JP4625657B2 - Solution set for peritoneal dialysate preparation - Google Patents

Description

  The present invention relates to a peritoneal dialysis solution, and more particularly, to a preheated and sterilized solution set for preparing a peritoneal dialysis solution.

  Continuous outpatient peritoneal dialysis (CAPD) is used to maintain the balance of various body fluid components by excreting the renal function in the peritoneum for the maintenance of life in patients with end-stage renal failure who have lost renal function. It is known as one of the therapies. In CAPD, peritoneal dialysis fluid is infused into the peritoneal cavity, thereby allowing waste products (typically urea, creatinine), sodium ions and chloride ions and other minerals and water that are normally excreted by the kidneys. And the like diffuse across the peritoneum from the bloodstream to the dialysate, thereby removing them from the body.

  The type and rate of substances removed from the body by peritoneal dialysis is a function of the type and concentration of solutes present in the peritoneal dialysate. Physiological salts such as sodium chloride, calcium chloride, and magnesium chloride are generally present in the peritoneal dialysis solution at a slightly lower concentration than in blood, and such salts in blood correspond to the excess amount of peritoneal dialysis. Diffuses into the liquid. In addition, lactic acid is generally used as a buffering agent for maintaining the pH of the peritoneal dialysis solution within a certain range.

  In addition to the physiological salts as described above, other solutes are added to the peritoneal dialysate to generate the osmotic pressure necessary to remove water from the patient (which is generally necessary). Such other solutes are typically glucose, usually at a minimum concentration of 5 g / L in the peritoneal dialysis solution, and higher if desired to increase ultrafiltration from the patient. Contained.

  The current dialysate is put in one container as an aqueous solution in which an osmotic substance, a buffer, and inorganic salts are mixed. Peritoneal dialysis fluid must be sterilized, and heat sterilization is performed. However, glucose is easily decomposed during heat sterilization. If neutral to basic, caramelization occurs and the solution turns brown. If the pH is 3.5 or lower, decomposition products such as 5-hydroxymethylfurfural (5-HMF) and levulinic acid are used. [Richard J., et al. Ulbricht et al. , "A Review of 5-Hydroxymethylfurfural (HMF) in Parental Solutions", Fundamental and Applied Toxology, 4: 843-853 (1984); The degradation product, 5-hydroxymethylfurfural (5-HMF), is considered harmful to the maintenance of peritoneal function [I. S. Henderson et al. , Blood Purif. , 7: p. 86-94 (1989); Non-Patent Document 2]. For this reason, the pH of the glucose-containing peritoneal dialysis solution to be subjected to heat sterilization in the production process is usually set to 5.0 to 5.4 for the purpose of suppressing various decompositions caused by heat sterilization. Therefore, even after sterilization, the pH of such a solution is considerably more acidic than the physiological pH of body fluids (pH 7.4 for blood).

  This is not preferable in terms of biocompatibility for peritoneal dialysis fluid to be injected into the abdominal cavity [“Frontiers in Peritoneal dialysis”, p. 261-264, 1984, I.D. S. Henderson et al. Non-Patent Document 3]. In addition, even in the heat sterilization of conventional glucose-containing peritoneal dialysis fluid prepared in the above pH range, the degradation of glucose is not completely prevented, and a small amount of degradation products such as 5-HMF are produced and contained in the product. This point is also required to be improved from the viewpoint of biocompatibility.

  On the other hand, WO 93/09820 publication (hereinafter referred to as “'820 publication”; Patent Document 1) describes a small (20 to 500 mL) concentrated (10 to 70%) aqueous glucose solution, glucose-free, A separately packaged sterilized peritoneal dialysis solution comprising an aqueous solution containing a large amount (about 2 L) of salt or the like is disclosed.

The '820 publication states that the reason why the aqueous glucose solution is made into a small amount of concentrated solution is that the higher the glucose concentration, the lower the generation rate of degradation products measured by absorbance at 228 nm.
WO 93/09820 publication Richard J., et al. Ulbricht et al. "A Review of 5-Hydroxymethylfurfural (HMF) in Parental Solutions", Fundamental and Applied Toxology, 4: 843-853 (1984). I. S. Henderson et al. , Blood Purif. , 7: p. 86-94 (1989) Frontiers in Peritoneal dialysis ", p. 261-264, 1984, IS Henderson et al.

