WO2010055963A1

WO2010055963A1 - Manufacturing method of acetate-free dialysate composition

Info

Publication number: WO2010055963A1
Application number: PCT/KR2008/006741
Authority: WO
Inventors: Jin Sik Lee; Jong Bok Kim; Chan Ho Jeong
Original assignee: Lee, Jin Tae
Priority date: 2008-11-17
Filing date: 2008-11-17
Publication date: 2010-05-20

Abstract

Provided is a method for preparing an acetate-free dialysate which is stable without inducing precipitation of calcium in blood. The preparation method includes mixing an acidifying agent prepared by dissolving sodium chloride, potassium chloride, calcium chloride, magnesium chloride, citric acid and an acid for adjusting acidity in purified water with an alkalizing agent containing sodium bicarbonate and purified water thus to prepare a dialysate of pH 7.25~7.45. The citric acid concentration of the dialysate is 0.5~2.5 mEq/L, and the acid added to adjust acidity may be selected from a group consisting of hydrochloric acid, lactic acid, malic acid or a combination thereof. Thus prepared dialysate may prevent blood coagulation, acetate intolerance and alkalosis during dialysis.

Description

MANUFACTURING METHOD OF ACETATE-FREE DIALYSATE COMPOSITION

Technical Field

[1] The present invention relates to a dialysate, a method for preparing the same and a use thereof, more particularly to preparation of an anticoagulant dialysate containing bicarbonate. Background Art

[2] The dialysate used in dialysis usually contains sodium bicarbonate as a major buffering component. It is to prevent metabolic acidosis during dialysis, which may be caused by the decreased bicarbonate concentration in the blood. The metabolic acidosis is known to negatively affect the bone metabolism. To prevent the metabolic acidosis, it is preferred to maintain the bicarbonate concentration in the blood at 22 mEq/L or above before and after dialysis [Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline, National Kidney Foundation].

[3] Usually, sodium bicarbonate is provided in powder form or in highly concentrated aqueous solution as an alkalizing agent. It is provided as a dialysate for dialysis after being admixed with an acidifying agent or purified water to have an acidity of pH 7.25~7.45, similar to that of the human blood plasma. In general, the acidifying agent is provided as alkali metal or alkaline earth metal salt and a buffering acid dissolved in purified water at high concentration. Acetic acid is the most widely used as the buffering acid, because it can effectively prevent the instability of the dialysate caused by the precipitation of divalent cations such as calcium and magnesium as carbonates.

[4] A dialysate manufacturing system using an acidifying agent containing acetic acid is highly advantageous in easiness of handling during dialysis and stability of the prepared dialysate. Currently commercially available dialysates are mainly bicarbonate-based dialysates containing about 800 mEq/L of acetic acid. However, the dialysate containing acetic acid may be associated with adverse effects caused by the acetate, which normally hardly exists in the body. Especially, acetate may result in cardiovascular instability by inhibiting the action of nitrogen monoxide and blood pressure decrease during dialysis through the peripheral vasodilation. Accordingly, development of a dialysate containing sodium bicarbonate but free of acetate which is commonly used as an acidic buffering agent is imminent. The key to its development is to find a substance that can stabilize the dialysate by acting as an acidic buffering agent instead of acetate.

[5] When designing a new acetate-free dialysate composition, prevention of blood co- agulation should be considered as well as effective prevention of carbonate precipitation. In the related art, it is customary to add an anticoagulant such as heparin to the dialysate to prevent blood coagulation. However, use of the heparin-containing dialysate may be contraindicated in patients with a high risk of bleeding. Accordingly, when carrying out hemodialysis for patients with a high risk of bleeding, such as those with pericarditis, coagulopathy, thrombocytopenia, cerebral hemorrhage or other bleeding, or those who have recently undergone surgery, it is customary to reduce the amount of heparin in the dialysate or not to use it at all.

[6] In the conventional dialysis using a heparin-free dialysate, the extracorporeal circuit is washed with heparin-containing saline before carrying out dialysis, and then the extracorporeal circuit is filled with the patient's blood or heparin-free saline to wash off the heparin-containing saline. Then, dialysis is carried out at the fastest speed that the patient can endure in order to minimize the risk of the dialysis disequilibrium syndrome.

