JP2021159305A - Porous molding for blood treatment that does not cause complement activation - Google Patents

Abstract

To provide a porous molding for blood treatment that does not activate a complement and can properly manage a phosphorus concentration in blood in the body.SOLUTION: A porous molding for blood treatment has an organic polymer resin and an inorganic ion adsorbent. The porous molding has a specific surface area of 51.5 m2/mL-Resin or more and 100 m2/mL-Resin or less and a surface pore size of 0.0005 μm or more and less than 0.200 μm.SELECTED DRAWING: Figure 1

Description

The present invention relates to a porous molded body for blood treatment containing an organic polymer resin and an inorganic ion adsorbent (also referred to as a porous molded body for blood treatment in this document). More specifically, the present invention relates to a porous molded body for blood treatment containing an organic polymer resin and an inorganic ion adsorbent, which has a high phosphorus adsorbing ability and can be safely used without inducing complement activation.

In a healthy adult with normal kidney function, excess phosphorus in the body is excreted mainly as urine. On the other hand, patients with renal disease who have impaired renal function, such as patients with chronic renal failure, cannot properly excrete excess phosphorus from the body, so that phosphorus gradually accumulates in the body, resulting in hyperphosphatemia and the like. Causes disease.
Persistent hyperphosphatemia causes secondary hyperparathyroidism, resulting in renal osteopathy characterized by bone pain, brittleness, deformity, and fragility, which is associated with high calcium. With hypercalcemia, there is an increased risk of developing heart failure due to cardiovascular calcification.
Since cardiovascular calcification is one of the most serious complications such as chronic renal failure, it is very difficult to properly control the amount of phosphorus in the body to prevent hyperphosphatemia in patients with chronic renal failure. Is important to.

In hemodialysis patients, phosphorus accumulated in the body is regularly removed and adjusted by dialysis therapy such as hemodialysis, hemodialysis, and blood filtration so as not to lead to hyperphosphoremia. In dialysis therapy, a treatment time of 4 hours is generally required 3 times a week.
However, when a hemodialysis patient ingests 1000 mg of phosphorus that a healthy adult ingests daily, phosphorus (650 mg) that should normally be excreted from the kidney accumulates in the body, and 4550 mg accumulates in one week. In normal hemodialysis, about 800 to 1000 mg of phosphorus can be removed by one dialysis, and about 3000 mg of phosphorus can be removed by dialysis three times a week. The amount of phosphorus that can be removed by dialysis therapy (3000 mg) does not reach the amount of phosphorus accumulated in one week (4550 mg), and as a result, phosphorus is accumulated in the body.

In particular, maintenance dialysis patients, who are patients with chronic renal failure, have lost the renal function, which is the main excretion route of phosphorus, and therefore the function of excreting phosphorus into urine is almost lost. In dialysis therapy, since phosphorus is not contained in the dialysate, phosphorus can be removed from the body by the diffusion phenomenon into the dialysate, but the actual situation is that sufficient discharge cannot be achieved under the current dialysis time and dialysis conditions. Is.
As described above, since the phosphorus removing effect is insufficient only by dialysis therapy, in addition to dialysis therapy, diet therapy and drug therapy by ingesting a phosphorus adsorbent can be mentioned in order to control phosphorus, but it is important. After evaluating the patient's nutritional status and confirming that it is not undernourished, the phosphorus intake should be restricted.

As a phosphorus control, the serum phosphorus level is 3.5 to 6.0 mg / dL in the CKD-MBD (abnormal bone mineral metabolism associated with chronic kidney disease) guideline.
When the serum phosphorus level is 3.5 mg / dL or less, hypophosphatemia causes rickets and bone softening, and when the serum phosphorus level is 6.0 mg / dL or more, hyperphosphatemia occurs, which causes cardiovascular calcification. It becomes.
It is difficult to control the phosphorus concentration in the body in the diet because the diet that suppresses the intake of phosphorus has a balance with the nutritional status of the patient and the preference of the patient itself must be considered.

In drug therapy, oral phosphorus adsorbents that combine with food-derived phosphate ions in the digestive tract to form insoluble phosphates and suppress the absorption of phosphorus from the intestinal tract are administered before or during each meal. By taking it, the phosphorus concentration is controlled. However, in drug therapy, the dose of phosphorus adsorbent at each meal is considerably large. Therefore, as side effects when taking phosphorus adsorbents, vomiting, bloating, constipation, accumulation of drugs in the body, etc. occur with high probability, and the resulting dosing compliance is very low (also said to be 50% or less). It is difficult for both doctors and patients to control phosphorus levels with drugs.

In the following Patent Document 1, by circulating a dialysis composition containing a phosphorus adsorbent in a dialysate during hemodialysis treatment, phosphorus in the blood can be efficiently removed without causing the phosphorus adsorbent to come into direct contact with blood. It is disclosed to remove.
Further, Patent Document 2 below discloses a hemodialysis system in which a phosphorus adsorbent made of a polycation polymer for removing phosphorus accumulated in blood in an extracorporeal blood circuit is arranged separately from a hemodialysis machine. ing.
Further, Patent Document 3 below discloses a porous molded body suitable for an adsorbent capable of adsorbing and removing phosphorus and the like at high speed.

Further, Patent Documents 4 and 5 disclose a porous molded body capable of appropriately controlling the phosphorus concentration in the blood in the body, but Patent Documents 4 and 5 improve fouling. Therefore, since an organic polymer resin having a hydroxyl group at the end is used, there is a concern that the hydroxyl group may induce activation of complement. That is, since the organic polymer resin has a hydroxyl group at the terminal, excellent carrying performance of the inorganic ion adsorbent can be exhibited in the porous molded body, and in addition, the organic polymer resin having high hydrophobicity can be used. Since it has a hydroxyl group at the end, hydrophilicity is improved and fouling is less likely to occur in the porous molded body, but having a large number of hydroxyl groups on the surface of the organic polymer resin activates the complement. It becomes easier and poses a great concern for use in contact with blood.

Complement is a group of blood proteins that mediate the immune response and is synthesized primarily in the liver. Complement activates when it recognizes a foreign substance and exerts actions such as breaking the cell membrane of a pathogen. Therefore, when complement activation occurs in a blood treatment treatment device, the activated complement activates blood cells responsible for immunity such as monocytes and macrophages. Activated monocytes and macrophages produce cytokines. Increased cytokines in dialysis patients have a profound effect on the development of arteriosclerotic lesions, malnutrition, chronic inflammation and adversely affect the patient's prognosis. That is, it is extremely important for the blood treatment device not to activate complement.

However, none of Patent Documents 1 to 5 describes complement activation.

International Publication No. 2011/125758 Japanese Unexamined Patent Publication No. 2002-102335 Japanese Patent No. 4671419 International Publication No. 2016/08365 International Publication No. 2018/21269

In view of the above-mentioned level of the prior art, the problem to be solved by the present invention is a porous molded body for blood treatment that does not activate complement and can appropriately control the phosphorus concentration in the blood in the body. Is to provide.

As a result of diligent studies and experiments to solve the above problems, the present inventor has found that the specific surface area and surface of the porous molded body for blood treatment containing the organic polymer resin and the inorganic ion adsorbent. It was unexpectedly found that the above-mentioned problems could be solved by setting the pore diameter within a predetermined range, and the present invention was completed.

