JP2009263269A - Artificial oxygen carrier used for treating hemorrhage - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hemoglobin-based artificial oxygen carrier which is needed on treatments of hemorrhage shocks or in processes for treating hemorrhage shocks and enables efficient oxygen supply to sites having oxygen partial pressures of ≤40 mmHg and efficient oxygen supply to sites having oxygen partial pressures between 100 mmHg and 40 mmHg in response to the state of the oxygen partial pressure of a tissue. <P>SOLUTION: The artificial oxygen carrier is characterized by together administering the artificial oxygen carrier having low oxygen affinity and the artificial oxygen carrier having high oxygen affinity. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an artificial oxygen carrier used for bleeding treatment. More specifically, the present invention relates to an artificial oxygen carrier capable of supplying oxygen according to the state of oxygen partial pressure of a tissue during or after bleeding shock treatment.

Various artificial oxygen carriers for treatment of bleeding have been studied based on hemoglobin. As the hemoglobin-based one, there are a hemoglobin solution type and a hemoglobin-containing liposome type. Allosteric factors (detailed in 0013) can be used to control the oxygen affinity of hemoglobin. In order to increase the amount of oxygen transport between the normal oxygen partial pressure of 100 mmHg in the lung and the oxygen partial pressure of 40 mmHg at the end of the tissue, a method for controlling oxygen affinity has been studied (Japanese Patent Publication No. 4-66456). At the time of hemorrhagic shock, the end of the tissue is deficient in oxygen because of blood flow failure, and the oxygen partial pressure at the end of the tissue is lower than 40 mmHg. In the past, studies that considered not only oxygen supply between an oxygen partial pressure of 100 mmHg and an oxygen partial pressure of 40 mmHg but also oxygen supply to a site with an oxygen partial pressure of 40 mmHg or less were not sufficiently performed.
4-66456 Artificial organ 18 (1), 369-372 (1989)

In a hemoglobin-based artificial oxygen carrier, when human blood is used as a raw material, 2,3-DPG (a phosphate compound that increases oxygen release capacity), an allosteric factor originally present in human erythrocytes, is lost in the process of removing hemoglobin from erythrocytes. Is called. As a result, there is a problem that the oxygen dissociation curve (details are described in 0013) shifts to the left, and the oxygen carrying efficiency (details is described in 0013) is lowered. In order to solve this problem, hemoglobin solution type artificial oxygen carrier chemically binds allosteric factor to hemoglobin, or hemoglobin-containing liposome type artificial oxygen carrier previously dissolves allosteric factor in hemoglobin solution. Studies have been made to make liposomes and increase oxygen carrying efficiency. All of these were methods for controlling the oxygen release capacity in order to increase the amount of oxygen transport between the normal oxygen partial pressure of 100 mmHg and the normal oxygen partial pressure of 40 mmHg at the end of the tissue. However, in the hemorrhagic shock, blood is lost and blood flow is insufficiency, so that the end of the tissue is deficient in oxygen, and thus is in a state lower than the normal oxygen partial pressure of 40 mmHg. Considering this point, studies focusing on supplying oxygen to a portion where the oxygen partial pressure is lower than 40 mmHg are also being conducted recently. In other words, compared to natural red blood cells, it is difficult to release oxygen between the normal oxygen partial pressure of 100 mmHg of the lung and the oxygen partial pressure of 40 mmHg at the end of the tissue, and it is easier to release oxygen at the oxygen partial pressure of 40 mmHg or less. In this study, an artificial oxygen carrier that shifts the oxygen dissociation curve to the left (referred to as high oxygen affinity) compared to erythrocytes is used to treat bleeding. In the present invention, when the oxygen dissociation curve is shifted to the left as compared with normal natural erythrocytes, it is called high oxygen affinity, and when compared with normal natural erythrocytes, the oxygen dissociation curve is on the right. The shifted case is called low oxygen affinity. Compared with the conventional method of increasing the oxygen carrying amount between the oxygen partial pressure of 100 mmHg and the oxygen partial pressure of 40 mmHg, it aims at the opposite direction in terms of oxygen release capacity. At present, some hemoglobin-based artificial oxygen carriers worldwide have progressed to the clinical stage, but some have high oxygen affinity and some have low oxygen affinity. In other words, in terms of oxygen release capacity, it seems that contradictions seem to contradict that those aiming in the opposite direction have advanced to the clinical trial stage. However, in the early stage of hemorrhagic shock treatment, it is important to supply oxygen to sites with an oxygen partial pressure of 40 mmHg or less. After an artificial oxygen carrier is administered, oxygen supply to hypoxic tissues and the amount of intravascular circulation are ensured. This time, we focused on the point that oxygen supply is required between the normal oxygen partial pressures of 100mmHg and 40mmHg. That is, for the treatment of bleeding, oxygen supply to a site having an oxygen partial pressure of 40 mmHg or lower and oxygen supply between oxygen partial pressures of 100 mmHg to 40 mmHg are necessary depending on the situation. However, there has been no investigation focusing on this point.
The present invention uses a low oxygen affinity artificial oxygen carrier and a high oxygen affinity artificial oxygen carrier at the time of bleeding treatment, and oxygen supply between oxygen partial pressures of 100 mmHg to 40 mmHg is also reduced to an oxygen partial pressure of 40 mmHg or less. Therefore, it is also possible to provide an artificial oxygen carrier and its administration method that can supply oxygen depending on the situation.

