JP2000198743A - Albumin formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an albumin formulation capable of stably dissolving every components without losing a quickly improving effect on symptoms by hemorrhage, not generating a precipitate even in sterilization by including electrolytic ions containing a citric acid ion and a bicarbonate ion, albumin and water. SOLUTION: This albumin formulation is obtained by including an electrolytic ion containing a citric acid ion and a bicarbonate ion, albumin and water. Preferably, the formulation contains 50-150 meq/l of sodium ion, 2-6 meq/l of potassium ion, 1-3 meq/l of magnesium ion, 1-5 meq/l of calcium ion, 50-150 meq/l of chlorine ion, 1-5 meq/l of citric acid ion, at least 20 meq/l of a bicarbonate ion, albumin and water. The concentration of the albumin is preferably at least 0.5 wt.% and pH of the formulation is preferably adjusted at the vicinity of neutral.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an albumin preparation, and more particularly to an infusion preparation to be replenished in an emergency when body fluid is lost. And
The infusion preparation is characterized in that its effects are maintained for a long time even after the administration is completed.

[0002]

2. Description of the Related Art When a large amount of body fluid is lost such as unexpected massive bleeding during an operation or vascular damage due to an accident, a decrease in circulating plasma to peripheral tissues, a decrease in blood pressure, and a resulting gas exchange in the lungs. It causes a decrease in the ability to resorb bicarbonate ions in the kidneys, a decrease in cardiac contractility due to a decrease in oxygen carrying capacity, and an increase in lactic acid levels due to anaerobic metabolism due to lack of oxygen. These factors lead to very severe acidosis and the patient's condition deteriorates rapidly. The condition can be fatal if not treated promptly and accurately.

[0003] In the treatment of these pathological conditions, a blood pressure is sometimes maintained by using a vasopressor such as dopamine or dobutamine for the purpose of improving blood pressure and increasing the myocardial contractility of the patient. However, this is only an auxiliary means, and replacement therapy such as blood transfusion or transfusion is mainly performed. It is desirable for patients to replace lost blood by transfusion,
Because of urgency, it is not possible to wait for the result of blood type determination, not enough blood is always secured, not only for the purpose of increasing plasma, but also for correcting acidosis, etc. For example, administration of a large amount of lactated Ringer's solution or Ringer's acetate solution or administration of human serum albumin is performed.

[0004] In the conventional treatment method, it has been considered that a sufficient therapeutic effect can be obtained by administering a large amount of lactated Ringer's solution or administering albumin to supplement a colloidal agent.
However, it cannot be said that the effect is insufficient if only the conventional Ringer's solution or colloidal solution is used. On the other hand, an albumin-containing electrolyte solution prepared by imitating a human plasma component is known (Japanese Patent Publication No. Sho 61-502941).
The prior art described in the patent includes Shimasek liver perfusion,
Krebs kidney perfusion, hepatocyte culture, Burlman kidney perfusion,
Fullgraph is an electrolyte solution used for renal perfusion, all of which contain L-lactic acid. As an improvement on these electrolyte solutions, Krebs albumin solution containing no L-lactic acid, containing sodium ions, potassium ions, calcium ions, magnesium ions, chloride ions, bicarbonate ions, phosphate ions, and albumin, It is described in that patent. However, when the present inventors prepared an electrolyte solution containing the albumin, a precipitate considered to be calcium carbonate or calcium phosphate was confirmed, and it was difficult to obtain an infusion preparation that can be administered intravenously.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to prepare an electrolyte solution which does not lose the effect of promptly improving the condition caused by bleeding. In particular, the present invention provides an infusion preparation which does not generate a precipitate even when each composition is stably dissolved and sterilized in an autoclave or the like.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on the composition of an infusion preparation effective for improving blood pressure when a large amount of body fluid is lost due to bleeding and correcting acidosis. Found that an acidosis correcting effect, which was not observed at all, could be recognized by combining it with albumin. In addition, they have found that by containing citrate ions as electrolyte ions in an electrolyte solution containing albumin and bicarbonate, a stable infusion preparation that does not precipitate even after autoclaving can be obtained, and the present invention has been achieved.