That is, the present invention is as follows.
[1] Organic polymer resin and a blood processing porous formed article comprising an inorganic ion adsorbent, the porous molded body, a specific surface area of 51.5m ² / mL-Resin least 100m ² / mL-Resin A porous molded article for blood treatment having a surface pore size of 0.0005 μm or more and less than 0.200 μm.
[2] The porosity for blood treatment according to the above [1], wherein the organic polymer resin is at least one selected from the group consisting of polyethersulfone, polysulfone, ethylene vinyl alcohol copolymer, and polyacrylonitrile. Molded body.
[3] The inorganic ion adsorbent has the following formula (1):
_{MN x O n · mH 2 O} ··· (1)
{In the equation, _x is 0-3, _n is 1-4, m is 0-6, and M and N are Ti, Zr, Sn, Sc, Y, La, Ce. , Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb, and Ta It is a metal element selected from the group of, and is different from each other. } The porous molded article for blood treatment according to the above [1] or [2], which contains at least one metal oxide represented by.
[4] The metal oxide is the following group (a) to (c):
(A) At least one selected from the group consisting of hydrated titanium oxide, hydrated zirconium oxide, hydrated tin oxide, hydrated cerium oxide, hydrated lanthanum oxide, and hydrated yttrium oxide;
(B) A composite of at least one metal element selected from the group consisting of titanium, zirconium, tin, cerium, lantern, and yttrium and at least one metal element selected from the group consisting of aluminum, silicon, and iron. Metal oxides; and (c) activated alumina;
The porous molded article for blood treatment according to the above [3], which is selected from the above.

By using the porous molded article for blood treatment according to the present invention, the phosphorus concentration in the blood in the body can be appropriately controlled without activating complement.

It is a schematic diagram of the column flow test apparatus of the phosphorus adsorption amount of the porous molded article for blood treatment of this embodiment.

Hereinafter, embodiments for carrying out the present invention (hereinafter, referred to as “embodiments”) will be described in detail. The present invention is not limited to the present embodiment, and can be variously modified and implemented within the scope of the gist thereof.

(Pollous molded body for blood treatment)
One embodiment of the present invention is a porous molded article for blood treatment containing an organic polymer resin and an inorganic ion adsorbent, and the specific surface area of the porous molded article is 51.5 m ² / mL-Resin or more. A porous molded article for blood treatment having a surface pore size of 0.0005 μm or more and less than 0.200 μm, which is 100 m ^{2 / mL-Resin or less.}

The porous molded article for blood treatment of the present embodiment can have a biocompatible polymer on its surface.
The term "porous molded product" refers to a product having communication holes and a porous structure.
The specific surface area of the porous molded body of the present embodiment measured by the BET adsorption method is 51.5 m ² / mL-Resin (R) or more and 100 m ² / mL-R or less, and 51.5 m ² / mL-R. More than 85 m ² / mL-R is preferable, 51.5 m ² / mL-R or more and 75 m ² / mL-R or less is more preferable, and 51.5 m ² / mL-R or more and 60 m ² / mL-R or less is further preferable. preferable.

において、Ｓ_wは、比表面積であり、σは、吸着分子１個の占有面積であり、ｖ_mは、単分子層が完成した時の吸着分子の吸着量であり、そしてＮは、アボガドロ数である。
ｖ_mは、以下のＢＥＴ式を用いてＰ／Ｐ０とＰ／ｖ（Ｐ０−Ｐ）の関係から求めることができる。

ここで、Ｐは、気体の圧力であり、ｖは気体の吸着量であり、Ｐ₀は、気体の飽和蒸気圧であり、Ｅ１は、吸着第１層の吸着熱であり、ＥＬは、吸着気体の凝縮熱であり、Ｒは、気体定数であり、そしてＴは、絶対温度である。 In the present embodiment, the specific surface area is obtained from the BET adsorption type using gaseous nitrogen, as described below.
The following formula:

In, _Sw is the specific surface area, σ is the occupied area of one adsorbed molecule, v _m is the adsorbed amount of the adsorbed molecule when the monolayer is completed, and N is the Avogadro's number. Is.
v _m can be determined from the relationship P / P0 and P / v (P0-P) using the following BET equation.

Here, P is the pressure of the gas, v is the adsorption amount of _{the gas, P 0} is the saturated vapor pressure of the gas, E1 is the heat of adsorption of the first layer of adsorption, and EL is the adsorption amount. It is the heat of condensation of the gas, R is the gas constant, and T is the absolute temperature.

The surface pore size of the porous molded body for blood treatment of this actual form measured from the photograph taken by SEM is such that the phosphate molecules efficiently contact and adsorb the inorganic ion adsorbent in the pores of the porous molded body. From this point of view, 0.0005 μm or more and less than 0.200 μm, 0.005 μm or more and less than 0.200 μm are preferable, 0.010 μm or more and less than 0.200 μm are more preferable, and 0.020 μm or more and less than 0.200 μm are preferable. More preferred. It is preferably less than 0.200 μm in order for the complement molecules to come into contact with the intrapore structure of the porous molded product, that is, to prevent the complement molecules from entering the pores and to prevent complement activation from occurring.
The surface pore diameter is determined by observing the surface of the porous molded body by SEM, photographing the surface structure so that the surface structure can be understood, and binarizing the image using ImageJ image analysis software to obtain the pore diameter.

In the present embodiment, the amount of the inorganic ion adsorbent contained in the porous molded body is preferably 30% by mass to 95% by mass, more preferably 40% by mass to 90% by mass, and further preferably 50% by mass to 50% by mass. It is 80% by mass. If the amount supported is less than 30% by mass, the frequency of contact between the substance to be adsorbed with ions and the inorganic ion adsorbent as the adsorption substrate tends to be insufficient, while if it exceeds 95% by mass, the porous molded body is likely to be inadequate. The strength is likely to be insufficient.

The average particle size of the porous molded article of the present embodiment is preferably 100 μm to 2500 μm and is preferably in the form of substantially spherical particles, and the average particle shape is more preferably 150 μm to 2000 μm. It is more preferably 200 μm to 1500 μm, and even more preferably 300 μm to 1000 μm.
The porous molded product of the present embodiment is preferably in the form of spherical particles, but the spherical particles may be not only true spherical particles but also elliptical spherical particles.
In the present embodiment, the average particle size means a median diameter having a sphere-equivalent diameter obtained from an angular distribution of scattered light intensity of diffraction by laser light, regarding the porous molded body as a sphere.
When the average particle size is 100 μm or more, the pressure loss is small when the porous molded product is filled in a container such as a column or a tank, so that it is suitable for high-speed water flow treatment. On the other hand, when the average particle size is 2500 μm or less, the surface area of the porous molded body when filled in a column or tank can be increased, and ions can be reliably adsorbed even in a high-speed liquid passing treatment. ..

(Organic polymer resin)
The organic polymer resin (porous molded body-forming polymer) capable of forming the porous molded body according to the present embodiment may be any polymer capable of forming the porous molded body, for example, a polysulfone-based polymer. , Polyfluoride vinylidene polymer, Polyvinylidene chloride polymer, Acrylonitrile polymer, Polymethyl methacrylate polymer, Polyamide polymer, Polyimide polymer, Cellulosic polymer, Ethylene vinyl alcohol copolymer polymer, Polyaryl ether sulfone, Polypropylene Examples include based polymers, polystyrene-based polymers, polycarbonate-based polymers, and many types. That is, the organic polymer resin can be at least one selected from the group consisting of polyethersulfone, polysulfone, ethylene vinyl alcohol copolymer, and polyacrylonitrile.

Among them, aromatic polysulfone is preferable because it is excellent in thermal stability, acid resistance, alkali resistance and mechanical strength.
The aromatic polysulfone used in this embodiment has the following formula:
-O-Ar-C (CH ₃ ) _2- Ar-O-Ar-SO _2- Ar-
{In the formula, Ar is a disubstituted phenyl group at the para position. } Or the following formula:
-O-Ar-SO ₂ -Ar-
{In the formula, Ar is a disubstituted phenyl group at the para position. } Can be mentioned as having a repeating unit represented by. The degree of polymerization and molecular weight of aromatic polysulfone are not particularly limited.