  At the time of hemorrhage treatment, we focused on the fact that oxygen supply to the normal tissue end oxygen partial pressure of 40 mmHg or less and oxygen supply between oxygen partial pressure of 100 mmHg to 40 mmHg depending on the situation, Since the examination from the viewpoint was not performed, the above-mentioned problems were solved as follows.

An artificial oxygen oxygen carrier for use in bleeding treatment, wherein the artificial oxygen carrier having a low oxygen affinity and the artificial oxygen carrier having a high oxygen affinity are used in combination.

(2) An artificial oxygen carrier used for bleeding treatment, characterized by administering the artificial oxygen carrier having a low oxygen affinity for the first time, and then administering the artificial oxygen carrier having a high oxygen affinity. The artificial oxygen carrier according to claim 1, wherein:

(3) The artificial oxygen carrier according to claim 1 or 2, wherein the artificial oxygen carrier is a suspension of hemoglobin-containing liposomes.

  As described above in detail, the present invention uses the artificial oxygen carrier having a low oxygen affinity and the artificial oxygen carrier having a high oxygen affinity at the time of bleeding treatment, thereby providing oxygen necessary for the treatment of bleeding. It is possible to provide an artificial oxygen carrier capable of supplying oxygen at a partial pressure of 40 mmHg or less and oxygen supply at an oxygen partial pressure of 100 mmHg to 40 mmHg depending on the situation.

  As the artificial oxygen carrier of the present invention, a hemoglobin solution type or a hemoglobin-containing liposome type may be used. Hereinafter, a hemoglobin-containing liposome type is used as the artificial oxygen carrier. The case will be described more specifically.

<Liposome membrane-forming lipid>
The liposome membrane-forming lipid in the present invention can be a natural or synthetic lipid. In particular, phospholipids are preferably used, and those obtained by hydrogenation according to a conventional method can be mentioned. Further, higher lipophilic fatty acids may be added to the liposome membrane-forming lipid as desired, such as a membrane reinforcing agent such as sterol or a charged substance. Preferably, hydrogenated soybean phospholipid is used as the phospholipid, cholesterol is used as the film strengthening agent, and stearic acid is used as the charged substance.

<Hemoglobin contained in liposome aqueous phase>
As the hemoglobin contained in the aqueous phase of liposomes of the present invention, concentrated human-derived hemoglobin is used after removing leukocytes, platelets, plasma and erythrocyte membrane from a human expired concentrated erythrocyte preparation by a known method.