[0007]

That is, the present invention is an albumin preparation containing electrolyte ions including citrate ions and bicarbonate ions, albumin and water.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION As electrolytes of the albumin preparation of the present invention, cations such as sodium ion, potassium ion, magnesium ion and calcium ion, citrate ion and bicarbonate ion, chloride ion,
Contains anions such as gluconate ion and sulfate ion.
Specifically, salts composed of these cations and anions are used. As a raw material compound giving such a composition, any compound which is usually used in an infusion preparation or a pharmacologically acceptable compound may be used. Specifically, sodium chloride, potassium chloride, potassium gluconate, magnesium sulfate, calcium chloride, calcium gluconate,
Examples include sodium bicarbonate (referred to as baking soda), citric acid, and the like. Although the concentration of these electrolytes is not particularly limited, it is generally desirable that they be close to the concentrations of various electrolytes constituting the body fluid.

The albumin preparation of the present invention preferably contains the following components. Sodium ion 50-150 mEq / l, potassium ion 2-6 mEq / l, magnesium ion 1-3 mEq / l, calcium ion 1-5 mEq / l, chloride ion 50-150 mEq / l citrate ion 1-5 mEq / l, bicarbonate ion at least 20 mEq / l, albumin, and water.

[0010] To prepare the albumin preparation of the present invention,
First, salts that generate electrolyte ions are dissolved in physiological saline. At this time, in the present invention, in order to suppress precipitation due to generation of calcium carbonate and magnesium carbonate, citric acid is dissolved together with other electrolytes other than bicarbonate, and after complete dissolution, Dissolve salts, especially sodium bicarbonate. Separately, albumin is dissolved in physiological saline. Next, the electrolyte solution and the albumin solution are mixed to obtain an albumin preparation of the present invention. The solution is passed through a 0.22-0.45 micron diameter membrane filter to remove impurities. After each solution is filtered through the above-mentioned filter, it is desirable to fill the obtained filtrate into a container and sterilize by high-pressure steam.

The albumin preparation of the present invention is prepared by dissolving carbon dioxide gas in an electrolyte solution before sterilization and adjusting its pH to about 7.0 in order to prevent precipitation of calcium carbonate and magnesium carbonate even after a sterilization operation such as an autoclave. Prepare no more than 4. As a method of dissolving carbon dioxide gas in the electrolyte solution, there is a method of enclosing carbon dioxide gas of an appropriate concentration in a head space of a container, bubbling carbon dioxide gas, and the like. Among them, bubbling of carbon dioxide is simple. Also, when administered intravascularly, to reduce irritation,
It is preferable that the albumin preparation of the present invention is adjusted to pH 6.5 to 7.4.

In the present invention, the pH of the albumin preparation
A suitable acid can be mixed for the purpose of maintaining the pH around neutral, and specifically, hydrochloric acid, acetic acid, malic acid and the like are used. If necessary, saccharides may be added to the albumin preparation of the present invention. Specific examples of the saccharide include monosaccharides such as glucose and fructose, disaccharides such as maltose, and sugar alcohols such as sorbitol and xylitol.

The concentration of albumin is usually a dose used for infusion, and may be within a range in which a plasma increasing effect and a blood pressure increasing effect can be obtained. Specifically, at least 0.5% by weight of the albumin preparation %, Preferably 2.0 to 5.0
It is preferred to contain the weight%. The albumin used in the present invention is not particularly limited, such as animal-derived albumin and albumin produced by genetic engineering.
However, from the aspect of antigenicity, human-derived albumin is desirable. Examples of human-derived albumin include human serum albumin, human albumin produced by genetic engineering, and the like. Any albumin that is generally equivalent to albumin used for medical purposes may be used. In addition, heat-treated albumin is preferred for virus inactivation. During the heat treatment, it is preferable to add an appropriate stabilizer in order to increase the stability of albumin against heat. Specific examples include sodium N-acetyltryptophan and sodium caprylate. Furthermore, in the present invention, for the purpose of avoiding virus contamination, the use of albumin produced by genetic engineering is also suitable. The method for producing albumin obtained by the genetic recombination technique is not particularly limited. Usually, a gene encoding albumin is inserted into a vector, and a host cell, for example, yeast, Escherichia coli or an animal cell is transformed with the vector,
The transformed cells are cultured to collect the recombinant albumin. Albumin is isolated and purified from the culture supernatant or cultured cells according to a conventional method. Preferably, albumin contains at least 96% of the total protein.