[7] Another practice of dialysis using a heparin-free dialysate is to reduce the calcium ion level in the blood flowing in the extracorporeal circuit to prevent blood coagulation. An example of the method of decreasing the ionized calcium ion concentration of the blood in the extracorporeal circuit is to carrying out dialysis using a calcium-free dialysate while injecting sodium citrate into the arterial circuit. However, this method may be problematic since the blood with very low calcium ion level flows back into the patient. As a result, calcium chloride has to be injected to the venous circuit to prevent hypocalcemia.

[8] Another method of dialysis using a heparin-free dialysate is to use a dialysate containing citrate which has anticoagulant action. It is disclosed in US Patent Nos. 6,610,206 and 7,186,420. According to the patents, the acidity of the dialysate is adjusted to be almost equal to the physiological pH by controlling the amount of citric acid in the acidifying agent, which is mixed with the alkalizing agent and purified water to prepare the final dialysate. Here, acetate is further added as a buffering agent in order to prevent precipitation of bicarbonate. However, even in this case, a problem of adverse effect of the acetate added as the buffering agent for stabilization, i.e. acetate intolerance, still persists. Disclosure of Invention Technical Problem

[9] Dialysis is primarily used to remove waste products and water resulting from metabolism from the blood when the kidneys are in renal failure. In general, a patient who receives dialysis 3 times a week experiences 1 to 3 kg increase of body weight in between dialyses due to accumulation of water. Although dialysis usually takes 3 to 4 hours, the patients with excessive free water need to have the water removed more quickly.

[10] A low-sodium dialysate may result in osmotic imbalance. Accordingly, control of body weight in between dialyses, use of bicarbonate dialysate, control of dialysate temperature, or the like are attempted to prevent hypotension that may occur during hemodialysis. In order to use alkaline sodium bicarbonate in a dialysate, sodium acetate or acetic acid has been used. Development of a completely acetate-free dialysate has been restricted with regard to stability of the dialysate. At present, a bicarbonate-based dialysate containing a small amount (812 mEq/L) of acetate for stabilization is now used. Sodium acetate may result in cardiovascular instability or blood pressure decrease during dialysis through the peripheral vasodilation, thereby leading to so-called acetate intolerance. In the currently used sodium bicarbonate dialysate, sodium acetate is added in an amount of about 0.4 to 0.7 g / 100 mL, and acetic acid is further added to adjust pH. The acetate concentration in the final dialysate is approximately 8 mEq/L, and the pH is about 7.35.

[11] In the prior art, heparin is customarily used to prevent blood coagulation during hemodialysis. However, when carrying out hemodialysis for patients with a high risk of bleeding, such as those with pericarditis, coagulopathy, thrombocytopenia, cerebral hemorrhage or other bleeding, or those who have recently undergone surgery, it is customary to reduce the amount of heparin in the dialysate or not to use it at all. The mechanism of heparin-free dialysis is to prevent blood coagulation by reducing ionized calcium level in the blood in the extracorporeal circuit. One way of reducing the ionized calcium level in the blood in the extracorporeal circuit is to inject sodium citrate into the arterial circuit and using a dialysate completely free of calcium. In this case, since the blood with very low calcium ion level flows back into the patient, calcium chloride has to be injected to the venous circuit to prevent hypocalcemia.

[12] However, increasing the citrate of the dialysate to prevent blood coagulation may lead to the generation of bicarbonate as the citrate absorbed from the blood is metabolized. Especially, when a dialysate with high citrate concentration is used, the blood bicarbonate level may increase markedly, which may be very dangerous for patients with a risk of alkalosis. The increased blood bicarbonate level may result in post-dialysis hypotension, muscle spasm, nausea or vomiting during dialysis, and fatigue between dialyses.

[13] Fig. 1 illustrates the tricarboxylic acid (TCA) cycle by which citric acid is metabolized. The TCA cycle is a process in the cellular respiration, by which glycolyzed metabolites of carbohydrate, fat or amino acid are oxidized to store some of energy to adenosine triphosphate (ATP) and to transfer the remainder to the electron transport chain in the from of intermediates such as NAD⁺, FAD, etc. The cycle was named such because the carbon compound entering the cycle is citric acid having three carboxylic groups. It is also called the citric acid cycle or the Krebs cycle after the name of its discoverer.