<Liposome surface modifier>
As a protein adsorbent on the liposome surface or inhibition of liposome aggregation (Japanese Patent Publication No. 7-20857) and to reduce the possibility of transient blood pressure reduction after intravascular administration of the liposome (Japanese Patent Application No. 2007-267469) A compound having hydrophobicity at one end and a hydrophilic polymer at the other end is used for the surface modification of the liposome.

<Allosteric factor and oxygen dissociation curve>
The allosteric factor described in the present invention is a factor that affects the oxygen dissociation curve (a curve showing the relationship between the oxygen saturation of hemoglobin and the partial pressure of oxygen. See FIG. 1 for the oxygen dissociation curve of human natural blood). . Allosteric factors shift the oxygen dissociation curve to the right, resulting in higher oxygen carrying efficiency. In general, the oxygen carrying efficiency of natural erythrocytes indicates the difference in oxygen saturation of hemoglobin between the normal oxygen partial pressure of 100 mmHg and the oxygen partial pressure of 40 mmHg at the end of the tissue, which is the site of oxygen supply. As shown in Fig. 1, in human natural red blood cells, oxygen saturation is about 100% in the lung (oxygen partial pressure 100mmHg), and in the vein (oxygen partial pressure 40mmHg), oxygen saturation is about 75%. In between, 25% of the oxygen saturation is supplied to the tissue. In a hemoglobin-containing liposome suspension as an artificial oxygen carrier, when human blood is used as a raw material, in the process of taking out hemoglobin from red blood cells, 2,3-DPG (which enhances the oxygen release capacity) of the allosteric factor originally present in human red blood cells Phosphoric acid compound) is lost. As a result, the oxygen dissociation curve shifted to the left, and there was a problem that the oxygen carrying efficiency between 100 mmHg and 40 mmHg obtained with natural red blood cells was lowered. The present inventors have intensively studied a method for solving this problem by dissolving an allosteric factor in a hemoglobin solution in advance and converting it into a liposome (Japanese Patent Publication No. 4-66456).
However, at the time of hemorrhagic shock, peripheral circulation failure occurs due to the loss of blood, and oxygen is insufficient at the end of the tissue. The oxygen partial pressure at the end of the tissue is even lower than the normal oxygen partial pressure at the end of the tissue of 40 mmHg. ing. In order to supply oxygen to a part with an oxygen partial pressure lower than the oxygen partial pressure of 40 mmHg, the oxygen transport efficiency between the oxygen partial pressure of 40 mmHg and the oxygen partial pressure of 0 mmHg is important, If the range is shifted to the left, it is difficult to release oxygen at an oxygen partial pressure of 100 mmHg to 40 mmHg compared to natural red blood cells, and oxygen is easily released at a site where the oxygen partial pressure is 40 mmHg or less. In the present invention, when the oxygen dissociation curve is shifted to the right as compared with natural erythrocytes, it is referred to as low oxygen affinity, and when it is shifted to the left, high oxygen affinity. Therefore, in order to increase the amount of oxygen transport that can be transported to the hypoxic tissue, it is advantageous to reduce or not add the allosteric factor that acts to shift the oxygen dissociation curve to the right.
In the present invention, the high oxygen affinity hemoglobin-containing liposome suspension (with little or no allosteric factor added) is administered at the initial stage of treatment at the time of bleeding shock, and the oxygen partial pressure is 40 mmHg or less. After efficient oxygen supply to the hypoxic site and ensuring of the amount of intravascular circulation were performed, oxygen supply between the partial oxygen pressure of the lung of 100 mmHg and the partial oxygen pressure of the tissue end of 40 mmHg is required. . Therefore, after administration of a high oxygen affinity artificial oxygen carrier, administration of a low oxygen affinity allosteric factor-added hemoglobin-containing liposome suspension shifts the oxygen dissociation curve to the right compared to natural erythrocytes. Therefore, the oxygen carrying efficiency set between 100 mmHg and 40 mmHg becomes high, and it becomes easy to supply oxygen between oxygen partial pressures of 100 mmHg and 40 mmHg.