  However, the present inventor examined this and found that the degradation products detected by the above-described absorption at 228 nm decreased with time, and the absorption at 284 nm increased correspondingly. In particular, with commercially available peritoneal dialysis fluid, the absorption at 228 nm is only a trace due to the passage of days after production. The component having absorption at 284 nm is known to be 5-HMF, and therefore, the decomposition product having absorption at 228 nm is presumed to be a precursor of 5-HMF. Since the precursor becomes 5-HMF and remains in the solution, it is necessary to quantitatively evaluate the decomposition product based mainly on the amount of 5-HMF.

  Based on the above knowledge and consideration, the present inventor tried to obtain a peritoneal dialysis solution closer to physiological pH while minimizing the generation of decomposition products by heat sterilization mainly using 5-HMF as an index.

  The present inventor found that lactate ions used in peritoneal dialysis fluid promoted the decomposition of glucose during heat sterilization, and suppresses the generation of 5-HMF by heat sterilizing separately from lactate ions. I found out that I can do it. At the same time, the present invention has also found that sodium ions, calcium ions, magnesium ions and chloride ions do not promote glucose degradation. In addition, when the present inventor divided the peritoneal dialysis solution into a glucose-containing solution and a lactate ion-containing solution, contrary to the above-mentioned '820 publication, in the peritoneal dialysis solution consisting of these two parts, It has been found that the production of 5-HMF is suppressed by increasing the volume ratio and keeping the glucose concentration in the glucose-containing solution relatively low. Furthermore, the present inventor further reduced the production of 5-HMF by making the aqueous glucose solution an aqueous solution having a pH of 4.0 to 5.0, and further added the aqueous glucose solution in the pH range to sodium lactate as a lactate ion-containing solution. It has also been found that when the containing solution is mixed after heat sterilization, a peritoneal dialysis solution having a pH close to physiological pH that could not be obtained by conventional methods can be obtained. The present invention has been completed by further studies based on these findings.

  That is, the present invention is a solution set for preparing a peritoneal dialysis solution comprising a first solution and a second solution packaged separately from each other, wherein (a) the first solution contains glucose and lactate ions (B) the second solution is heat sterilized with an aqueous solution containing sodium lactate and not containing glucose, and (c) the second solution is heat sterilized. Either one or both of the first liquid and the second liquid contain at least one of sodium chloride, calcium chloride, and magnesium chloride, and (d) the volume ratio of the first liquid to the second liquid is 5 In the range of 5-9: 1, (e) the glucose concentration of the solution obtained when the first liquid and the second liquid are mixed is 5.0-50.0 g / L, and (f ) The pH of the solution obtained when the first liquid and the second liquid are mixed is 6. It is within the scope of to 7.3, a peritoneal dialysis fluid preparation solution set.

  With the above configuration, when the first liquid and the second liquid are heat sterilized, the decomposition of glucose is less than in the case of conventional heat sterilization. Furthermore, by mixing the first liquid and the second liquid after sterilization, a peritoneal dialysis solution having a pH closer to physiological pH than that of the conventional one can be obtained.

  The amount of sodium lactate contained in the second liquid is preferably such that the concentration of lactic acid ions in the solution obtained when the first liquid and the second liquid are mixed is 40 mEq / L or less. . In addition, sodium lactate should just function so that pH may be maintained at 6.0-7.3 in the liquid obtained by mixing the 1st liquid and the 2nd liquid, and sodium lactate which is the 2nd liquid before sterilization It is not necessary to adjust the pH of the aqueous solution containing no glucose and no glucose. An example of the aqueous solution is an aqueous sodium lactate solution itself.

  In addition, sodium chloride, calcium chloride, and magnesium chloride may be contained in either the first liquid or the second liquid, or may be contained in both. The sodium ion concentration in the solution obtained when the two solutions are mixed is 132 mEq / L or less, the calcium ion concentration is 3.5 mEq / L or less, the magnesium ion concentration is 1.5 mEq / L or less, and the chlorine ion concentration is 102 mEq. It is preferable that the amount be less than / L.

  In addition, as a typical example of the glucose concentration of the solution obtained when mixing the first liquid and the second liquid, 13.6 g / L, 22.7 g / L, 38. Concentrations such as 6 g / L can be mentioned.

  The solution set for peritoneal dialysis solution preparation of the present invention is a solution set in which the first solution and the second solution are filled and sterilized in two independent bags each having a known connecting part that can be connected aseptically at the time of use. In addition, it may be filled and sterilized in each chamber of a container having two chambers separated by a passage or a weak heat seal that can be operated from the outside to break and communicate with the partition wall. In addition, any sterilizable container known to those skilled in the art suitable for aseptically mixing the two solutions may be used.