[14] Referring to Fig. 1, when citrate is transferred form a dialysate to blood, it may be metabolized in the body by the Krebs cycle to form bicarbonate. Specifically, as citrate is oxidized in the Krebs cycle, two molecules of carbon dioxide are produced, which are dissolved in the blood to form HCO₃ ². Therefore, a dialysate with a high citrate content may accelerate alkalization of the blood, and a great care is required for patients with alkalosis. In case of bicarbonate-free dialysis, bicarbonate may be released from the blood to the dialysate for the first hour after the onset of dialysis. In the case where a bicarbonate-containing dialysate is used, the bicarbonate level may be maintained at an allowable level during the dialysis. However, with the lapse of time, the blood bicarbonate level may increase due to the citrate metabolism. The level continues to increase for hours, as the citrate absorbed from the dialysate is metabolized. Therefore, the inventors of the present invention have developed a method for preparing an acetate-free dialysate capable of reducing citrate level so that it may be used for patients with alkalosis and having a stable acidity around pH 7.35. Technical Solution

[15] In an embodiment of the present invention, a dialysate provided for dialysis for patients with renal failure may be prepared by mixing an acidifying agent, an alkalizing agent and purified water at a weight ratio of 1 : 1~1.5 : 30~35 immediately before dialysis.

[16] The acidifying agent may be prepared by mixing an alkali metal, an alkaline earth metal, salts thereof, citric acid, an acid for adjusting acidity, and purified water.

[17] Specifically, the acidifying agent may be prepared by dissolving sodium chloride, potassium chloride, calcium chloride, magnesium chloride, citric acid and an acid for adjusting acidity in purified water. The acid for adjusting acidity may be hydrochloric acid, lactic acid, malic acid or a combination thereof. The chloride content of the acidifying agent may be adjusted to 8,000~ 13,000 mEq/L.

[18] The alkalizing agent may be a concentrated aqueous solution of sodium bicarbonate or sodium bicarbonate. The sodium bicarbonate content of the alkalizing agent may be adjusted to 25.0-35.0 mEq/L.

[19] The citrate concentration of the dialysate should be adjusted to one sufficiently high to exhibit stable anticoagulant effect during dialysis and, at the same time, to one as low as to prevent alkalization of the blood that may be caused by metabolism of the citrate. Citrate is also an important factor determining acidity of the acetate-free dialysate. Advantageous Effects

[20] Since the dialysate prepared in accordance with the present invention is acetate-free, it does not induce acetate intolerance. Since it provides anticoagulant effect without containing heparin, it may be used for the patients who are at risk of bleeding. In addition, by further comprising an acid for adjusting acidity, the concentration of citrate used to provide anticoagulant effect may be adjusted within an allowable range. As a result, alkalosis caused by the metabolism of citrate may be prevented. Brief Description of Drawings

[21] The above and other aspects, features and advantages of the disclosed exemplary embodiments will be more apparent from the following detailed description taken in conjunction with the accompanying drawings in which:

[22] Fig. 1 schematically shows the tricarboxylic acid (TCA) cycle by which citric acid is metabolized;

[23] Fig. 2 shows the acidity of the acidifying agent depending on citric acid concentration; and

[24] Fig. 3 shows the acidity of the dialysate depending on citric acid content.

Best Mode for Carrying out the Invention

[25] Exemplary embodiments now will be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments are shown. This disclosure may, however, be embodied in many different forms and should not be construed as limited to the exemplary embodiments set forth therein. Rather, these exemplary embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of this disclosure to those skilled in the art. In the description, details of well-known features and techniques may be omitted to avoid unnecessarily obscuring the presented embodiments.

[26] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of this disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, the use of the terms a, an, etc. does not denote a limitation of quantity, but rather denotes the presence of at least one of the referenced item. The use of the terms "first", "second", and the like does not imply any particular order, but they are included to identify individual elements. Moreover, the use of the terms first, second, etc. does not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another. It will be further understood that the terms "comprises" and/or "comprising", or "includes" and/ or "including" when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.

[27] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Mode for the Invention

[28] The examples and experiments will now be described. The following examples and experiments are for illustrative purposes only and not intended to limit the scope of this disclosure.

