JPH0871146A - Peritoneum dialyzing liquid containing cyclodextrin or derivative thereof - Google Patents

Abstract

PURPOSE: To provide a peritoneum dialyzing liquid which withstands heating sterilization near neutral and substantially prevents the degradation of an osmotic pressure. CONSTITUTION: This peritoneum dialyzing liquid consists of an aq. soln. which contains at least one of the compds. selected from a group consisting of a 2-hydroxyethyl ether deriv. of α-, β-and γ-cyclodextrins, 2-hydroxypropyl ether deriv., 6-O-α-glucosyl deriv. and 6-O-α-martosyl deriv. as well as α-cyclodextrin and γ-cyclodextrin and physiological salts at the concn. sufficient for safe execution of removal of the solute and water from a patient by a peritoneum dialysis and has physiologically permissible pH.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a peritoneal dialysate.

[0002]

2. Description of the Related Art Continuous outpatient peritoneal dialysis (CAPD) is
It is known as a technique for maintaining the life of a patient who has lost renal function. In CAPD, peritoneal dialysate is infused into the abdominal cavity, whereby waste products (typically urea, creatinine), sodium and chloride ions and other minerals and water, which are normally excreted by the kidneys, are added. Substances diffuse across the natural body membranes from the bloodstream into 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, sodium lactate, and sodium acetate are generally present in the peritoneal dialysate in slightly lower concentrations,
Such salts in the blood diffuse into the peritoneal dialysate in response to its excess.

In order to generate the osmotic pressure necessary to remove water from the patient, which is generally necessary, the peritoneal dialysate is prepared by adding other solutes in addition to the physiological salts mentioned above. The osmotic pressure can be adjusted. The other solute added for such purpose is typically glucose, which is usually contained in the peritoneal dialysate at a concentration of at least 5 g / L. This concentration can also be increased further if it is desired to increase ultrafiltration from the patient.

[0005]

However, glucose is easily decomposed particularly in the vicinity of neutral or basic side during heat sterilization, and decomposition products such as 5-hydroxymethylfurfural are produced. 5-Hydroxymethylfurfural is considered to be harmful to the peritoneum [Henderson
et al., Blood Purif., 7: p.86-94 (1989)]. Therefore, the glucose-containing peritoneal dialysate to be heat-sterilized in the manufacturing process is adjusted to an acidic pH for the purpose of minimizing decomposition by heat sterilization, and therefore the product after sterilization also has an acidic pH. This is not preferable from the viewpoint of biocompatibility for the peritoneal dialysate that is injected into the abdominal cavity.

Further, even when heat sterilizing a glucose-containing peritoneal dialysate adjusted to an acidic pH, the decomposition of glucose cannot be completely prevented, and a decomposition product such as 5-hydroxymethylfurfural is produced although it is a small amount. It is included in the product, and this is also problematic from the viewpoint of biocompatibility.

In addition, glucose in the peritoneal dialysate injected into the abdominal cavity diffuses relatively quickly into the bloodstream through the peritoneum, and the diffusion causes a decrease in osmotic pressure of the peritoneal dialysate. The initial glucose concentration in the dialysate must be set relatively high in anticipation of a decrease in osmotic pressure, which is problematic in that the initial osmotic pressure can be unduly high.

[0008]

The present inventor has replaced cyclodextrin or a derivative thereof, in particular α, with glucose.
-, Β- and γ-cyclodextrin of 2 respectively
-Hydroxyethyl ether derivative, 2-hydroxypropyl ether derivative, 6-O-α-glucosyl derivative, and 6-O-α-maltosyl derivative (these have at least one corresponding residue bonded to each cyclodextrin structure). The present invention has been completed by finding that the above problems can be solved by using α-cyclodextrin or γ-cyclodextrin. That is, the present invention provides a 2-hydroxyethyl ether derivative, a 2-hydroxypropyl ether derivative, a 6-O-α-glucosyl derivative, and a 6-O-α-maltosyl derivative of α-, β- and γ-cyclodextrin. And α
-Cyclodextrin, and at least one compound selected from the group consisting of γ-cyclodextrin and physiological salts, at a concentration sufficient to safely perform solute and water removal from the patient by peritoneal dialysis, It is a peritoneal dialysate composed of an aqueous solution having a physiologically acceptable pH.