Peritoneal dialysis fluid having the following findings and the following characteristics is provided:
It was found that lactate ions used in peritoneal dialysis fluid promoted the decomposition of glucose during heat sterilization, and that generation of 5-HMF can be suppressed by heat sterilization separately from lactate ions. At the same time, the present invention has also found that sodium ions, calcium ions, magnesium ions and chloride ions do not promote glucose degradation. In addition, when the present inventor divided the peritoneal dialysis solution into a glucose-containing solution and a lactate ion-containing solution, the volume occupied by the glucose-containing solution in the peritoneal dialysis solution consisting of these two parts, contrary to the prior art It has been found that the production of 5-HMF is suppressed by increasing the ratio to keep the glucose concentration in the glucose-containing solution relatively low. Furthermore, by forming the aqueous glucose solution into an aqueous solution having a pH of 4.0 to 5.0, the formation of 5-HMF is further suppressed, and the aqueous glucose solution in the pH range is combined with a sodium lactate-containing solution as a lactate ion-containing solution. When mixed after heat sterilization, a peritoneal dialysis solution having a pH close to physiological pH that could not be obtained by conventional methods can be obtained.

  An example for carrying out the present invention will be described below.

(First liquid)
Glucose 2.27g
Sodium chloride 0.538g
Calcium chloride dihydrate 0.026g
Magnesium chloride hexahydrate 0.005g
0.1N hydrochloric acid
Purified water total volume 70mL
pH 4.00, 4.30, 4.50, 4.70, 5.00
(Second liquid)
60% sodium lactate 0.74g
Purified water total volume 30mL
The first solution (70 mL) having each pH prepared according to the above formulation was accommodated in each container, and the second solution (30 mL) prepared according to the above formulation was accommodated in another container. Each solution was sterilized by heating (121 ° C., 40 minutes) in a container. After cooling to room temperature, each 1st liquid and 2nd liquid were mixed, and the pH of the liquid mixture and the light absorbency of 284 nm (5-HMF) and 228 nm were measured. The results are shown in the following table. As is apparent from comparison with Comparative Example 1 (conventional type) described later, the object of the present invention is achieved, in which the pH after mixing is brought close to the physiological pH and the generation of decomposition products is also suppressed.

［比較例１］
比較例として、従来型の、全溶質を含有する単一組成物としての腹膜透析液を、実施例１の各溶質量に対応させて調製した。すなわち下記の処方
グルコース ２．２７ｇ
塩化ナトリウム ０．５３８ｇ
塩化カルシウム二水和物 ０．０２６ｇ
塩化マグネシウム六水和物 ０．００５ｇ
６０％乳酸ナトリウム ０．７４ｇ
０．１規定塩酸 適量
精製水 全量１００ ｍＬ
ｐＨ５．２、５．５及び６．０
に従い腹膜透析液を調製し容器に収容した。実施例と同一条件で滅菌し、室温まで冷却後、溶液のｐＨ並びに２８４ｎｍ（５−ＨＭＦ）及び２２８ｎｍの吸光度を測定した。結果を次の表に示す。

[Comparative Example 1]
As a comparative example, a conventional peritoneal dialysis solution as a single composition containing all solutes was prepared corresponding to each solute mass of Example 1. That is, the following prescribed glucose 2.27 g
Sodium chloride 0.538g
Calcium chloride dihydrate 0.026g
Magnesium chloride hexahydrate 0.005g
60% sodium lactate 0.74g
0.1N hydrochloric acid
100 mL of purified water
pH 5.2, 5.5 and 6.0
The peritoneal dialysis solution was prepared according to the procedure described above and stored in a container. The solution was sterilized under the same conditions as in the Examples, and after cooling to room temperature, the pH of the solution and the absorbance at 284 nm (5-HMF) and 228 nm were measured. The results are shown in the following table.

実施例１の結果との比較から明らかなように、比較例１においては、滅菌前ｐＨを実施例１の第１液よりも高く設定していたにもかかわらず、滅菌後ｐＨ（実施例１の混合後ｐＨに対応する）は大幅に低下し、実施例１の混合後ｐＨ値の各々に比して顕著に酸性側に偏っていた（ｐＨ５．１５〜５．３７）。また比較例１において滅菌後の酸性側への偏りの最も小さい処方（Ｈ）では、実施例１に比して２８４ｎｍ（５−ＨＭＦ）の吸光度が著明に増大し（０．８８４）、グルコースの分解が促進されてしまうことが示された。

As is clear from the comparison with the results of Example 1, in Comparative Example 1, the pH after sterilization (Example 1) was set even though the pH before sterilization was set higher than that of the first liquid in Example 1. (Corresponding to the pH after mixing) was significantly reduced, and was significantly biased toward the acidic side compared with each of the pH values after mixing in Example 1 (pH 5.15 to 5.37). In Comparative Example 1, the prescription (H) with the least bias toward the acidic side after sterilization significantly increased the absorbance at 284 nm (5-HMF) compared to Example 1 (0.884), and glucose It was shown that the decomposition of was promoted.