(Inorganic ion adsorbent)
The inorganic ion adsorbent containing or constituting the porous molded body in the present embodiment means an inorganic substance exhibiting an ion adsorption phenomenon or an ion exchange phenomenon.
Examples of natural product-based inorganic ion adsorbents include various mineral substances such as zeolite and montmorillonite.
Specific examples of various mineral substances include aluminosilicate kaolin minerals with a single-layer lattice, muscovite with a two-layer lattice structure, glauconite, montmorillonite, pyrophyllite, talc, and feldspar with a three-dimensional skeleton structure. , Zeolite, montmorillonite and the like.
Examples of the synthetic inorganic ion adsorbent include metal oxides, salts of polyvalent metals, and insoluble hydrous oxides. The metal oxide includes a composite metal oxide, a composite metal hydroxide, a metal hydrous oxide and the like.

The inorganic ion adsorbent is an adsorbed object, and in particular, from the viewpoint of phosphorus adsorption performance, the following formula (1):
MN _x O _n · mH ₂ O
{In the formula, x is 0-3, n is 1-4, m is 0-6, and M and N are Ti, Zr, Sn, Sc, Y, La, Ce. , Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb, and Ta It is a metal element selected from the group of, and is different from each other. } Is preferably contained at least one kind of metal oxide.
The metal oxide may be a non-hydrated (unhydrated) metal oxide in which m is 0 in the above formula (1), or a metal hydroxide (water) in which m is a value other than 0. Japanese metal oxide) may be used.
In the metal oxide when x in the above formula (1) is a numerical value other than 0, each contained metal element is regularly distributed throughout the oxide and is contained in the metal oxide. It is a composite metal oxide represented by a chemical formula in which the composition ratio of each metal element is fixed.
Specifically, a perovskite structure, a spinel structure, etc. are formed, and nickel ferrite (NiFe ₂ O ₄ ) and zirconium hydrous iron salt (Zr · Fe ₂ O ₄ · mH ₂ O, where m is 0. 5 to 6) and the like.
The inorganic ion adsorbent may contain a plurality of types of metal oxides represented by the above formula (1).

Metal oxides as inorganic ion adsorbents are the following groups (a) to (c) from the viewpoint of excellent adsorption performance of phosphorus, especially phosphorus.
(A) At least one selected from the group consisting of hydrated titanium oxide, hydrated zirconium oxide, hydrated tin oxide, hydrated cerium oxide, hydrated lanthanum oxide, and hydrated yttrium oxide;
(B) A composite of at least one metal element selected from the group consisting of titanium, zirconium, tin, cerium, lantern, and yttrium and at least one metal element selected from the group consisting of aluminum, silicon, and iron. Metal oxides; and (c) activated alumina;
It is preferable to be selected from.
The material may be selected from any of the groups (a) to (c), or the material selected from any of the groups (a) to (c) may be used in combination. The materials in each of the groups (a) to (c) may be used in combination. When used in combination, it may be a mixture of two or more materials selected from any of the groups (a) to (c), and two or more groups of groups (a) to (c). It may be a mixture of two or more materials selected from.

The inorganic ion adsorbent may contain activated alumina impregnated with aluminum sulfate from the viewpoint of being inexpensive and having high adsorptivity.
As the inorganic ion adsorbent, in addition to the metal oxide represented by the above formula (1), a solid solution of a metal element other than M and N is obtained from the viewpoint of the adsorptivity of inorganic ions and the production cost. More preferred.
For example, _{iron is dissolved in hydrated zirconium oxide represented by ZrO 2} · mH ₂ O (m is a numerical value other than 0).
Examples of the salt of the polyvalent metal include the following formula (2):
_{^{M 2+ (1-p) M}} 3+ p (OH -) (2 + pq) (A n-) q / r ··· (2)
{In the formula, M ²⁺ is at least one divalent metal ion selected from the group consisting of ^{Mg 2+} , Ni ²⁺ , Zn ²⁺ , Fe ²⁺ , Ca ²⁺ , and Cu ^2+. M ³⁺ is at least one trivalent metal ion selected from the group consisting of ^{Al 3+} and Fe ^{3+ , An-} is an n-valent anion, 0.1 ≤ p ≤ 0.5. , 0.1 ≦ q ≦ 0.5, and r is 1 or 2. } Can be mentioned as a hydrotalcite-based compound.
The hydrotalcite compound represented by the above formula (2) is preferable because the raw material is inexpensive as an inorganic ion adsorbent and the adsorptivity is high.
Examples of the insoluble hydrous oxide include insoluble heteropolylates and insoluble hexacyanoferrates.

As an inorganic ion adsorbent, metal carbonate has excellent performance from the viewpoint of adsorption performance, but from the viewpoint of elution, it is necessary to study the application when using carbonate.
From the viewpoint that an ion exchange reaction with carbonate ions can be expected as the metal carbonate, the following formula (3):
QyRz (CO ₃ ) s · tH ₂ O. .. .. (3)
{In the formula, y is 1-2, z is 0-1, s is 1-3, t is 0-8, and Q and R are Mg, Ca. , Sr, Ba, Sc, Mn, Fe, Co, Ni, Ag, Zn, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu. It is a metal element selected from the group, and is different from each other. } Can contain at least one kind of metal carbonate.
The metal carbonate may be a non-hydrated (unhydrated) metal carbonate in which t is 0 in the above formula (3), or may be a hydrate having a value other than 0. good.
As the inorganic ion adsorbent, the following group (d):
(D) Magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, scandium carbonate, manganese carbonate, iron carbonate, cobalt carbonate, nickel carbonate, silver carbonate, zinc carbonate, yttrium carbonate, lantern carbonate, cerium carbonate, placeodium carbonate, neodymium carbonate , Samalium Carbonate, Europium Carbonate, Gadrinium Carbonate, Terbium Carbonate, Disprosium Carbonate, Formium Carbonate, Elbium Carbonate, Thurium Carbonate, Itterbium Carbonate, and Rutetium Carbonate;
It is preferable to be selected from.

As the mechanism for adsorbing inorganic ions of metal carbonate, elution of metal carbonate and recrystallization of inorganic ions and metal ions on the metal carbonate are expected. Therefore, the higher the solubility of metal carbonate, the more inorganic ions are adsorbed. The amount is high, and excellent adsorption performance can be expected. At the same time, there is a concern about metal elution from the inorganic ion adsorbent, so sufficient consideration is required for use in applications where metal elution is a problem.
The inorganic ion adsorbent constituting the porous molded body of the present embodiment may contain an impurity element mixed due to the production method or the like within a range that does not impair the function of the porous molded body. Examples of impurity elements that may be mixed include nitrogen (nitrite, nitrite, ammonium), sodium, magnesium, sulfur, chlorine, potassium, calcium, copper, zinc, bromine, barium, hafnium and the like. Be done.
The inorganic ion adsorbent constituting the porous molded body of the present embodiment may contain an impurity element mixed due to the production method or the like within a range that does not impair the function of the porous molded body. Examples of impurity elements that may be mixed include nitrogen (nitrite, nitrite, ammonium), sodium, magnesium, sulfur, chlorine, potassium, calcium, copper, zinc, bromine, barium, hafnium and the like. Be done.

The method of substituting with an organic liquid is not particularly limited, and the inorganic ion adsorbent containing water may be dispersed in the organic liquid and then centrifuged and filtered, or filtered with a filter press or the like. After that, an organic liquid may be passed through. In order to increase the substitution rate, it is preferable to repeat the method of dispersing the inorganic ion adsorbent in the organic liquid and then filtering.
The substitution rate of the water contained in the production with an organic liquid may be 50% by mass to 100% by mass, preferably 70% by mass to 100% by mass, and more preferably 80% by mass to 100% by mass. good.
The substitution rate of the organic liquid is as follows when the substitution rate with the organic liquid is Sb (mass%) and the water content of the filtrate after treating the inorganic ion adsorbent containing water with the organic liquid is Wc (mass%). Equation (4):
Sb = 100-Wc. .. .. (4)
The value represented by.
The water content of the filtrate after treatment with an organic liquid can be determined by measuring with the Karl Fischer method.
By replacing the water contained in the inorganic ion adsorbent with an organic liquid and then drying, aggregation during drying can be suppressed, the pore volume of the inorganic ion adsorbent can be increased, and the adsorption capacity thereof can be increased. Can be increased.
When the substitution rate of the organic liquid is less than 50% by mass, the effect of suppressing aggregation during drying is reduced and the pore volume of the inorganic ion adsorbent does not increase.