<Oxygen carrying amount setting of hemoglobin-containing liposome suspension>
In the present invention, 1 mL of a liposome suspension having hemoglobin as an inner aqueous phase can carry oxygen between an oxygen partial pressure of 100 mmHg and an oxygen partial pressure of 40 mmHg (low oxygen affinity setting), or an oxygen partial pressure of 40 mmHg and 0 mmHg. In the present invention, the oxygen transport amount (high oxygen affinity setting) that can be transported between (1) hemoglobin concentration in the liposome suspension (hemoglobin is the main role of oxygen transport) (2) the liposome suspension Hemoglobin metration rate in liquid (hemoglobin is oxidized and loses oxygen carrying ability when it becomes methemoglobin) (3) Theoretically calculated from the oxygen carrying efficiency of the liposome suspension (described later). The oxygen carrying efficiency of the present invention is set between oxygen partial pressures of 100 mmHg and 40 mmHg for low oxygen affinity (difference between oxygen partial pressures of 100 mmHg and 40 mmHg oxygen saturation in the oxygen dissociation curve). Further, the oxygen carrying efficiency of the present invention is set between oxygen partial pressures of 40 mmHg and 0 mmHg for setting high oxygen affinity (difference in oxygen saturation between oxygen partial pressures of 40 mmHg and 0 mmHg in the oxygen dissociation curve).
Hemoglobin concentration in the liposome suspension: Aw / v%, hemoglobin metration rate in the liposome suspension: B%, oxygen transport efficiency of the liposome suspension (low oxygen affinity setting or high oxygen affinity) Setting): If C%, the amount of oxygen DmL (37 ° C, 1 atm) that can be transported between 1 mL of the liposome suspension and oxygen partial pressures of 100 mmHg and 40 mmHg, or between oxygen partial pressures of 40 mmHg and 0 mmHg. Is calculated theoretically as follows:
The number of oxygen molecules that can bind to hemoglobin (moL) in 1 mL of liposome suspension is four oxygen molecules that can bind to hemoglobin.
{A (1-B / 100) × 4/64500} / 100. . . . . (1).
Furthermore, since the oxygen carrying efficiency is C%, the number of oxygen molecules (moL) released by 1 mL of liposome suspension is
(1) x (C / 100). . . . . (2)
From the equation of state of gas PV = nRT R (atm · 1 · · · K · moL) = 0.082,
D (mL) = (2) × 0.082 × (37 + 273) × 1000. . . . . (3)
As described above, in the hemoglobin-containing liposome suspension, (1) hemoglobin concentration in the liposome suspension (2) oxygen transport efficiency in the liposome suspension (3) hemoglobin methonation in the liposome suspension By appropriately controlling and setting the rate, an appropriate oxygen carrying amount can be set.

<Hemoglobin concentration in liposome suspension>
The main role of oxygen transport of the hemoglobin-containing liposome suspension as an artificial oxygen transporter in the present invention is hemoglobin. If the hemoglobin concentration in the liposome suspension is too high, the concentration of liposome-forming lipids for lysing hemoglobin into liposomes will inevitably increase, and the total lipid concentration administered to the living body will increase, leading to safety aspects. There are concerns. On the other hand, if the hemoglobin concentration in the liposome suspension is too low, the absolute amount of hemoglobin, which is the main oxygen transporter, is insufficient, which is disadvantageous in setting the oxygen transport amount. Therefore, the appropriate hemoglobin concentration in the liposome suspension is 5.6 to 6.7 w / v%, more preferably 5.7 to 6.6 w / v%.