These cyclodextrin compounds are
It is chemically stable in an aqueous solution, can withstand heat sterilization even near neutral, and hardly decomposes. Therefore, by preparing a peritoneal dialysate using these cyclodextrin compounds instead of glucose, a peritoneal dialysate having a pH in the vicinity of neutrality and containing no decomposition products even after heat sterilization can be commercialized. Is possible. Furthermore, since its molecular weight is much larger than that of glucose, diffusion through the peritoneum is unlikely to occur. Therefore, the peritoneal dialysate containing these cyclodextrin compounds can solve the above-mentioned problems in the conventional peritoneal dialysate containing glucose.

All of these cyclodextrin compounds are known and can be produced by methods well known to those skilled in the art. For example, 2-hydroxypropyl-β-cyclodextrin, which is one of the 2-hydroxypropyl ether derivatives, is obtained by reacting propylene oxide with β-cyclodextrin according to the description in, for example, U.S. Patent No. 3,459,731 or U.S. Patent No. 4,727,064. Can be manufactured by. Further, 2-hydroxyethyl-β-cyclodextrin, which is one of the 2-hydroxyethyl ether derivatives, can be similarly produced by the reaction of ethylene oxide and β-cyclodextrin. Hydroxyethyl (or hydroxypropyl) -γ-cyclodextrin is also described in US Pat. No. 4,764,60.
As described in No. 4, it can be produced by reacting γ-cyclodextrin with ethylene oxide (or propylene oxide). In addition, glucosyl-β-cyclodextrin is obtained from β-cyclodextrin synthetic mother liquor by the cyclomaltodextrin glucanotransferase of Bacillus ohbensis [Koizumi et al., Chem. Pha.
rm. Bull. 35 (8), 3413-3418 (1987) and references cited therein]. Maltosyl-β- and γ-cyclodextrin is derived from the original cyclodextrin and maltose.
Pseudomonas isoamylase or Klebsiella aerogenes
Glucosyl-can be produced by the reverse action of pullulanase.
γ-Cyclodextrin can be produced by enzymatic hydrolysis of maltosyl-γ-cyclodextrin [see Ogata et al., Chem. Pham. Bull., 36 (6), 2176-2185 (1988) and references cited therein]. A method for producing maltosyl-β-cyclodextrin by reacting maltose and β-cyclodextrin in the presence of pullulanase is disclosed in Japanese Patent Application Laid-Open No.
61-287902 and JP-A-61-197602. The production of maltosyl-α-cyclodextrin is described in JP-A-61-070996.

The concentration of the cyclodextrin compound contained in the peritoneal dialysate of the present invention is preferably 10 to 200 g /
L, and more preferably 50 to 150 g / L.

As the physiological salts contained in the peritoneal dialysate of the present invention, salts generally used in the peritoneal dialysate can be used. Particularly preferably, as the physiological salt component, sodium ion 110 to 140 mEq / L, potassium ion 0 to 0.05 mEq / L, magnesium ion 0 to 2 mEq / L, calcium ion 0 to 4 mE
It contains q / L and chloride ions of 80 to 110 mEq / L.

Further, the peritoneal dialysate of the present invention can have a buffering property, for which the physiological salt component is preferably selected from the group consisting of lactic acid, malic acid, acetic acid, succinic acid and the like. Ions 50 mEq / L or less and / or 40 mEq / L or less hydrogen carbonate ions can be contained.

In addition, the peritoneal dialysate of the present invention may also contain suitable amounts of one or more other compounds which increase osmolality. Examples of such suitable amounts of compounds include amino acids 0 to 50 g / L, glycerol 0 to 100 g / L, sorbitol 0 to 50 g / L, fructose 0 to 50 g / L.
L, xylitol 0 to 50 g / L, mannitol 0 to
50 g / L, and maltose 0 to 50 g / L can be mentioned.

The pH of the peritoneal dialysate of the present invention can be set to around neutral as described above, preferably pH 5.0 to 7.5, more preferably pH 5.5 to 7.
3, particularly preferably pH 6.0 to 7.3.

[Stability Test in Heat Sterilization] Example 1
Each of the peritoneal dialysate described in Nos. 3 to 3 and a conventional peritoneal dialysate prepared as follows (comparative example) was placed in a glass bottle, sealed, and sterilized by a sterilizer (121 ° C., 40 minutes). The pH was measured before and after sterilization, and the amounts of the cyclodextrin compound and glucose, and the presence or absence and the amount of these decomposition products were examined by UV spectrum and liquid chromatography. (Production of Comparative Example) Glucose 2.5 g, sodium chloride 0.
Weigh 538 g, calcium chloride dihydrate 0.026 g, magnesium chloride hexahydrate 0.005 g and 60% sodium lactate 0.74 g, dissolve and stir them in 100 mL of purified water, and adjust the pH to 6.51 with diluted hydrochloric acid. Thus, the peritoneal dialysis solution of the present invention was produced.