(Phosphorus adsorption capacity of porous molded product)
The porous molded article of the present embodiment is suitably used for phosphorus adsorption in hemodialysis of dialysis patients. The blood composition is divided into a plasma component and a blood cell component, and the plasma component is composed of 91% water, 7% protein, a lipid component and inorganic salts, and phosphorus is present in the plasma component as a phosphate ion in the blood. The blood cell component is composed of 96% red blood cells, 3% white blood cells and 1% platelets. The size of red blood cells is 7 to 8 μm in diameter, the size of white blood cells is 5 to 20 μm in diameter, and the size of platelets is 2 to 3 μm in diameter. be.
Since the most frequent pore diameter of the porous molded body measured by the mercury porosimeter is 0.08 μm to 0.70 μm, the abundance of inorganic ion adsorbents on the outer surface is large, so even if the liquid is passed through at high speed, phosphorus ions are formed. Can be reliably adsorbed, and the phosphorus ions permeate and diffuse into the porous molded body and have excellent adsorptivity. Furthermore, blood flowability does not decrease due to clogging of blood cell components or the like.

In the present embodiment, by having a biocompatible polymer on the surface of such a porous molded product, it can be used as a more suitable phosphorus adsorbent for blood treatment.
By containing a porous molded product having the most frequent pore diameter of 0.08 to 0.70 μm and having a biocompatible polymer on the surface of the porous molded product, phosphorus ions in blood are selectively and reliably adsorbed. By doing so, the blood phosphorus concentration returned to the body becomes almost zero. It is considered that returning blood containing almost no phosphorus to the body activates the movement of phosphorus into the blood from inside or outside the cell, and the refilling effect is enhanced.
In addition, by inducing a refilling effect that attempts to supplement phosphorus in the blood, extracellular fluid that cannot normally be excreted and phosphorus existing inside the cell may also be excreted.
As a result, even if the dialysis patient does not take the oral phosphorus adsorbent or takes a small amount (auxiliary use), the phosphorus concentration in the body blood is appropriately controlled without causing side effects of the dialysis patient. can do.
A blood purifier filled with a porous molded body in a container (column) or the like can be used by connecting it in series or in parallel before and after the dialyzer during dialysis. The blood purifier of the present embodiment can be used as a blood purifier for phosphorus adsorption, and is excellent in the selectivity and adsorption performance of inorganic phosphorus even in a state where the phosphorus concentration in blood is low and the space velocity is high.
From the viewpoint of easily inducing the refilling effect, it is preferable to connect a blood purifier filled with the porous body of the present embodiment before and after the dialyzer.
From the viewpoint that a refilling effect can be expected, the phosphorus adsorption rate (%) (ratio of phosphorus adsorbed in blood) is preferably 50% or more, more preferably 60% or more, and 70% or more. , 80% or more, 85% or more, 90% or more, 95% or more, 99% or more are preferable. Further, the phosphorus adsorption amount (when the space velocity SV = 120 hr ^-1 ) in 4 hours, which is the same as the dialysis treatment time, is preferably 1.6 mg-P / mL-Resin or more, preferably 2.0 mg-P / mL. -Resin or more is more preferable.

(Ability to suppress complement activity of porous molded body)
The main components of complement are represented by C1 to C9, and each component may become two or more fragments in the process of activating the complement system (C3a, C3b, etc.). Three types of complement activation pathways (classical pathway, second pathway, and lectin pathway) are known, and each pathway has a process in which C3 is decomposed into C3a and C3b. Further, C3b contributes to the decomposition of C5a and C5b of C5, and finally a complex called C5b6789 (C5b-9) is produced. The final product, C5b-9, is known to have membrane-damaging (hemolysis and cell-damaging) effects, and other fragments of C5a are also said to have physiological activity. Complement activity has been evaluated using one or more soluble fragments (C3a, C5a, sC5b-9, etc.) because of their physiological effects and ease of detection. The porous molded article of this embodiment has substantially "no complement activity". In the present specification, "no complement activity" means that sC5b-9 in blood is 1600 ng / ml or less in the test described below. Since activation of complement occurs when the surface of the substance to be evaluated comes into contact with blood or the like, a contact test between the substance to be evaluated and blood is carried out. For example, a test in which the substance to be evaluated is immersed in blood, or a test in which the substance to be evaluated is placed in a column or the like, a liquid passage circuit is connected, and blood is circulated using a liquid feeding means such as a pump may be used. As the blood or the like used in the contact test, plasma or serum may be used instead of whole blood (whole blood, Who Blood). Plasma is preferably free of anticoagulants that chelate divalent metal ions, such as EDTA or citric acid. Further, when the serum is coagulated and centrifuged, it is preferable that the coagulation component does not contain complement. After a contact test for a certain period of time, a solution for measurement is recovered from blood or the like, and sC5b-9, which is a soluble fragment contained therein, is measured to evaluate complement activity. The storage of the measurement solution until the evaluation of complement activity is preferably −80 ° C. or lower. In addition, it is preferable to add EDTA and nafamostat mesylate as activation inhibitors so that complement activation does not occur during storage due to factors other than the substance to be evaluated. The concentration of the soluble fragment may be measured by any method, but it is preferable to use an enzyme immunoassay method because of its high selectivity and simplicity.

The material of the container (column) of the blood purifier accommodating the porous molding of the present embodiment is not limited, and for example, polystyrene-based polymer, polysulfone-based polymer, polyethylene-based polymer, polypropylene-based polymer, polycarbonate-based polymer, styrene. A mixed resin such as a butadiene block polymer can be used. From the viewpoint of material cost, polyethylene-based polymers and polypropylene-based polymers are preferably used.

(Manufacturing method of porous molded product)
Next, a method for producing the porous molded product of the present embodiment will be described in detail.
The method for producing the porous polymer of the present embodiment is, for example, (1) a step of drying the inorganic ion adsorbent, (2) a step of crushing the inorganic ion adsorbent obtained in step (1), and (3). A slurry is prepared by mixing the inorganic ion adsorbent obtained in step (2), a good solvent for the porous molded body-forming polymer, the porous molded body-forming polymer, and optionally a hydrophilic polymer (water-soluble polymer). This includes a step of molding the slurry obtained in the step (4) step (3), and a step of solidifying the molded product obtained in the step (5) step (4) in a poor solvent.

(Step (1): Drying step of inorganic ion adsorbent)
In step (1), the inorganic ion adsorbent is dried to obtain a powder. At this time, in order to suppress agglutination during drying, it is preferable to replace the water contained in the production with an organic liquid and then dry. The organic liquid is not particularly limited as long as it has the effect of suppressing the aggregation of the inorganic ion adsorbent, but it is preferable to use a liquid having high hydrophilicity. For example, alcohols, ketones, esters, ethers and the like can be mentioned.
The substitution rate with the organic liquid may be 50% by mass to 100% by mass, preferably 70% by mass to 100% by mass, and more preferably 80% by mass to 100% by mass.
The method of substituting with an organic liquid is not particularly limited, and the inorganic ion adsorbent containing water may be dispersed in the organic liquid and then centrifuged and filtered, or filtered with a filter press or the like. After that, an organic liquid may be passed through. In order to increase the substitution rate, it is preferable to repeat the method of dispersing the inorganic ion adsorbent in the organic liquid and then filtering.
The substitution rate with an organic liquid can be determined by measuring the water content of the filtrate by the Karl Fischer method.
By replacing the water contained in the inorganic ion adsorbent with an organic liquid and then drying, aggregation during drying can be suppressed, the pore volume of the inorganic ion adsorbent can be increased, and the adsorption capacity thereof can be increased. Can be increased.
When the substitution rate of the organic liquid is less than 50% by mass, the effect of suppressing aggregation during drying is reduced and the pore volume of the inorganic ion adsorbent does not increase.

