrane continuously while it is running.

The plasma separator of the present invention can be sterilized by any of the following sterilization methods: ethylene oxide gas sterilization, high-pressure steam sterilization, or γ-ray sterilization. However, in order to sterilize the latter two, all the components that make up the plasma separator must be able to withstand high pressure steam or gamma rays. Almost all the parts used can be used without being affected by EOG, so there are no restrictions on the parts used, and since they are not exposed to harsh conditions such as high-pressure steam or gamma rays, there are no problems with the toxicity of decomposition products. It is preferable that it does not become.

Next, in order to clarify the effects of the present invention, Examples will be shown. However, the present invention is not limited to these Examples. The various physical properties were measured by the following methods. Pore diameter (μm) The pore diameter that indicates the pore volume at the pole of the total pore volume on the pore diameter-pore volume integral curve determined by a mercury porosimeter.

[Plasma mouth overvelocity (layer! L/min)]

using bovine ACD (citric acid-sodium citrate-glucose) supplemented blood (hematocrit 35%) at 37°C.
Measure the appropriate amount of plasma when blood flow is 80ml and differential pressure across the membrane is 50mmHg.

[Extractables test]

The Ministry of Health and Welfare's standards for artificial kidneys for dialysis were applied mutatis mutandis.

(Example 1) High density polyethylene (density 0J8B, MI value 5.
5 (trade name: HIZEX 2208J) using a circular double spinneret at a spinneret temperature of 15G''C, and the resulting hollow fibers were annealed at 115℃ for 2 hours, then 30%
Then, hot stretching was carried out at 105° C. for 400 dollars to obtain a hollow fiber polyethylene porous structural matrix. The inner diameter of the matrix was 3301 Lm, and the film thickness was 50 g.m.

An ethylene-vinyl alcohol copolymer having a vinyl alcohol content of 72% by weight (trade name: Soarnol E, manufactured by Nippon Gosei Kagaku Kogyo Co., Ltd.) was heated and dissolved in a 75% by volume ethanol aqueous solution to form a 0.5% by weight solution. 1,700 of the above hollow fiber matrices were bundled and immersed in an ethylene-vinyl alcohol copolymer solution maintained at 50°C for 10 minutes.Then, the excess copolymer solution was removed, and the remaining fibers were dried with hot air at 50°C for 3 hours. was completely removed. The resulting bundle of hollow fiber composite porous membranes was housed in a polycarbonate cylindrical container with an inner diameter of 24 layers, and both ends were fixed with a urethane adhesive to produce a hollow fiber bundle module. The pore diameter of the composite porous membrane is 0.
The effective length of the hollow fiber bundle was 13 cm, and the effective membrane area was 0.23 m'. The module was sterilized with ethylene oxide gas to obtain a dried plasma separator.

In order to measure the plasma separation ability of this plasma separator, the separator was first brimmed with physiological saline, but no swelling of the hollow fiber membrane due to wetting was observed.

The plasma separation ability was high as 17mM/min of plasma was separated when the blood flow was 60mm/min. In addition, the eluate test of this plasma separator was conducted in accordance with the Ministry of Health and Welfare's artificial kidney standards for dialysis.
Biological tests and sterility tests were conducted, and both passed, confirming a high degree of safety. Furthermore, we conducted extracorporeal circulation experiments using this plasma separator using adult mongrel dogs. Using ACD solution (citric acid-sodium citrate-glucose solution) as an anticoagulant, we conducted an experiment in which blood was circulated extracorporeally at 601 cycles/min and plasma was collected at 20 cycles/min using a metering pump for 20 minutes. Ta. After the experiment, the blood contact surface of the plasma separator was washed with physiological saline, fixed with glutaraldehyde, and observed with a scanning electron microscope.No hemolysis was observed during the experiment, and the number of blood cell components in the dog was Almost no change was observed. In addition, almost no residual blood was observed inside the hollow fibers, and electron microscopic observation of the membrane surface showed almost no adhesion of blood cells, and no fibrin formation was observed, confirming that there were no adverse effects on blood. Ta.