[29] Example 1 : Acidity of acidifying agent depending on citric acid content

[30] An acidifying agent was prepared by dissolving NaCl (21.48 g), KCl (0.65 g), CaCl₂

O 2H₂O (0.772 g) and MgCl₂ O 6H₂O (0.53 g) in purified water (100 mL) and then adding citric acid at various concentrations. The change of acidity of the acidifying agent was measured at room temperature.

[31] Fig. 2 shows the acidity of the acidifying agent depending on the citric acid content.

[32] Referring to Fig. 2, the pH of the acidifying agent was 5.3 when the citric acid concentration was 0.0 mEq/L. The pH decreased to about 1.3 when the citric acid concentration was 70 mEq/L, and to about 1.1 when citric acid was added at a concentration of 280 mEq/L. Considering that the pH decreases to about 4.5 when 280 mEq/L of acetic acid is added to a dialysate as a buffering agent of an acidifying agent, the use of citric acid results in a markedly decreased pH of the dialysate even at low concentration.

[33] Example 2: Acidity of dialysate depending on citric acid content

[34] Acidity of a dialysate prepared by mixing an acidifying agent comprising citric acid, an alkalizing agent and purified water was measured depending on citric acid concentration. To this end, a citric acid-free acidifying agent was prepared by dissolving NaCl (21.48 g), KCl (0.65 g), CaCl₂ o 2H₂O (0.772 g) and MgCl₂ o 6H₂O (0.53 g) in purified water (100 mL), which was mixed with an alkalizing agent containing 7 g / 100 mL of sodium bicarbonate and purified water, at a weight ratio of 1 : 1.26 : 32.74. Then, citric acid was added to the mixture. The pH of the final mixture solution was measured at various citric acid concentrations. To use the mixture solution as a dialysate, its acidity should be adjusted to normal pH range of arterial blood. Since the normal pH range of the arterial blood is 7.25~7.45, there is a concern of acidosis if the pH of the dialysate is lower than 7.25, and there is a concern of alkalosis if the pH of the dialysate is higher than 7.45.

[35] Table 1 shows the acidity of the dialysate depending on the citric acid content, and Fig. 3 shows the acidity of the dialysate depending on citric acid content. [36] Table 1 [Table 1] [Table ]

[37] Referring to Table 1 and Fig. 3, if the citric acid is 4 mEq/L or lower, the pH of the dialysate is higher than the normal pH of the arterial blood and alkalosis may occur. On the other hand, if the citric acid is higher than 5 mEq/L, the dialysate is lower than the normal pH of the arterial blood and acidosis may occur. Accordingly, when adjusting the acidity of the dialysate to the normal pH range of the arterial blood by adjusting the addition amount of citric acid, without any acid, e.g. acetic acid, other than citric acid, the citric acid concentration of the dialysate should be controlled within a very narrow range around 4.5 mEq/L.

[38] Furthermore, even when the citric acid concentration of the dialysate is precisely controlled to adjust the acidity of the dialysate to the normal pH range of 7.25~7.45, the blood pH may increase as the citrate diffused into the blood of the patient during dialysis and is metabolized by the citric acid cycle illustrated in Fig. 1, thereby resulting in alkalosis.

[39] Accordingly, the citric acid concentration should be controlled such that the pH of the dialysate is maintained within the normal pH range of the arterial blood, while being the minimum concentration required to prevent blood coagulation or higher, and being not too high to cause alkalosis.

[40] Example 3: Optimization of dialvsate composition comprising citric acid and other acid for adjusting acidity [41] According to blood coagulation experiments performed by the inventors of the present invention, the citric acid concentration of the dialysate should be at least 0.1 mEq/L to exhibit anticoagulant effect. And, if the blood citric acid concentration exceeds 5.0 mEq/L, alkalosis may occur as the citric acid is metabolized. Accordingly, the citric acid concentration of the dialysate should be adjusted to 0.1~5.0 mEq/L, more preferably 0.5~2.5 mEq/L. A dialysate having a citric acid content within this range exhibits a pH value of about 9.0~9.4, which is considerably higher than the normal pH of the arterial blood, which is about 7.35. Accordingly, as a way of attaining a dialysate with a pH about 7.35 while maintaining a citric acid concentration providing anticoagulant effect but not inducing alkalosis, addition of an acid for adjusting acidity of the dialysate may be considered. However, acetic acid is excluded from the acid for adjusting acidity because it may induce acetate intolerance. Therefore, the inventors of the present invention have selected hydrochloric acid, lactic acid and malic acid as the acid added to adjust the acidity of the dialysate, and investigated the acidity of the final dialysate while varying their concentrations in the dialysate.

