JP6419615B2 - Peritoneal dialysate - Google Patents

Description

  The present invention relates to a peritoneal dialysis solution containing icodextrin.

  Peritoneal dialysis, which is one of the symptomatic treatments for renal failure, is one of the home medical treatments because it requires less equipment and instruments and less time constraints than dialysis performed by artificial kidneys. Has been. Many peritoneal dialysates currently in use use glucose as an osmotic substance. Glucose has the advantage of being relatively safe and inexpensive, but because of its low molecular weight, it is rapidly absorbed from the peritoneum and cannot provide a continuous water removal effect. From the above situation, a search for an osmotic substance instead of glucose capable of maintaining ultrafiltration during long-time storage has been conducted, and it has been found that icodextrin, a glucose polymer, is suitable for peritoneal dialysis fluid.

  Icodextrin has a large molecular weight, so it is not absorbed rapidly through the peritoneum, but acts mainly as a colloid osmotic substance, and can obtain a water removal effect while maintaining the osmotic pressure with plasma. . Currently, peritoneal dialysis fluids that use icodextrin are formulated so that the drug solution is in the range of pH 5.0 to 5.5 in order to prevent decomposition and coloring of icodextrin.

  Recent studies have reported that such pH peritoneal dialysis solutions substantially reduce the immune defense mechanism of peritoneal macrophages and increase the risk of peritonitis against bacterial invasion. . There are also reports of prolonged fever and abdominal pain when introducing continuous peritoneal dialysis therapy, and abdominal pain when injecting dialysate. Furthermore, the peritoneal dialysis solution having a pH of 5.0 to 5.5 has extremely high damage to the cultured peritoneal mesothelial cells. To reduce the damage, the pH of the peritoneal dialysis solution is set to 6.5 or more. It has been reported to be effective.

  However, the pH of the peritoneal dialysis solution has a great influence on the stability of icodextrin. If the pH is increased as it is, a glucose degradation product is formed due to the degradation of glucose produced from icodextrin during production and storage. Recently, among the glucose degradation products, carbonyl compounds react non-enzymatically with the amino groups of proteins in the peritoneum to produce late glycation products, suggesting a decrease in peritoneal function. In particular, when the pH is increased, 3-deoxyglucosone, which is a glucose degradation product of the carbonyl compound, increases depending on the pH.

  Therefore, as a method for increasing the pH of the peritoneal dialysis solution while suppressing the degradation of glucose produced from icodextrin, icodextrin and a high-pH chemical component are separately stored until use, and aseptically immediately before use. A preparation to be mixed has been developed (Patent Document 1).

  However, the demand for the stability of peritoneal dialysis fluid and the safety of peritoneal dialysis fluid has become increasingly high in recent years, at a physiological pH that does not adversely affect the human body, and so far. The appearance of a stable peritoneal dialysis solution that suitably suppresses glucose degradation products generated from icodextrin is desired.

 Patent Document 1: JP 2010-150281

  An object of the present invention is to provide a peritoneal dialysis solution that maximizes the stability of icodextrin during heat sterilization and subsequent storage, and has a pH close to a physiological range.

  Said subject is achieved by the following this invention.

(1) The present invention is a sterilized peritoneal dialysis solution comprising an acidic first liquid containing icodextrin and an alkaline second liquid containing an alkaline pH adjuster, wherein the first liquid The concentration of the icodextrin is 84.5-92.9 g / L, the sterilization conditions are 110-130 ° C., 25-45 minutes, and the pH of the first liquid after sterilization is 2.3-2. .7, a peritoneal dialysis solution having a pH of 8.0 to 9.0 after sterilization and a pH of 6.0 to 7.5 after mixing the first and second fluids after sterilization; is there.

( 2 ) In the present invention, the first liquid may contain 16.6 to 347.8 g / L of sodium chloride, 1.22 to 25.7 g / L of calcium chloride, and 0.24 to 5.10 g / L of chloride. The peritoneal dialysis solution according to the above (1) , which contains at least one of magnesium and the second solution contains 21.3 to 448.0 g / L of sodium lactate.