(Step (2): Drying step of inorganic ion adsorbent)
In the step (2), the powder of the inorganic ion adsorbent obtained in the step (1) is pulverized. The pulverization method is not particularly limited, and dry pulverization or wet pulverization can be used.
The dry crushing method is not particularly limited, and an impact crusher such as a hammer mill, an air flow crusher such as a jet mill, a medium crusher such as a ball mill, a compression crusher such as a roller mill, or the like is used. be able to.
Among them, the airflow type crusher is preferable because the particle size distribution of the crushed inorganic ion adsorbent can be sharpened.
The wet grinding method is not particularly limited as long as it can grind and mix the good solvents of the inorganic ion adsorbent and the porous molded body-forming polymer together, and is not particularly limited, and is limited to pressure fracture, mechanical grinding, and ultrasonic waves. Means used for physical crushing methods such as treatment can be used.
Specific examples of the pulverizing and mixing means include a generator shaft type homogenizer, a blender such as a waring blender, a medium stirring type mill such as a sand mill, a ball mill, an attritor, and a bead mill, a jet mill, a mortar and pestle, a mortar, an ultrasonic processor, and the like. Can be mentioned.

Among them, a medium stirring type mill is preferable because it has high pulverization efficiency and can pulverize even a highly viscous one.
The ball diameter used in the medium stirring type mill is not particularly limited, but is preferably 0.1 mm to 10 mm. If the ball diameter is 0.1 mm or more, the ball mass is sufficient, so that there is crushing power and the crushing efficiency is high, and if the ball diameter is 10 mm or less, the fine crushing ability is excellent.
The material of the balls used in the medium stirring type mill is not particularly limited, but various types of metals such as iron and stainless steel, oxides such as alumina and zirconia, and non-oxides such as silicon nitride and silicon carbide. Examples include ceramics. Among them, zirconia is excellent in that it has excellent wear resistance and less contamination (mixture of wear) into the product.
After pulverization, it is preferable to perform filtration purification using a filter or the like in a state where the inorganic ion adsorbent is sufficiently dispersed in a good solvent of the porous molded body-forming polymer.
The particle size of the pulverized and purified inorganic ion adsorbent is 0.001 to 10 μm, preferably 0.001 to 2 μm, and more preferably 0.01 to 0.1 μm. In order to uniformly disperse the inorganic ion adsorbent in the membrane-forming stock solution, the smaller the particle size, the better. It tends to be difficult to produce uniform fine particles of less than 0.001 μm. With an inorganic ion adsorbent exceeding 10 μm, it tends to be difficult to stably produce a porous molded body.

(Step (3): Slurry preparation step)
In the step (3), the inorganic ion adsorbent obtained in the step (2), a good solvent for the porous molded body-forming polymer, the porous molded body-forming polymer, and in some cases, a water-soluble polymer (hydrophilic polymer) are used. Mix to make a slurry.
As a good solvent for the porous molded product-forming polymer used in the steps (2) and (3), the porous molded product-forming polymer is stably dissolved in excess of 1% by mass under the manufacturing conditions of the porous molded product. If there is, it is not particularly limited, and conventionally known ones can be used.
Examples of the good solvent include N-methyl-2pyrrolidone (NMP), N, N-dimethylacetamide (DMAC), N, N-dimethylformamide (DMF) and the like.
Only one kind of good solvent may be used, or two or more kinds may be mixed and used.

The amount of the porous molded product-forming polymer added in the step (3) is determined by the ratio of the porous molded product-forming polymer / (porous molded product-forming polymer + water-soluble polymer + good solvent of the porous molded product-forming polymer). It is preferably 3% by mass to 40% by mass, and more preferably 4% by mass to 30% by mass. When the content of the porous molded product-forming polymer is 3% by mass or more, a porous molded product having high strength can be obtained, and when it is 40% by mass or less, a porous molded product having a high porosity can be obtained.
In the step (3), the water-soluble polymer does not necessarily have to be added, but by adding the water-soluble polymer, a fibrous structure that forms a three-dimensionally continuous network structure on the outer surface and the inside of the porous molded body. A porous molded product containing a body can be uniformly obtained, that is, a porous molded product can be obtained in which the pore size can be easily controlled and ions can be reliably adsorbed even when the liquid is passed through at high speed.
The water-soluble polymer used in the step (3) is not particularly limited as long as it is compatible with the good solvent of the porous molded product-forming polymer and the porous molded product-forming polymer.

As the water-soluble polymer, any of a natural polymer, a semi-synthetic polymer, and a synthetic polymer can be used.
Examples of the natural polymer include guar gum, locust bean gum, color ginan, gum arabic, tragant, pectin, starch, dextrin, gelatin, casein, collagen and the like.
Examples of the semi-synthetic polymer include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl starch, methyl starch and the like.
Examples of the synthetic polymer include polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyvinylmethyl ether, carboxyvinyl polymer, polyethylene glycols such as sodium polyacrylate, tetraethylene glycol, and triethylene glycol.
Among them, synthetic polymers are preferable from the viewpoint of enhancing the supportability of the inorganic ion adsorbent, and polyvinylpyrrolidone (PVP) and polyethylene glycol are more preferable from the viewpoint of improving the porosity.
The mass average molecular weight of polyvinylpyrrolidone (PVP) and polyethylene glycols is preferably 400 to 35,000,000, more preferably 1,000 to 1,000,000, and 2,000 to 100, It is more preferably 000.
If the mass average molecular weight is 400 or more, a porous molded product having a high surface opening property can be obtained, and if it is 350,000 or less, the viscosity of the slurry at the time of molding is low, so that molding tends to be easy. be.

The mass average molecular weight of the water-soluble polymer can be measured by dissolving the water-soluble polymer in a predetermined solvent and performing gel permeation chromatography (GPC) analysis.
As for the amount of the water-soluble polymer added, the ratio of the water-soluble polymer / (water-soluble polymer + porous molded body-forming polymer + good solvent of the porous molded body-forming polymer) is 0.1% by mass to 40% by mass. It is preferable that the content is 0.1% by mass to 30% by mass, more preferably 0.1% by mass to 10% by mass.
When the amount of the water-soluble polymer added is 0.1% by mass or more, the porous molded product contains a fibrous structure that forms a three-dimensionally continuous network structure on the outer surface and inside of the porous molded product. Is uniformly obtained. When the amount of the water-soluble polymer added is 40% by mass or less, the aperture ratio of the outer surface is appropriate, and the amount of the inorganic ion adsorbent on the outer surface of the porous molded body is large, so that the liquid is passed through at high speed. However, a porous molded body capable of reliably adsorbing ions can be obtained.