<Hemoglobin methaization rate in liposome suspension>
When hemoglobin is oxidized to methemoglobin, it loses its ability to carry oxygen. Therefore, in hemoglobin-containing liposomes as an artificial oxygen carrier, antioxidation of hemoglobin (prevention of hemoglobin methation) is one of important issues. When the pH of hemoglobin is excessively lowered, the oxidation of hemoglobin is promoted, so that the manufacturing process is kept at a low temperature, and at the same time, the pH of hemoglobin is controlled in the manufacturing process, and a reducing agent is obtained by a known method (Japanese Patent Laid-Open No. 2006-104069). After aseptically filling the production bag in the deoxygenated and deoxygenated state after use, outer packaging is performed so that the deoxygenated state can be maintained. Immediately after the preparation of the liposome suspension and during the effective storage period, the hemoglobin metation rate is 10% or less. If the hemoglobin metrification rate is higher than this, the amount of oxygen transported in the liposome suspension is lowered, which is disadvantageous as an oxygen transporter.

  EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. In addition, the manufacturing process of the said liposome suspension was made into operation in aseptic environment.

<Production of high oxygen affinity hemoglobin-containing liposome suspension>
No allosteric factor is added and the oxygen dissociation curve is shifted to the left compared to natural erythrocytes.
317 g of water was added to a uniformly mixed lipid composed of 182 g of hydrogenated soybean phosphatidylcholine, 89 g of cholesterol and 46 g of stearic acid, and heated at 85 ° C. for 30 minutes to prepare a hydrated and swollen uniformly mixed lipid. Hemoglobin was purified and concentrated from the expired concentrated red blood cell preparation to prepare concentrated hemoglobin having a hemoglobin concentration of 42.0 w / v%. 2634 g of the concentrated hemoglobin solution was added to 634 g of the hydrated and swollen uniformly mixed lipid, and the mixture was stirred uniformly and pre-emulsified. After the pre-emulsification, the emulsification was carried out by a stronger stirring. The mixture after the main emulsification was diluted with physiological saline, and the particle size was controlled by circulation filtration using a 0.45 μm membrane. Next, 10 mg / mL sodium sulfite physiological saline solution was used, and after deoxygenation with sodium sulfite, a 0.5 mg / mL sodium sulfite physiological solution was used using an ultrafiltration membrane with a molecular weight cut off of 300,000. The hemoglobin that had not been converted to liposomes was removed by hydroconcentration with a saline solution to prepare a human-derived concentrated hemoglobin-containing liposome suspension. A PEG-linked phospholipid physiological saline solution in which DSPE-PEG5000 (manufactured by NOF Corporation) was dissolved in physiological saline was added to the liposome suspension as a PEG-conjugated phospholipid. After adjusting the liposome membrane-forming lipid concentration in the liposome suspension containing the liposome and PEG-bound phospholipid to 4.05 w / v% and adjusting the PEG-bound phospholipid concentration to 0.31 w / v%, The liposome suspension was treated at 37 ° C. for 24 hours to obtain a PEG-conjugated phospholipid immobilized on the liposome surface (referred to as sample A).
The hemoglobin concentration in the liposome suspension was 6.3 w / v%, and the stearic acid concentration was 0.58 w / v%. The hemoglobin metation rate in the liposome suspension immediately after production was 4.0%. The oxygen carrying efficiency (high oxygen affinity setting. Difference in oxygen saturation between oxygen partial pressure 40 mmHg and oxygen partial pressure 0 mmHg) determined from the oxygen dissociation curve (37 ° C) of the liposome suspension was 97% . Hemoglobin concentration in the liposome suspension: 6.3 w / v%, hemoglobin metration rate: 4.0%, oxygen transportation efficiency (high oxygen affinity setting) of the liposome suspension: 97% 3) When applied to the equation, the oxygen carrying amount (37 ° C., 1 atm) that 1 mL of the liposome suspension can be carried between oxygen partial pressures of 40 mmHg to 0 mmHg was calculated to be 0.092 mL. On the other hand, since the oxygen dissociation curve is shifted to the left from the natural erythrocytes, the oxygen carrying efficiency between 100 mmHg and 40 mmHg is only 3%, and the amount of oxygen that can be carried between 100 mmHg and 40 mmHg is as described in 0015 above. When applied to the equation (3), it becomes 0.0028 mL.