( 3 ) The present invention is the peritoneal dialysis solution according to the above (1) or (2) housed in a medical bag body, wherein the bag body is separated by a partition means capable of opening the inside thereof. A first chamber and a second chamber formed by the first chamber, the first chamber having a discharge port that communicates the inside and outside of the bag body, and the first liquid is in the first chamber, The second fluid is peritoneal dialysis fluid stored in the second chamber.

  The peritoneal dialysis fluid of the present invention can suppress an increase in absorbance at 228 nm of the peritoneal dialysis fluid, that is, significantly suppress glucose degradation products generated from icodextrin during heat sterilization and subsequent storage, and has excellent stability. Peritoneal dialysate can be provided.

  Hereinafter, the peritoneal dialysis solution of the present invention will be described in detail. The peritoneal dialysis solution of the present invention is mainly composed of a first solution containing icodextrin and an alkaline second solution not containing icodextrin, and the first and second solutions are mixed immediately before use. This is a type of peritoneal dialysis fluid having a pH of 6.0 to 7.5 after mixing.

  In the peritoneal dialysis solution of the present invention, the content of icodextrin in the first solution is 76.0 to 94.0 g / L, preferably 84.0 to 94.0 g / L. When the content of icodextrin is less than 76.0 g / L, in the peritoneal dialysis after mixing the first liquid and the second liquid, water removal does not occur and appropriate dialysis cannot be expected. When the content of icodextrin contained exceeds 94.0 g / L, the amount of glucose degradation products generated from icodextrin is not preferable. That is, this makes it possible to suitably suppress the glucose degradation products generated from icodextrin during heat sterilization and subsequent storage, and to realize a stable and excellent peritoneal dialysis solution.

  In the peritoneal dialysis solution of the present invention, the first solution contains an electrolyte. Specifically, it contains at least one of sodium chloride, calcium chloride, and magnesium chloride, but does not contain sodium lactate from the viewpoint of suppressing glucose degradation products generated from icodextrin.

  In the peritoneal dialysis solution of the present invention, the second solution contains an alkaline pH adjuster. Specifically, it contains sodium lactate, but may contain an electrolyte. Specifically, sodium chloride may be contained.

  In the peritoneal dialysis solution of the present invention, the pH of the first liquid after sterilization is in the acidic region, specifically, the range of pH 2.3 to 2.7 is preferable, and the range of pH 2.4 to 2.6 is preferable. More preferred. When the pH is less than 2.3, the pH after mixing does not become 6.0 to 7.5, which is not preferable. If the pH exceeds 2.7, the amount of 3-deoxyglucosone, which is a glucose degradation product generated from icodextrin, is increased, which is not preferable.

  In the present invention, since the first liquid is adjusted to be acidic, the pH may be adjusted using an acidic pH adjusting agent such as hydrochloric acid if necessary. This is the amount for adjusting the pH of the peritoneal dialysis solution after mixing the two solutions to pH 6.0 to 7.5.

  In the peritoneal dialysis solution of the present invention, the second liquid after sterilization is in an alkaline region, specifically, a range of pH 8.0 to 9.0 is preferable, and a range of pH 8.3 to 8.7 is more preferable. . If the pH is less than 8.0 or more than 9.0, the pH after mixing does not become 6.0 to 7.5, which is not preferable.

  In the present invention, since the second liquid is adjusted to be alkaline, the pH may be adjusted using an alkaline pH adjuster such as sodium hydroxide if necessary, but the amount is the first liquid after sterilization. And the second solution are mixed to adjust the pH of the peritoneal dialysis solution to pH 6.0 to 7.5.

  In the peritoneal dialysis solution of the present invention, if the pH after mixing is less than 6.0, the immune defense mechanism of macrophages is reduced and the peritoneal mesothelial cells are highly impaired. Concerned.

  In the present invention, the first liquid contains at least one of sodium chloride calcium chloride and magnesium chloride. The amount of these components is not particularly limited as long as the amount is the same as that of a normal peritoneal dialysis solution. Preferably, sodium chloride is 16.6 to 347.8 g / L, and sodium lactate is 21. 3 to 448.0 g / L, calcium chloride is 1.22 to 25.7 g / L, and magnesium chloride is 0.24 to 5.10 g / L.