The form of the albumin preparation of the present invention includes:
(1) A solution containing albumin and a solution containing bicarbonate and other electrolyte ions are filled in separate containers,
At the time of use, these can be connected aseptically to form a form that can be aseptically mixed, (2) a form in which the aseptically prepared solution is aseptically filled by, for example, a blow-fill filling machine, and (3) an albumin solution and bicarbonate. And a solution containing another electrolyte is separately prepared, and aseptically filled into bag-shaped bags divided into two chambers by a partition wall or welding, and these are connected at the time of use so that they can be aseptically mixed. (4) Sterilization treatment A solution prepared by any method, such as a two-part type, in which a required amount of an aseptically prepared albumin solution can be separately injected into a solution containing bicarbonate and other electrolytes. Is also good.

Among the above-mentioned embodiments, the method for sterilizing the electrolyte solution described in (1), (3) and (4) may be any method usually used for sterilizing infusion preparations and injections. Specific examples include filter sterilization and autoclave.

As the material for filling the albumin preparation of the present invention, various containers for filling medicines can be usually used. Specifically, it may be a glass container, a plastic film of polypropylene, polyethylene, polyvinyl chloride or the like, or a medical plastic container molded from a multilayer film of these. When such a plastic container is used, if a secondary packaging material having a high gas barrier property is used, a decrease in the bicarbonate ion concentration in the albumin preparation can be prevented, and a stable preparation can be supplied for a long period of time. Examples of the gas-impermeable secondary packaging material include a single-layer film such as an ethylene / vinyl alcohol copolymer, polyethylene terephthalate, and polyvinylidene chloride, or a material formed of a multilayer film of these. The container filled with the albumin preparation of the present invention can be double-packaged with another gas barrier packaging material in order to keep the carbon dioxide gas at a constant concentration.

[0017]

Next, the present invention will be described in detail with reference to examples. Example 1 The compositions shown in Table 1 below were dissolved in distilled water for injection at room temperature to make a total volume of 1600 L, and the solution was adjusted to pH 6.9 by bubbling carbon dioxide gas. This solution was filtered through a membrane filter having a pore size of 0.22 μm, and the filtrate was filled into glass vials at 200 ml each and sealed. Then, high-pressure steam sterilization was performed according to a conventional method.
The pH of this formulation was 7.22.

The above electrolyte solution and commercially available 25% human serum albumin (Table 2 below) were aseptically mixed at a ratio of 4: 1 (weight ratio) to obtain an albumin preparation containing bicarbonate and electrolyte. . The obtained albumin preparation was pale yellow and clear, and no precipitate was observed.

[0019]

[Table 1] Composition of sodium bicarbonate electrolyte solution for albumin mixing

[0020]

Table 2 Composition of 25% albumin solution (25% Buminate: Baxter)

Comparative Example 1 Each component shown in Table 3 below was dissolved in distilled water. This was filtered through a membrane filter having a pore size of 0.22 μm as in Example 1, and the filtrate was placed in a glass vial in an amount of 200 ml.
Each was filled and sealed. Subsequently, high-pressure steam sterilization was performed according to a conventional method. After dissolution, to examine the precipitation of the precipitate,
After filtration, the absorbance at 600 nm of each of the samples after high-pressure steam sterilization was measured. The measured values are shown in Table 4 below. The pH of this infusion preparation after filtration and after high-pressure steam sterilization were 7.37 and 7.39, respectively. For 200 ml of this electrolyte solution, 25%
47.8 ml of the albumin solution was aseptically added to obtain an infusion preparation.

[0022]

Table 3 Composition of Krebs albuminate (electrolyte solution before albumin mixing)

[0023]

[Table 4] Turbidity of Krebs albuminate (OD600)

The Krebs albumin immediately after dissolution showed very slight turbidity in the solution. This turbidity
Although it could be removed by passing through a 0.22 μm filter, more precipitate was observed after autoclaving. This precipitate did not disappear when mixed with the albumin solution. Therefore, it was confirmed that intravenous administration of the autoclaved infusion preparation of Krebs albuminate was impossible.