<Production of low oxygen affinity hemoglobin-containing liposome suspension>
Allosteric factor is added to shift the oxygen dissociation curve more to the right compared to natural red blood cells.
336 g of water was added to a uniformly mixed lipid consisting of 182 g of hydrogenated soybean phosphatidylcholine, 89 g of cholesterol, and 65 g of stearic acid, and heated at 85 ° C. for 30 minutes to prepare a hydrated and swollen uniformly mixed lipid. Hemoglobin was purified and concentrated from the expired concentrated erythrocyte preparation, and concentrated hemoglobin having a hemoglobin concentration of 42.6 w / v% was prepared by adding equimolar amounts of 12 sodium phytate to hemoglobin as an allosteric factor. Add 2,400 g of the 12 mg phytate-concentrated concentrated hemoglobin solution to 672 g of the hydrated and swollen uniformly mixed lipid, and add sodium hydroxide in an amount to neutralize the stearic acid in the hydrated and swollen uniformly mixed lipid, while uniformly adding Stir and pre-emulsify. After the pre-emulsification, the emulsification was carried out by a stronger stirring. The mixture after the main emulsification was diluted with physiological saline, and the particle size was controlled by circulation filtration using a 0.45 μm membrane. Next, 10 mg / ml sodium sulfite physiological saline was used, and after deoxygenation with sodium sulfite, a 0.5 mg / ml sodium sulfite physiological solution was used using an ultrafiltration membrane with a molecular weight cut off of 300,000. The hemoglobin and 12 sodium phytate which were not made into liposomes were removed by hydrofiltration concentration with saline solution, and a human-derived concentrated hemoglobin and allosteric factor-containing liposome suspension was prepared. To the liposome suspension, an aqueous PEG-conjugated phospholipid solution in which DSPE-PEG5000 (manufactured by NOF Corporation) was dissolved in physiological saline was added as a PEG-conjugated phospholipid. After adjusting the liposome membrane-constituting lipid concentration in the liposome suspension containing the liposome and PEG-bound phospholipid to 4.04 w / v% and adjusting the PEG-bound phospholipid concentration to 0.33 w / v%, The liposome suspension was treated at 37 ° C. for 24 hours to obtain a PEG-conjugated phospholipid immobilized on the liposome surface (referred to as sample B).
The hemoglobin concentration in the liposome suspension was 6.2 w / v%, the concentration of 12 sodium phytate as an allosteric factor was 0.077 w / v%, and the stearic acid concentration was 0.82 w / v%. The hemoglobin metation rate in the liposome suspension immediately after production was 4.5%. The oxygen carrying efficiency (high oxygen affinity setting: difference in oxygen saturation between oxygen partial pressure 40 mmHg and oxygen partial pressure 0 mmHg) determined from the oxygen dissociation curve (37 ° C) of the liposome suspension was 41% . When the hemoglobin concentration in the liposome suspension is 6.2%, the hemoglobin metation rate is 4.5%, and the oxygen carrying efficiency (high oxygen affinity setting) of 41% in the liposome suspension is applied to the equation (3) described in the above 0013. The amount of oxygen transport (37 ° C., 1 atm) that can be carried by 1 mL of the liposome suspension between an oxygen partial pressure of 40 mmHg to 0 mmHg was calculated to be 0.038 mL. On the other hand, the amount of oxygen that can be transported between oxygen partial pressures of 100 mmHg and 40 mmHg (37 ° C, 1 atm) has the oxygen dissociation curve shifted to the right. In this case, the oxygen transport efficiency (low oxygen affinity setting) Since it is 37%, it is 0.0345 mL when applied to the expression (3) described in 0013 above.