[Relationship between volume ratio of first liquid and second liquid and pH and glucose stability after mixing]
(First liquid)
1.36 g of glucose
Sodium chloride 0.538g
Calcium chloride dihydrate 0.026g
Magnesium chloride hexahydrate 0.005g
0.1N hydrochloric acid
Total amount of purified water 30, 50, 70, 90 mL
pH 4.5
(Second liquid)
60% sodium lactate 0.74g
Total amount of purified water 10, 30, 50, 70 mL
According to the said prescription, the 1st liquid and the 2nd liquid were prepared, and each accommodated in the container. The pH of the second liquid was 7.69, 7.26, 7.07, and 6.94 in the order of the total liquid volume 10, 30, 50, and 70 mL, respectively. Each solution is sterilized by heating (121 ° C., 40 minutes), cooled to room temperature, and then mixed with the corresponding first liquid and second liquid (combination to be 100 mL after mixing), and pH and 284 nm (5-HMF) The absorbance was measured. The results are shown in the following table.

表３に見られるように、第２液の体積に対する第１液の体積が大きい程（従って、グルコース濃度が低い程）、混合後の284 ｎｍ（５−ＨＭＦ）の吸光度が小さくなり、グルコースの分解が抑えられており、第１液：第２液の体積比５：５〜９：１の範囲では体積比３：７に比して顕著に優れている。また混合後ｐＨは第１液：第２液の体積比が７：３のときに最も中性寄りとなった。これらより総合的に判断して、第１液：第２液の体積比としては５：５〜９：１の範囲が好ましく、特に好ましいのは７：３の付近である。

As can be seen in Table 3, the greater the volume of the first liquid relative to the volume of the second liquid (and hence the lower the glucose concentration), the smaller the absorbance at 284 nm (5-HMF) after mixing. Decomposition is suppressed, and the volume ratio of the first liquid: second liquid is in the range of 5: 5 to 9: 1, which is remarkably superior to the volume ratio of 3: 7. The pH after mixing was most neutral when the volume ratio of the first liquid: second liquid was 7: 3. Judging from these comprehensively, the volume ratio of the first liquid to the second liquid is preferably in the range of 5: 5 to 9: 1, particularly preferably in the vicinity of 7: 3.

  A dialysate is provided for use in peritoneal dialysis, typically continuous ambulatory peritoneal dialysis (CAPD). More particularly, a pre-heat sterilized solution set for preparing peritoneal dialysis fluid is provided.

Claims (4)

A peritoneal dialysate preparation solution set consisting of a first liquid and a second liquid packaged separately from each other,
(A) The first liquid is obtained by heat sterilizing an aqueous solution having a pH of 4.0 to 5.0 containing glucose and not containing lactate ions,
(B) The second solution is obtained by sterilizing an aqueous solution containing sodium lactate and not containing glucose;
(C) the first liquid contains at least one of sodium chloride, calcium chloride, and magnesium chloride;
(D) the volume ratio of the first liquid to the second liquid is in the range of 5: 5 to 9: 1;
(E) The glucose concentration of the solution obtained when the first liquid and the second liquid are mixed is 5.0 to 22.7 g / L,
(F) the pH of the solution obtained when the first liquid and the second liquid are mixed is in the range of 6.0 to 7.3; and (g) the resulting solution is 5-hydroxy A solution set for preparation of peritoneal dialysis fluid , wherein the absorbance value of methylfurfural at 284 nm is about 0.610 or less. The second liquid contains sodium lactate in an amount such that the lactate ion concentration of the solution obtained when the first liquid and the second liquid are mixed is 40 mEq / L or less. Item 2. A solution set for preparing peritoneal dialysis fluid according to Item 1. In the solution obtained by mixing the first liquid and the second liquid, the sodium ion concentration is 132 mEq / L or less, the calcium ion concentration is 3.5 mEq / L or less, and the magnesium ion concentration is 1.5 mEq / L. L or less, and as the chlorine ion concentration of less than 102 mEq / L, the first liquid, sodium chloride is one containing at least one of calcium chloride and magnesium chloride, according to claim 1 or 2. A solution set for peritoneal dialysis solution preparation according to 2. The first chamber containing the first liquid, the second chamber containing the second liquid, and a separable heat seal in communication with the first chamber and the second chamber. Solution set for peritoneal dialysate preparation.