Example 2 SD rats weighing 280-320 g (n = 3-5)
Then, a catheter was inserted into each of the femoral artery, femoral vein, and carotid artery under urethane anesthesia, and blood pressure was measured from the carotid artery. 25 ml of whole blood volume at 1 ml / kg / min from femoral artery
10 minutes after the blood removal, the albumin preparation of Example 1 was injected twice as much as the blood removal amount from the femoral vein.
The effect of the albumin preparation on blood pressure was examined by monitoring the change in mean blood pressure over time from before the start of blood removal to 30 minutes after the end of the administration of the albumin preparation. For comparison, a Ringer's solution of sodium bicarbonate containing no albumin (Table 5 below) was similarly used. In addition, as a control group, a group to which only the blood removal treatment was performed and the albumin preparation of the present invention was not administered was prepared. FIG. 1 shows the transition of the mean blood pressure of the rat. In the figure, an albumin preparation of the present invention (●), a sodium bicarbonate solution containing no albumin (印), and a control (x) are shown.

[0026]

[Table 5] Composition of Ringer's sodium bicarbonate solution

As is clear from FIG. 1, the above albumin preparation and Ringer's sodium bicarbonate solution also showed a decrease in blood pressure due to blood removal.
Increased blood pressure was confirmed. Ringer's sodium bicarbonate solution did not reach the value before blood removal, and the blood pressure dropped again when the infusion was terminated. However, it was shown that the infusion containing albumin quickly reached the original value and maintained a normal value even after the infusion was completed.

Example 3 Male SD rats weighing 290-320 g (n = 4-
Using 6), a catheter was inserted into the right femoral artery, vein and carotid artery under urethane anesthesia, and blood pressure was recorded from the carotid artery before the start of blood removal and 10 minutes after the end of administration of the albumin preparation of the present invention. That is, 1 ml / kg /
The blood equivalent to 25% of the total blood volume was removed per minute, and the administration of the albumin preparation of the present invention was started from the femoral vein 10 minutes after the blood removal.
The administered infusion solution was twice as much as the blood removal volume, and the blood pressure of the rat was recorded until 1 hour after the administration. As the albumin preparation, albumin concentrations of 0, 0.2, 0.5,
A solution containing bicarbonate at 2.0.5.0% by weight and other electrolytes (see Table 3 for electrolyte concentrations). FIG.
Mean blood pressure before blood removal, after blood removal, immediately before administration of the infusion preparation (10 minutes after the end of blood removal), immediately after the end of the administration of the infusion preparation (30 minutes after the start of administration), and 30 minutes after the end of administration.

As is clear from FIG. 2, when the albumin concentration was 0.2% by weight, the change in blood pressure changed in the same manner as in the control group, and the effect of adding albumin was not recognized. Therefore, the concentration of albumin is considered to be at least 0.5% by weight.

Example 4 Kb1: jw white rabbit weighing 2.8 to 3.2 kg (n = 3 to
In 5), a catheter was inserted into the left femoral artery under pentobarbital anesthesia for blood removal and blood collection. Blood was removed from the femoral artery at 1 ml / kg / min for 20 minutes, and administration of the albumin preparation of the present invention (a sodium bicarbonate albumin solution, the product obtained in Example 1) was started 20 minutes after the blood removal. The dose of the infusion preparation was twice the amount of blood removed, and the transition of the acid-base equilibrium of the living body was observed until 180 minutes after the end of the administration. For comparison, Ringer's lactate solution (Table 6), Ringer's solution containing no albumin (Table 3), 5% albumin solution (Table 7), Ringer's lactate albumin solution (Lactate Ringer's solution and 25% albumin in a ratio of 4: 1 (weight ratio)) The blood mixture was collected from the femoral artery before, immediately after blood removal, 20 minutes after blood removal (immediately before administration of the infusion formulation), and 20 minutes after the start of administration of the infusion formulation, respectively. A blood gas analysis was performed (blood gas analyzer, Ciba Corning) Table 8 shows the blood pH, carbon dioxide partial pressure (pCO ₂ ),
It shows the time until the bicarbonate ion concentration (HCO ³⁻ ) and the acid-base equilibrium (BE) recover to normal values.