(Process (4): Molding process)
In the step (4), the slurry (molding slurry) obtained in the step (3) is molded. The molding slurry is a mixed slurry of a porous molded body-forming polymer, a good solvent for the porous molded body-forming polymer, an inorganic ion adsorbent, and if necessary, a water-soluble polymer.
The form of the porous molded body of the present embodiment can take any form such as a particle shape, a thread shape, a sheet shape, a hollow thread shape, a columnar shape, and a hollow columnar shape, depending on the method of molding the molding slurry.
The method of molding into particles, for example, spherical particles is not particularly limited, but for example, the molding slurry stored in the container is scattered from a nozzle provided on the side surface of the rotating container to form a liquid. Examples thereof include a rotary nozzle method for forming droplets. By the rotary nozzle method, it can be formed into a particulate form having a uniform particle size distribution.
Specifically, a method of spraying a molding slurry from a one-fluid nozzle or a two-fluid nozzle to coagulate in a coagulation bath can be mentioned.
The diameter of the nozzle is preferably 0.1 mm to 10 mm, more preferably 0.1 mm to 5 mm. If the diameter of the nozzle is 0.1 mm or more, the droplets are likely to scatter, and if it is 10 mm or less, the particle size distribution can be made uniform.
The centrifugal force is expressed by centrifugal acceleration, and is preferably 5G to 1500G, more preferably 10G to 1000G, and even more preferably 10G to 800G.

When the centrifugal acceleration is 5 G or more, the droplets are easily formed and scattered, and when the centrifugal acceleration is 1500 G or less, the molding slurry is discharged without forming a thread, and it is possible to suppress the widening of the particle size distribution. Due to the narrow particle size distribution, the water flow path becomes uniform when the column is filled with the porous compact, so ions (adsorption objects) leak out from the initial stage of water flow even when used for ultra-high-speed water flow treatment (the object to be adsorbed). It has the advantage that it does not break through.
Examples of the method of molding into a thread-like or sheet-like form include a method of extruding a molding slurry from a spout or die having a corresponding shape and coagulating it in a poor solvent.
As a method for forming the hollow filament-shaped porous molded body, by using a spun made of an annular orifice, it can be molded in the same manner as the method for forming the filament-shaped or sheet-shaped porous molded body.
As a method for forming a cylindrical or hollow cylindrical porous molded body, when the molding slurry is extruded from the spun, it may be solidified in a poor solvent while being cut, or it may be solidified into a thread and then cut. It doesn't matter.

(Step (5): Solidification step)
In the step (5), the solidified molded product obtained in the step (4) is solidified in a poor solvent to obtain a porous molded product.
<Poor solvent>
As the poor solvent in the step (5), a solvent having a solubility of 1% by mass or less of the porous molded product-forming polymer under the conditions of the step (5) can be used, and for example, alcohols such as water, methanol and ethanol can be used. , Ethers, aliphatic hydrocarbons such as n-hexane and n-heptane, and the like. Of these, water is preferable as the poor solvent.
In the step (5), a good solvent is brought in from the preceding step, and the concentration of the good solvent changes at the start and the end of the solidification step. Therefore, it may be a poor solvent to which a good solvent is added in advance, and it is preferable to perform the coagulation step by controlling the concentration while separately adding water or the like so as to maintain the initial concentration.

By adjusting the concentration of the good solvent, the structure (outer surface aperture ratio and particle shape) of the porous molded product can be controlled.
When the poor solvent is water or a mixture of a good solvent of the porous molded product-forming polymer and water, the content of the good solvent of the porous molded product-forming polymer with respect to water in the coagulation step may be 0 to 80% by mass. It is preferably 0 to 60% by mass, more preferably 0 to 60% by mass.
When the content of the good solvent of the porous molded product forming polymer is 80% by mass or less, the effect of improving the shape of the porous molded product can be obtained.
The temperature of the poor solvent is preferably 20 to 100 ° C. from the viewpoint of controlling the temperature and humidity of the space in the rotating container in which the droplets described below are scattered by centrifugal force.

(Manufacturing equipment for porous molded products)
When the porous molded body in the present embodiment is in the form of particles, the manufacturing apparatus includes a rotary container for scattering droplets by centrifugal force and a coagulation tank for storing the coagulation liquid, and coagulates with the rotary container. It can be provided with a cover that covers the space portion between the tanks, and is provided with a control means for controlling the temperature and humidity of the space portion.
The rotary container that scatters the droplets by centrifugal force is not limited to one having a specific structure as long as it has a function of making the molding slurry into spherical droplets and scatters by centrifugal force. Examples include a rotary nozzle.
In the rotating disk, the forming slurry is supplied to the center of the rotating disk, and the forming slurry is developed into a film with a uniform thickness along the surface of the rotating disk, and is split into droplets by centrifugal force from the periphery of the disk. To scatter fine droplets.
The rotary nozzle forms a large number of through holes in the peripheral wall of the hollow disk-shaped rotary container, or the nozzle is attached by penetrating the peripheral wall to supply the molding slurry into the rotary container and rotate the rotary container. At that time, a molding slurry is discharged from a through hole or a nozzle by centrifugal force to form droplets.
The coagulation tank for storing the coagulation liquid is not limited to one having a specific structure as long as it has a function of storing the coagulation liquid. Examples thereof include a coagulation tank having a structure in which a coagulation liquid naturally flows down along the inner surface of the body by gravity.
The coagulation tank with an open top surface is a device that naturally drops droplets scattered in the horizontal direction from a rotary container and captures the droplets on the water surface of the coagulation liquid stored in the coagulation tank with an open top surface.
The coagulation tank, which has a structure in which the coagulation liquid naturally flows down by gravity along the inner surface of the cylinder arranged so as to surround the rotating container, allows the coagulation liquid to flow out along the inner surface of the cylinder at a substantially uniform flow rate in the circumferential direction. , A device that captures and coagulates droplets in a coagulating liquid stream that naturally flows down along the inner surface.
The temperature and humidity control means of the space portion is a means for controlling the temperature and humidity of the space portion by providing a cover covering the space portion between the rotary container and the coagulation tank.

The cover covering the space is not limited to a specific structure as long as it has a function of isolating the space from the external environment and facilitating the practical control of the temperature and humidity of the space, for example, a box. It can be shaped like a cylinder, a cylinder, or an umbrella.
Examples of the material of the cover include metal stainless steel and plastic. It can also be covered with a known insulating agent in terms of isolation from the external environment. The cover may be provided with a partial opening to adjust the temperature and humidity.
The means for controlling the temperature and humidity of the space portion need only have a function of controlling the temperature and humidity of the space portion, and is not limited to a specific means. Humidifiers such as a device and a heating type humidifier can be mentioned.
From the viewpoint of simple structure, a means of heating the coagulation liquid stored in the coagulation tank and controlling the temperature and humidity of the space portion by using the steam generated from the coagulation liquid is preferable.

(Coating of biocompatible polymer)
Hereinafter, a method for forming a coating layer of a biocompatible polymer on the surface of a porous molded product will be described.
In the present embodiment, a coating film can be formed by applying, for example, a coating liquid containing a PMEA or PVP-based polymer to the surface of the porous molded product. At this time, for example, the PMEA coating liquid penetrates into the pores formed in the porous molded body, and does not significantly change the pore diameter on the surface of the porous molded body, but covers the entire pore surface of the porous molded body. PMEA can also be included.
The solvent of the PMEA coating liquid is particularly limited as long as it is a solvent that can dissolve or disperse PMEA without dissolving a polymer such as a porous molded body-forming polymer or a water-soluble polymer constituting the porous molded body. However, water or an aqueous alcohol solution is preferable because of the safety of the process and the ease of handling in the subsequent drying process. From the viewpoint of boiling point and toxicity, water, ethanol aqueous solution, methanol aqueous solution, isopropyl alcohol aqueous solution, water / ethanol mixed solvent, water / methanol mixed solvent and the like are preferably used.
The type of solvent of the coating liquid and the composition of the solvent are appropriately set in relation to the polymer constituting the porous molded product.
The concentration of PMEA in the PMEA coating liquid is not limited, but can be, for example, 0.001% by mass to 1% by mass, more preferably 0.005% by mass to 0.2% by mass of the coating liquid. ..
The method of applying the coating liquid is not limited, but for example, a porous molded body is filled in an appropriate column (container), the coating liquid containing PMEA is flowed from above, and then an excess solution is applied using compressed air. A method of removing can be adopted.
Then, it can be used as a medical device by washing with distilled water or the like to replace and remove the remaining unnecessary solvent, and then sterilizing it.