(Test Results) 1) Change in pH As shown in Table 1 below, in the comparative peritoneal dialysate containing glucose, the pH of the solution was decreased by about 1 by heat sterilization, whereas the cyclodextrin compound was In the peritoneal dialysis solutions of Examples 1 to 3, which contained in place of glucose, almost no change in pH due to heat sterilization was observed.

[0018]

[Table 1]

2) Changes in Cyclodextrin Compound and Glucose Content and Degradation Products The results of measurement by HPLC are shown in Table 2 below. It can be seen that the amount of glucose has decreased by about 7.5% after heat sterilization.
In contrast, the variation of cyclodextrin in Examples 1 to 3 was only about 1%.

[0020]

[Table 2]

[0021] By HPLC, the production of 5-hydroxymethylfurfural, which is a major decomposition product of glucose, was observed only in the comparative example, but not in the peritoneal dialysates of Examples 1 to 3. This could be confirmed by comparing the absorbance at 284 nm with the UV spectrum.

[0022]

【Example】

Example 1 6-O-α-glucosyl-β-cyclodextrin (1 glycosyl group per cyclodextrin ring)
2.5 g, sodium chloride 0.538 g, calcium chloride dihydrate 0.026 g, magnesium chloride hexahydrate 0.005 g, and 60% sodium lactate 0.74 g are each weighed and added to 100 mL of purified water. Was dissolved and stirred, and the pH was adjusted to 6.46 with dilute hydrochloric acid to prepare the peritoneal dialysis solution of the present invention (before sterilization).

Example 2 6-O-α in Example 1
Except that 2.5 g of 6-O-α-maltosyl-β-cyclodextrin (having one maltosyl group per cyclodextrin ring) was used instead of 2.5 g of -glycosyl-β-cyclodextrin and the pH of the solution was 6.49. In the same manner as in Example 1, the peritoneal dialysate of the present invention was produced.

[Embodiment 3] 6-O-α in Embodiment 1
2.5 g of 6-O-2-hydroxypropyl-β-cyclodextrin (having one 2-hydroxypropyl group per cyclodextrin ring) instead of 2.5 g of glycosyl-β-cyclodextrin and the pH of the solution
The peritoneal dialysis solution of the present invention was produced in the same manner as in Example 1 except that the ratio was 7.20.

Claims (6)

[Claims] 1. A 2-hydroxyethyl ether derivative, a 2-hydroxypropyl ether derivative, a 6-O-α-glucosyl derivative, and a 6-O-α-maltosyl derivative of α-, β- and γ-cyclodextrin. And α
-Cyclodextrin, and at least one compound selected from the group consisting of γ-cyclodextrin and physiological salts, in a concentration sufficient to safely perform solute and water removal from the patient by peritoneal dialysis, A peritoneal dialysate consisting of an aqueous solution having a physiologically acceptable pH. 2. The peritoneal dialysis solution according to claim 1, wherein the concentration of the compound is 10 to 200 g / L. 3. As the physiological salt component, sodium ion 110 to 140 mEq / L, potassium ion 0 to 0.05
mEq / L, magnesium ion 0 to 2 mEq / L,
Calcium ion 0 to 4 mEq / L and chlorine ion 80
The peritoneal dialysis solution according to claim 1 or 2 containing 110 to 110 mEq / L. 4. As the physiological salt component, an ion selected from the group consisting of lactic acid, malic acid, acetic acid, succinic acid and citric acid is 50 mEq / L or less, and / or 40 mEq / L or less bicarbonate ion is contained. The peritoneal dialysis solution according to any one of claims 1 to 3. 5. Amino acid 0 to 50 g / L, glycerol 0
To 100 g / L, sorbitol 0 to 50 g / L, fructose 0 to 50 g / L, xylitol 0 to 50 g / L,
Mannitol 0 to 50 g / L, maltose 0 to 50 g / L
The peritoneal dialysis fluid according to any one of claims 1 to 4, further containing at least one of L. 6. The physiologically acceptable pH is 5.0 to 7.5.
The peritoneal dialysis fluid according to any one of claims 1 to 5, which is