  In the present invention, the second liquid contains an alkaline pH adjuster. Specifically, it contains sodium lactate. The amount of sodium lactate is not particularly limited as long as it contains the same amount as that of a normal peritoneal dialysis solution, and is preferably 21.3% to 448.0g / L.

  In the peritoneal dialysis solution of the present invention, the first solution and the second solution are separately filled and packaged in a container made of polypropylene or polyvinyl chloride, sterilized, and immediately before use, the first solution and the second solution The solution is mixed aseptically.

  In particular, the peritoneal dialysis solution of the present invention is a medical bag body, and has a first chamber and a second chamber formed by being separated by a partitioning means capable of opening the inside thereof. It is preferable that the first liquid and the second liquid are separated and accommodated in one having a discharge port that communicates the inside and outside of the medical bag body. At this time, it is preferable to store the first liquid in the first chamber and the second liquid in the second chamber. Thereby, even if the first liquid and the second liquid are administered without mixing, administration of the first liquid that is relatively safe in terms of osmotic pressure can be administered.

   Examples of the partitioning means that can be opened include a heat seal that can be broken by the hydraulic pressure of the first or second liquid stored when one of the first chamber and the second chamber is pressed. Thereby, mixing with a 1st liquid and a 2nd liquid can be performed easily. As a medical bag, specifically, a container of Midperic (registered trademark) (manufactured by Terumo Corporation) can be mentioned.

  In the present invention, examples of the sterilization method include autoclave sterilization (high pressure steam sterilization). The conditions are 110 to 130 ° C. for 25 to 45 minutes, preferably 115 to 125 ° C. and 30 to 40 minutes.

  The peritoneal dialysis solution of the present invention is usually externally packaged with an oxygen-permeable membrane material such as a three-layer film made of polypropylene-polyamide-polypropylene. In order to prevent alteration of the dialysis solution in the container, oxygen is further added. It may be externally wrapped with a non-permeable membrane material.

  Examples of the oxygen-impermeable membrane material include a three-layer laminate film containing, for example, an ethylene-vinyl alcohol copolymer film, a polyvinyl alcohol film, a polyvinylidene chloride film as an intermediate layer (for example, an outer layer is a polyester film, a stretched nylon film, It includes a stretched polypropylene film and the like, and an inner layer includes a laminate film composed of an unstretched polypropylene film), a laminate film including an aluminum layer (eg, a polyester film-aluminum layer-a laminate film composed of an unstretched polypropylene film), and an inorganic vapor deposition film Laminated film (for example, polyester film-silicon vapor deposited film-unstretched polypropylene film, stretched nylon film-silicon vapor deposited film- Oriented polypropylene film, a polyester film - aluminum-deposited film - unstretched polypropylene film, alumina-deposited polyester film - polyvinylidene chloride film - such as a laminate film consisting of unstretched polypropylene film) and the like.

  The peritoneal dialysis solution of the present invention has been described in detail above, but the present invention is not limited to this, and various improvements and modifications may be made without departing from the gist of the present invention.

  Hereinafter, the present invention will be described in more detail with reference to specific examples of the present invention. The present invention is not limited to the following examples.

Example 1
75.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection, and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. First, 840 mL of the first liquid and 160 mL of the second liquid were filled in a polypropylene multi-chamber container (a container of Midperic (registered trademark) (manufactured by Terumo Corporation)), and then placed in a three-sided bag made of polypropylene / nylon / polypropylene. I wrapped it. Then, after performing heat sterilization (121 degreeC, 30 minutes) using an autoclave, pH of the 1st liquid, the 2nd liquid, and a liquid mixture (peritoneal dialysate) was measured. The pH of the first liquid was 2.5, the pH of the second liquid was 8.8, and the pH of the mixed liquid was 6.8.

(Example 2)
78.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 2.3, the pH of the second liquid was 8.8, and the pH of the mixed liquid was 6.7.

(Example 3)
71.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection, and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 2.7, the pH of the second liquid was 8.3, and the pH of the mixed liquid was 6.7.