[0031]

[Table 6] Composition of Ringer lactate solution (Lacto Ringer solution Fuso: Fuso Pharmaceutical)

[0032]

Table 7 Composition of 5% albumin solution (5% Buminate:
Baxter)

[0033]

[Table 8] Recovery time (min) n = 3-5

The time required from the start of the infusion until the blood gas analysis value of each individual exceeds the normal value (the average value before blood removal in all cases) is referred to as “recovery time” and is displayed as the average value of each group. did. The case where the normal value was not exceeded by the end of the experiment (180 minutes after the start of infusion) was calculated as the recovery time of 180 minutes.

As is clear from Table 8, in the infusion solution containing no albumin, many measurement items did not recover to normal values. However, in the albumin preparation of the present invention, almost all items recovered to normal values within the experimental time, and among them, the infusion preparation containing both bicarbonate and other electrolytes recovered the fastest. Therefore, it was clarified that the albumin preparation of the present invention showed a great effect in correcting acidosis.

[0036]

[Table 9] Composition table of each infusion preparation (1): Krebs albuminate (described in Comparative Example 1) (2): Lactated Ringer's solution (described in Example 4) (3): Baking soda Ringer's solution (described in Examples 2 and 4) (4): 5% human Serum albumin solution (described in Example 4) (5): Ringer lactate albumin solution (described in Example 4) (6): Ringer albumin solution of sodium bicarbonate (described in Examples 1-4)

[0037]

The albumin preparation of the present invention contains electrolytes, particularly bicarbonate ions, and further contains albumin and citric acid, so that precipitates such as calcium carbonate and calcium phosphate are not produced as compared with conventional infusion preparations. This is an effect. Therefore, these electrolyte components make it possible to provide a stable infusion preparation capable of autoclaving. By aseptically mixing the electrolyte solution and albumin, it is possible to prepare a safe infusion preparation capable of intravenous administration.

When the albumin preparation of the present invention is administered intravenously, a decrease in blood pH, a decrease in blood bicarbonate ion, a decrease in acid-base equilibrium and a decrease in blood pressure caused by blood removal treatment can be carried out using a conventional lactated Ringer's solution. And can be improved in a shorter time than a human serum albumin solution. this is,
This is achieved by combining an extracellular fluid electrolyte containing bicarbonate, which rapidly corrects acidosis without going through a metabolic process, and albumin, which is smaller than the electrolyte solution and has a reliable plasma volume increasing effect. In particular, the effect of bicarbonate and other electrolyte solutions to correct the acidosis cannot be fully exerted except for albumin. This allows the albumin preparations of the invention to allow for immediate treatment, especially in emergency situations. This improvement effect is superior to that obtained by mixing a commercially available Ringer's lactate solution and human serum albumin solution.

[Brief description of the drawings]

FIG. 1 is a graph showing changes in mean blood pressure when an albumin preparation of the present invention and a sodium bicarbonate ringer solution containing no albumin are administered to rats subjected to blood removal.

FIG. 2 is a graph showing changes in mean blood pressure when an albumin preparation containing 0 to 5.0% by weight of human serum albumin is administered to a rat subjected to blood removal.

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Claims (4)

[Claims] 1. An albumin preparation containing an electrolyte ion containing citrate ion and bicarbonate ion, albumin and water. 2. The albumin preparation according to claim 1, which comprises the following components. Sodium ion 50-150 mEq / l, potassium ion 2-6 mEq / l, magnesium ion 1-3 mEq / l, calcium ion 1-5 mEq / l, chloride ion 50-150 mEq / l citrate ion 1-5 mEq / l, bicarbonate ion at least 20 mEq / l, albumin, and water. 3. The albumin preparation according to claim 1, wherein the albumin concentration is at least 0.5% by weight. 4. The albumin preparation according to claim 1, wherein the pH is adjusted to around neutrality.