The porous molded body of the present embodiment contains an organic polymer resin and an inorganic ion adsorbent, has a specific surface area of 51.5 m ² / mL-R or more by the BET method, and has a surface pore diameter of 0.200 μm. Blood phosphorus that contains less than a porous molded body and has a biocompatible polymer on the surface of the porous molded body, thereby selectively and reliably adsorbing phosphate ions in the blood and returning to the body. The acid concentration is almost zero. It is considered that by returning the blood containing almost no phosphoric acid to the body, the movement of phosphoric acid into the blood from the intracellular or extracellular side becomes active and the refilling effect is enhanced. In addition, by inducing a refilling effect that attempts to supplement the phosphate in the blood, it may be possible to excrete extracellular fluid that cannot normally be excreted and phosphoric acid that exists inside the cell. In the phosphorus adsorbent for blood treatment of the present embodiment, the water-soluble polymer may be used as a component constituting the porous molded product.

(Freeze-drying of porous molded product)
Freeze-drying was carried out using a freeze-dryer (FDS-1000 type (trade name) manufactured by EYELA). 1 to 10 mL of the wet porous molded body is weighed using a measuring cylinder or the like, put into a 100 mL glass eggplant flask, and then allowed to stand in a freezer at -18 ° C or lower for 6 hours or more to be contained. After freezing the water, an eggplant flask was connected to a freeze-dryer, and freeze-dried for 10 hours or more under the conditions of a vacuum degree of 20 Pa or less and a trap temperature of −80 ° C. or less.

Hereinafter, examples and comparative examples will be described, but the present invention is not limited thereto. The physical characteristics of the porous molded product, the performance of the blood purifier, etc. were measured as follows. The scope of the present invention is not limited to the following examples and the like, and various modifications can be made within the scope of the gist thereof.

(Measurement of average particle size of porous molded body and average particle size of inorganic ion adsorbent)
The average particle size of the porous molded body and the average particle size of the inorganic ion adsorbent were measured with a laser diffraction / scattering particle size distribution measuring device (LA-950 (trade name) manufactured by HORIBA). Water was used as the dispersion medium. When measuring the sample using cerium hydrated oxide as the inorganic ion adsorbent, the value of cerium oxide was used for the refractive index. Similarly, when measuring a sample using lanthanum hydroxide as an inorganic ion adsorbent, use the value of lanthanum oxide (III) as the refractive index, and when measuring a sample using hydrated zirconium oxide, use the refractive index. When measuring the value of zirconium oxide and the sample using yttrium hydroxide, the value of yttrium oxide (III) was used as the refractive index.

(Measurement of specific surface area of porous molded product)
The porous molded product was freeze-dried, and then measured with a specific surface area and pore distribution measuring device (BELSORP-miniII (trade name) manufactured by Microtrac Bell Co., Ltd.).
Approximately 0.3 g of the freeze-dried porous molded body is measured, placed in a dedicated 5 mL glass cell, and the pore volume and specific surface area are measured by adsorption and desorption of nitrogen gas while cooling the glass cell with liquid nitrogen. Was done. Nitrogen gas having a purity of 99.99% by volume or more was used as the adsorbent, and helium gas having a purity of 99.99% by volume or more was used as the purge gas. As a reference cell, an empty glass cell having the same volume as the glass cell for measurement was used, and the measurement was performed with the setting to correct the measured value. The measurement method was a simple method, and the measurement was performed by setting the suction relative pressure upper limit to 0.95 and the desorption relative pressure lower limit to 0.3.
The analysis by the BET method and the BJH method after the measurement was performed using analysis software (BEL Master (Version 6.3.1.0) manufactured by Microtrack Bell Co., Ltd.). The specific surface area was determined by the steam measurement method.

(Measurement of surface pore diameter of surface porous molded product)
Observation of the porous molded body with a scanning electron microscope (SEM) was performed with a scanning electron microscope FlexSEM1000 of Hitachi High-Tech Co., Ltd. A sample of the porous molded body was held on a carbon adhesive tape / alumina reagent and coated with osmium (OS) as a conductive treatment to prepare an outer surface SEM observation sample. The image of the outer surface of the molded body taken with a scanning electron microscope was analyzed using Image J image analysis software to determine the surface pore size. More specifically, the obtained SEM image is recognized as a shading image, and the threshold value is manually adjusted so that the dark part has an opening and the light part has a porous structure (skeleton structure), and the thick part is formed. The diameter of the circle was calculated. For the same sample (lot) as an image, 10 or more SEM images were taken, and the diameter of the hole was measured at 10 or more places per image.

(Measurement of complement activity)
The degree of complement activation was measured by measuring the concentration of sC5b-9 produced from blood among the complements. Add 4 mL of heparinized blood (heparin concentration 1 U / mL) to a test tube containing 1 mL of the porous molded body, and shake and heat the test tube at 37 ± 1 ° C. for 3 hours, during which time once every 30 minutes. The frequency of overturning was mixed. After heating, 1.0 mL of heparinized blood is collected from a test tube, 0.1 mL of EDTA-2K (1.5 mg), 1 mg / mL nafamostat mesylate (fusan) physiological saline is added, mixed, and complemented. It was used as a sample for body measurement.
The complement measurement sample was centrifuged at about 2000 G for 15 minutes under a setting of 4 ° C., and plasma was collected to prepare an sC5b-9 measurement sample. The sC5b-9 measurement sample was stored at −70 ° C. or lower and subjected to measurement within 2 weeks. The sC5b-9 concentration was measured by enzyme immunoassay using a commercially available kit.

(Phosphorus adsorption capacity in bovine plasma)
Using the apparatus shown in FIG. 1, the amount of phosphorus adsorbed by a column flow test using low-phosphorus serum using bovine plasma was measured. Considering the case where a phosphorus adsorber is used after the dialyzer during dialysis treatment, it was decided to measure the phosphorus adsorption amount at a blood inorganic phosphorus concentration of 0.2 to 1.0 mg / dL at the outlet of the dialyzer during dialysis treatment. Using bovine plasma adjusted to a low phosphorus concentration (0.8 mg / dL), the column (container) was filled under the same ^{conditions as general dialysis conditions (space velocity SV = 120 hr -1, 4 hours dialysis).} The phosphorus adsorption amount (mg-P / mL-Resin (porous molded product)) of the porous molded product was measured. The phosphate ion concentration was measured by the direct molybdate method.
When the phosphorus adsorption amount when the liquid passing speed was SV120 was 2.0 (mg-P / mL-Resin) or more, it was judged that the adsorption capacity was large and the phosphorus adsorbent was good.
<Column flow test with low phosphorus serum using bovine plasma>
The amount of phosphorus adsorbed at a low inorganic phosphorus concentration was measured assuming the blood inorganic phosphorus concentration at the outlet of the dialyzer during dialysis treatment. Therefore, the phosphorus concentration of the test plasma solution was adjusted.
Commercially available bovine blood (anticoagulant: sodium heparin) was centrifuged (3500 rpm, 5 min) to prepare 2000 mL of plasma as the supernatant. The phosphorus concentration in plasma was 10.8 mg / dL.
A porous compact was added to half (1000 mL) of the obtained plasma, and the mixture was stirred at room temperature for 2 hours and centrifuged (3500 rpm, 5 min) to obtain about 950 mL of plasma having a phosphorus concentration of 0.
35 mL of plasma having a phosphorus concentration of 10.8 mg / dL and 465 mL of plasma having a phosphorus concentration of 0 were mixed and centrifuged (3500 rpm, 5 min) to obtain plasma having a phosphorus concentration of 0.8 mg / dL and 495 mL as a supernatant.
450 mL of the obtained plasma was passed through a column containing 1 mL of the porous molded product at ^{a flow rate of 2 mL / min (SV = 120 hr -1} ), 10 mL was collected for the first fraction, and 20 mL was collected for each sample thereafter. .. Normally, the average dialysis condition is that dialysis is performed at a flow rate Qb = 200 mL / min for 4 hours, so that the total blood flow rate is 200 mL × 4 hours = 48000 mL. It becomes. This time, the experiment was performed on a 1/100 scale, so 340 mL of liquid was used as a guide.