(Comparative Example 1)
75.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection, and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 1.8, the pH of the second liquid was 8.0, and the pH of the mixed liquid was 5.9.

(Comparative Example 2)
75.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection, and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 3.5, the pH of the second liquid was 8.0, and the pH of the mixed liquid was 6.8.

(Comparative Example 3)
75.0 g icodextrin, 5.35 g sodium chloride, 0.257 g calcium chloride, and 0.051 g magnesium chloride hexahydrate were dissolved in 840 mL of water for injection to prepare a first solution. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 5.7, the pH of the second liquid was 8.1, and the pH of the mixed liquid was 7.5.

(Comparative Example 4)
120.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 2.5, the pH of the second liquid was 8.5, and the pH of the mixed liquid was 6.5.

(Comparative Example 5)
120.0 g of icodextrin, 5.35 g of sodium chloride, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate are dissolved in 840 mL of water for injection and the pH is adjusted with lactic acid. A liquid was prepared. Also, 4.48 g of sodium lactate was dissolved in 160 mL of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first liquid was 4.0, the pH of the second liquid was 8.0, and the pH of the mixed liquid was 6.3.

(Comparative Example 6)
120 g of icodextrin, 0.257 g of calcium chloride, and 0.051 g of magnesium chloride hexahydrate were dissolved in 840 mL of water for injection to prepare a first solution. In addition, 5.35 g of sodium chloride, 4.48 g of sodium lactate were dissolved in 160 mL of water for injection to prepare a second solution. After filling and heat-sterilizing 840 mL of the first liquid and 160 mL of the second liquid under the same conditions as in Example 1, the pH of the first liquid, the second liquid, and the mixed liquid (peritoneal dialysis liquid) was measured. The pH of the first solution was 4.9, the pH of the second solution was 6.9, and the pH of the mixed solution was 6.5.

(Confirmation test)
About the 1st liquid after heat sterilization of Examples 1-3 and Comparative Examples 1-6, the light absorbency of 228 nm which is a parameter | index of 3-deoxyglucoso which is a main glucose degradation product was measured.

  The peritoneal dialysis fluids of Examples 1 to 3 are indicators of 3-deoxyglucoso, which is a glucose degradation product generated from icodextrin as shown in Table 1 in the first fluid containing icodextrin even after heat sterilization. None of the samples had an absorbance at 228 nm exceeding 0.27. Moreover, pH after mixing was 6.0 to 7.5.

  On the other hand, in the comparative example, it was as follows. In Comparative Example 1, as shown in Table 2, the absorbance at 228 nm was the same level as in Example, but the pH of the first liquid after sterilization was less than 2.3, so the pH after mixing was 6.0 to 6.0. It was not 7.5. In Comparative Examples 2 to 6, as shown in Table 2, the absorbance at 228 nm exceeded 0.30.

Claims (3)

A sterilized peritoneal dialysis solution consisting of an acidic first solution containing icodextrin and an alkaline second solution containing an alkaline pH adjuster, wherein the concentration of icodextrin in the first solution is 84.5 to 92.9 g / L, the sterilization conditions are 110 to 130 ° C. and 25 to 45 minutes, the pH of the first liquid after sterilization is 2.3 to 2.7, and the sterilization is performed A peritoneal dialysis solution in which the pH of the second solution is 8.0 to 9.0, and the pH after mixing the first and second solutions after sterilization is 6.0 to 7.5. The first liquid contains at least one of 16.6 to 347.8 g / L sodium chloride, 1.22 to 25.7 g / L calcium chloride, and 0.24 to 5.10 g / L magnesium chloride. and peritoneal dialysis solution of claim 1 wherein the second liquid contains sodium lactate 21.3~448.0g / L. The peritoneal dialysis solution according to claim 1 or 2 , which is housed in a medical bag, wherein the bag is separated by a partitioning means capable of opening the interior thereof, and a first chamber. And the first chamber has a discharge port communicating between the inside and the outside of the bag body, the first liquid being in the first chamber and the second liquid being in the second chamber. The peritoneal dialysis solution stored.