<Examination of administration method>
The high oxygen affinity hemoglobin-containing liposome suspension described in 0017 is referred to as sample A, and the low oxygen affinity hemoglobin-containing liposome suspension described in 0018 is referred to as sample B. The amount of oxygen that each sample 1mL can carry between oxygen partial pressures of 40 mmHg to 0 mmHg (37 ° C, 1 atm) and the amount of oxygen that can be transferred between oxygen partial pressures of 100 mmHg to 0 mmHg (37 ° C, 1 atm) ) Are summarized in Table 1. The administration method was simulated as follows.
(Administration method 1) Only sample A is administered at the beginning of treatment When only sample A is administered at the time of bleeding shock, oxygen is efficiently supplied to a site having an oxygen partial pressure of 40 mmHg or less from Table 1 (sample 1 mL After the oxygen supply to an oxygen partial pressure of 40 mmHg or less and the circulatory volume in the blood vessel are secured, oxygen supply at an oxygen partial pressure of 100 mmHg to 40 mmHg is required. The amount of oxygen transported by is small, and oxygen is transported by the blood flow in which the remaining natural red blood cells are secured.
(Administration method 2) Administration of sample B only at the initial stage of treatment When only sample B is administered at the time of hemorrhagic shock, according to Table 1, 0.038 mL of oxygen per mL of sample at a site with an oxygen partial pressure of 40 mmHg or less The amount is less than 1/2 compared to the administration method 1. According to Table 1, the oxygen supply amount between the partial pressure of oxygen of 100 mmHg and 40 mmHg after administration of sample B is 0.0345 mL per 1 mL of sample, and oxygen is transported together with the remaining natural red blood cells.
(Administration method 3) If sample A is administered at the initial stage of treatment and then sample B is administered at the time of hemorrhage shock, if sample A is administered at the initial stage of treatment, according to Table 1, per 1 mL of sample at a site where oxygen partial pressure is 40 mmHg 0.092 mL is supplied. If sample B is administered after oxygen is supplied to the site where the partial pressure of oxygen is 40 mmHg or less by administration of sample A and the vascular circulation volume is secured, the oxygen supply amount between 100 mmHg and 40 mmHg of oxygen partial pressure is 1 mL of sample. 0.0345mL, which carries oxygen in conjunction with the remaining natural red blood cells.
In each administration method according to the above simulation, the amount of oxygen transported to a site having an oxygen partial pressure of 40 mmHg or less, and the oxygen partial pressure between 100 mmHg and 40 mmHg, which can transport 1 mL of the hemoglobin-containing liposome suspension in the present invention. The transport amount is summarized in Table 2.
After administration of high oxygen affinity artificial oxygen carrier at the initial stage of hemorrhagic shock treatment by administration method 3, oxygen is efficiently provided to sites with an oxygen partial pressure of 40 mmHg or less, and the amount of intravascular circulation is secured. It can be seen that an oxygen-affinity artificial oxygen carrier is administered and oxygen supply is efficiently performed at an oxygen partial pressure of 100 mmHg to 40 mmHg. The dose and timing of administration of each sample are selected depending on the bleeding situation and the patient's condition.

The oxygen dissociation curve of human natural blood is shown.

Claims (3)

  An artificial oxygen oxygen carrier for use in bleeding treatment, wherein the artificial oxygen carrier having a low oxygen affinity and the artificial oxygen carrier having a high oxygen affinity are used in combination.   An artificial oxygen carrier used for bleeding treatment, wherein the artificial oxygen carrier having a low oxygen affinity is administered for the first time, and then the artificial oxygen carrier having a high oxygen affinity is administered. 2. The artificial oxygen carrier according to 1.   3. The artificial oxygen carrier according to claim 1 or 2, wherein the artificial oxygen carrier is a suspension of hemoglobin-containing liposomes.

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