[Example 1]
2000 g of cerium sulfate tetrahydrate (Wako Pure Chemical Industries, Ltd.) is put into 50 L of pure water, dissolved using a stirring blade, and then 3 L of 8M caustic soda (Wako Pure Chemical Industries, Ltd.) is 20 ml / min. A precipitate of hydrated cerium oxide was obtained by dropping at the rate of. After filtering the obtained precipitate with a filter press, 500 L of pure water is passed through the solution for washing, and 60 L of ethanol (Wako Pure Chemical Industries, Ltd.) is passed through the solution to remove the water contained in the hydrated cerium oxide. Replaced with ethanol. At this time, 10 ml of the filtrate at the end of filtration was collected, and the water content was measured with a Karl Fischer Moisture Analyzer (CA-200 (trade name) manufactured by Mitsubishi Chemical Analytech Co., Ltd.). Was 5% by mass, and the substitution rate of the organic liquid was 83% by mass. The hydrated cerium oxide containing the obtained organic liquid was air-dried to obtain dried hydrated cerium oxide.
The obtained dry hydrated cerium oxide was used in a jet mill device (SJ-100 (trade name) manufactured by Nisshin Engineering Co., Ltd.) under the conditions of a pressure pressure of 0.8 MPa and a raw material feed rate of 100 g / hr. The mixture was pulverized to obtain a hydrated helium oxide powder having an average particle size of 1.05 μm.

Add 40 g of polyether sulfone (PES) to 220 g of N-methyl-2-pyrrolidone (NMP) and 1 g of polyvinylpyrrolidone (PVP, Nippon Shokubai PVP-K85) as a water-soluble polymer, and shake at 150 rpm overnight. And dissolved. Subsequently, 75 g of hydrated cerium oxide powder having an average particle size of 1.05 μm was added, and shaking was continued again to disperse cerium hydroxide. After dispersion, the slurry was filtered through a 90 μm sieve to obtain a uniform molding slurry liquid.
The obtained molding slurry liquid was supplied to the inside of a cylindrical rotary container having a nozzle having a diameter of 0.3 mm on the side surface, and the container was rotated to form droplets from this nozzle by centrifugal force. Subsequently, a coagulation liquid having an NMP content of 50% by mass with respect to water was stored in the coagulation tank at 23 ° C., and droplets were allowed to land in the coagulation tank having an upper opening to solidify the molding slurry liquid. Further, it was washed and classified to obtain a spherical porous molded product.

[Example 2]
Add 110 g of dimethylacetamide (DMAc) to a good solvent for the organic polymer, 20 g of polysulfone to the organic polymer resin, and 5 g of PVP (PVP-K85) to the water-soluble polymer, heat to 60 ° C, and shake. A spherical porous molded body was obtained in the same manner as in Example 1 except that the coagulating solution was dissolved and the coagulating solution having a DMAc content of 50% by mass with respect to water was used at 50 ° C.

[Example 3]
Instead of the polyether sulfone of Example 1, a copolymer of 91.5% by mass of acrylonitrile, 8.0% by mass of methyl acrylate, and 0.5% by mass of sodium metharylsulfonic acid having an extreme viscosity [η] = 1.2. A spherical porous molded body was obtained in the same manner as in Example 1 except that 10 g of the polymer (organic polymer resin, PAN) and 2 g of PVP (PVP-K85) were used as the water-soluble polymer.

[Example 4]
20 g of dimethylsulfoxide (DMSO) as a good solvent for organic polymers, 160 g of ethylene vinyl alcohol copolymer (EVOH) as an organic polymer resin, 5 g of PVP (PVP-K85) as a water-soluble polymer, and cerium oxide powder. A spherical porous polymer was obtained in the same manner as in Example 1 except that the charge amount was 250 g, the coagulating liquid was water, and the nozzle diameter was 0.51 mm.

[Example 5]
A spherical porous molded body was obtained in the same manner as in Example 1 except that lanthanum hydroxide (La (OH) _{3) was charged in place of cerium hydrate and the amount was 124 g.}

[Example 6]
A spherical porous molded product was obtained in the same manner as in Example 1 except that zirconium oxide (ZrO _{2) was charged in place of cerium hydrate and the amount was 81 g.}

[Example 7]
A spherical porous molded body was obtained in the same manner as in Example 1 except that yttrium hydroxide (Y (OH) _{3) was charged in an amount of 122 g instead of cerium hydrated oxide.}

[Example 8]
A spherical porous molded product was obtained in the same manner as in Example 1 except that the amount of the hydrated cerium oxide powder charged was 150 g.

[Example 9]
A spherical porous molded product was obtained in the same manner as in Example 1 except that 10 g of PVP (PVP-K85) was used as the water-soluble polymer.

[Comparative Example 1]
A spherical porous molded body was obtained in the same manner as in Example 1 except that 240 g of NMP was used as a good solvent and 10 g of PVP (PVP-K85) was used as a water-soluble polymer and the temperature of the coagulating solution was set to 60 ° C. ..

[Comparative Example 2]
A spherical porous molded product was obtained in the same manner as in Example 1 except that 8 g of PVP (PVP-K85) was used as the water-soluble polymer and the temperature of the coagulation bath was set to 50 ° C.

[Comparative Example 3]
A spherical porous molded product was obtained in the same manner as in Example 1 except that 10 g of PVP (PVP-K30) was used as the water-soluble polymer and the temperature of the coagulating liquid was set to 60 ° C.

The porous molded body for blood treatment according to the present invention can appropriately control the phosphorus concentration in the blood in the body without activating complement complement, and is therefore used in medical applications, especially for blood treatment. It can be suitably used for removing harmful substances.

1 Constant temperature bath 2 Laboratory table 3 Pump 4 Column with porous absorber 5 Pressure gauge 6 Sampling

Claims (4)

A porous molded article for blood treatment containing an organic polymer resin and an inorganic ion adsorbent, wherein the specific surface area of the porous molded article is 51.5 m ² / mL-Resin or more and 100 m ² / mL-Resin or less. A porous molded article for blood treatment having a surface pore diameter of 0.0005 μm or more and less than 0.200 μm. The porous molded body for blood treatment according to claim 1, wherein the organic polymer resin is at least one selected from the group consisting of polyethersulfone, polysulfone, ethylene vinyl alcohol copolymer, and polyacrylonitrile. The inorganic ion adsorbent has the following formula (1):
_{MN x O n · mH 2 O} ··· (1)
{In the equation, _x is 0-3, _n is 1-4, m is 0-6, and M and N are Ti, Zr, Sn, Sc, Y, La, Ce. , Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb, and Ta It is a metal element selected from the group of, and is different from each other. } The porous molded article for blood treatment according to claim 1 or 2, which contains at least one metal oxide represented by. The metal oxides are the following groups (a) to (c):
(A) At least one selected from the group consisting of hydrated titanium oxide, hydrated zirconium oxide, hydrated tin oxide, hydrated cerium oxide, hydrated lanthanum oxide, and hydrated yttrium oxide;
(B) A composite of at least one metal element selected from the group consisting of titanium, zirconium, tin, cerium, lantern, and yttrium and at least one metal element selected from the group consisting of aluminum, silicon, and iron. Metal oxides; and (c) activated alumina;
The porous molded article for blood treatment according to claim 3, which is selected from.

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