(Example 2) According to the method disclosed in JP-A-57-49487, N,
A hollow fiber polypropylene porous structure matrix was obtained by a melt phase separation method using N-bis-2hydroxyethyl-hexadecylamine. In order to completely remove the N,N-bis-2hydroxyethyl-hexadecylamine used in the production, in addition to washing with ethanol for 3 hours, Soxhlet extraction with chloroform was performed for 16 hours. When this porous structure matrix bundle was housed in a cylindrical container and formed into a hollow fiber bundle module by bonding both ends, the membrane showed no water wettability and had no plasma permeation ability. The above porous structure matrix was similar to Example 1, except that a copolymer with a vinyl alcohol content of 77% by weight (Meiko Bar EP-F, manufactured by Kuraray Co., Ltd.) was used as the ethylene-vinyl alcohol copolymer. A composite porous membrane was manufactured by forming an ethylene-vinyl alcohol copolymer coating layer by the method. The composite porous membrane had an inner diameter of 300 pm, a membrane thickness of 15Q4 m, and a pore diameter of O.BOpm. This composite porous membrane was molded into a hollow fiber bundle module with an effective membrane area of 0.23 in accordance with Example 1, and sterilized with ethylene oxide gas to obtain a dried plasma separator. When the plasma separation ability was measured in the same manner as in Example 1, 15 servings/minute of plasma was separated.

(Example 3) Using the same hollow fiber polyethylene porous structural matrix as that used in Example 1, various composites were prepared using block copolymers consisting of various hydrophilic monomer units and hydrophobic monomer units shown in Table 1. A porous membrane was prepared and molded into a hollow fiber bundle module in the same manner as in Example 1 to obtain a dry protein separator.Table 1 shows the hydrophilic blocks constituting the coating layer polymer,
Hydrophobic block, fraction of the hydrophilic block, solvent of coating layer polymer used for manufacturing the composite porous membrane, and Example 1
The plasma separation ability tested in the same manner as above is shown.

(Structure of the Invention) The plasma separator of the present invention does not cause dimensional changes in the membrane or decrease in mechanical strength due to wetting, does not contain blood-eluting compounds such as surfactants as wood-carrying agents, and furthermore Because it is stored in a dry state, it is easy to maintain sterility and is a highly safe plasma separator.

Claims (8)

[Claims] (1) A dried plasma separator that includes a porous membrane and is characterized by having the following requirements (a), (b), and (c). (a) The porous membrane is a composite porous membrane formed by a porous structured matrix made of a hydrophobic polymer and a coating layer made of a water-insoluble hydrophilic polymer that substantially covers the pore surface of the matrix. be. (b) The porous membrane does not substantially contain blood-eluting organic or inorganic compounds such as surfactants and wetting agents. (c) There is no water anywhere in the internal space of the plasma separator. (2) The dried plasma separator according to claim 1, wherein the hydrophobic polymer is a polyolefin. (3) The dried plasma separator according to claim 2, wherein the polyolefin is polyethylene. (4) The dried plasma separator according to claim 2 or 3, wherein the porous structural matrix is a porous structural matrix manufactured by a stretched pore method. (5) The water-insoluble hydrophilic polymer is a copolymer consisting of hydrophilic monomer units and hydrophobic monomer units, and the fraction of the hydrophilic monomer units is 40 to 85% by weight. The dried plasma separator according to any one of items 1 to 4. (6) The dried plasma separator according to claim 5, wherein the hydrophobic monomer unit is ethylene. (7) The dried plasma separator according to claim 6, wherein the hydrophilic monomer unit is vinyl alcohol. (8) Claims 1 to 2, wherein the porous membrane is hollow fiber-shaped.
8. The dried plasma separator according to any one of Item 7.