[42] To this end, an acidifying agent comprising citric acid was mixed with an alkalizing agent and purified water to prepare a dialysate. While varying the citric acid concentration of the dialysate within 1~5 mEq/L, the effect of the addition of the acid for adjusting acidity was measured.

[43] Specifically, NaCl (21.48 g), KCl (0.65 g), CaCl₂ O 2H₂O (0.772 g), MgCl₂ O 6H₂O

(0.53 g), and citric acid with various amounts were dissolved in purified water (100 mL) to prepare an acidifying agent, which was mixed with an alkalizing agent containing 7 g / 100 mL or 8.17 g / 100 mL of sodium bicarbonate and purified water, at a weight ratio of 1 : 1.26 : 32.74. Then, as the acid for adjusting acidity, each of hydrochloric acid, lactic acid and malic acid was added at various concentrations. The addition amount of hydrochloric acid, lactic acid and malic acid was recorded when the pH of the dialysate reached 7.35. The result is shown in Table 2.

[44] Table 2

[Table 2] [Table ]

[45] As another example, NaCl (22.50 g), KCl (0.522 g), CaCl₂ O 2H₂O (0.644 g), MgCl₂

O 6H₂O (0.356 g), glucose (3.5 g), and citric acid with various amounts were dissolved in purified water (100 mL) to prepare an acidifying agent, which was mixed with an alkalizing agent containing 7 g / 100 mL or 8.17 g / 100 mL of sodium bicarbonate and purified water, at a weight ratio of 1 : 1.26 : 32.74. Then, as the acid for adjusting acidity, each of hydrochloric acid, lactic acid and malic acid was added at various concentrations. The addition amount of hydrochloric acid, lactic acid and malic acid was recorded when the pH of the dialysate reached 7.35. The result is shown in Table 3.

[46] Table 3 [Table 3] [Table ]

[47] As seen in Tables 2 and 3, a desirable effect is attained by the addition of the acid for adjusting acidity within the citric acid concentration of 0.5~2.5 mEq/L in the dialysate. For instance, when the citric acid concentration is lower than 2.0 mEq/L, the pH of the dialysate becomes higher than 7.54 if no acid for adjusting acidity is added, and thus alkalosis may occur. To conclude, by adding an adequate amount of the acid for adjusting acidity, i.e. hydrochloric acid, lactic acid or malic acid, to the dialysate, a dialysate having a normal pH of the arterial blood, i.e. pH 7.25~7.45, may be stably prepared.

[48] While the exemplary embodiments have been shown and described, it will be understood by those skilled in the art that various changes in form and details may be made thereto without departing from the spirit and scope of this disclosure as defined by the appended claims. [49] In addition, many modifications can be made to adapt a particular situation or material to the teachings of this disclosure without departing from the essential scope thereof. Therefore, it is intended that this disclosure not be limited to the particular exemplary embodiments disclosed as the best mode contemplated for carrying out this disclosure, but that this disclosure will include all embodiments falling within the scope of the appended claims.

Claims

[1] A method for preparing a dialysate of pH 7.25~7.45, comprising mixing: an acidifying agent prepared by dissolving sodium chloride, potassium chloride, calcium chloride, magnesium chloride, citric acid, and an acid for adjusting acidity in purified water; an alkalizing agent comprising sodium bicarbonate; and purified water, wherein the dialysate has a citrate concentration of 0.5~2.5 mEq/L, and the acid for adjusting acidity is one selected from a group consisting of hydrochloric acid, lactic acid, malic acid or a combination thereof.

[2] The method for preparing a dialysate according to claim 1, wherein, in said preparation of the acidifying agent, glucose is further dissolved in purified water, in addition to the sodium chloride, potassium chloride, calcium chloride, magnesium chloride, citric acid, and the acid for adjusting acidity.

[3] The method for preparing a dialysate according to claim 1, wherein the dialysate has a chloride concentration of 8,000~ 13,000 mEq/L.

[4] The method for preparing a dialysate according to claim 1, wherein the dialysate has a bicarbonate concentration of 25.0~35.0 mEq/L.