HK1148963A - Peritoneal dialysate - Google Patents

Description

Peritoneal dialysis solution

Technical Field

The present application relates to a peritoneal dialysis solution for use in peritoneal dialysis.

Background

Peritoneal dialysis is a treatment means in which a sufficient amount of peritoneal dialysis solution is injected into the abdominal cavity of a patient suffering from acute or chronic renal failure in which renal function has been lost, and left for a predetermined period of time, thereby draining the waste in the body fluid into the dialysis solution via the peritoneal membrane. At the same time, the aim of adjusting the balance of various body fluid components by the treatment means is achieved. Peritoneal dialysis is typically performed using a solution known as peritoneal dialysis solution.

One of such solutions is, for example, a dialysate for Continuous Ambulatory Peritoneal Dialysis (CAPD). Such dialysate is disclosed in the prior art: in addition to general electrolyte components such as sodium chloride, calcium chloride, and magnesium chloride, glucose is added as an osmotic pressure substance for maintaining an osmotic pressure higher than that of a body fluid in order to maintain a pH value close to that of the body fluid, contain a lactate, a bicarbonate, and the like as an alkalizer, and ensure super-permeation of a dialysate (patent document 1).

Patent document 1: japanese patent laid-open No. 2000-51348

However, the influence of hyperglycemia on the body and metabolism due to the presence of high-concentration glucose has been a problem in the glucose-containing peritoneal dialysis solution described in patent document 1. In particular, since renal failure of diabetes origin has increased remarkably in recent years, there is a concern that the use of glucose in peritoneal dialysis solution will further worsen renal failure.

In addition, when the pH of the glucose solution is adjusted to 6.0 to 7.5 for the purpose of achieving a neutral to slightly alkaline condition close to physiological conditions, a part of glucose is polymerized with each other or reacts with a remaining trace substance to be colored when the glucose solution is sterilized at a high temperature. In particular, when a trace amount of amino acid is present, browning reactions caused by Maillard reactions occur significantly, and glucose decomposition products that are damaging to peritoneal cells are generated.

Further, at the above neutral to weakly alkaline pH, there are also the following problems: glucose decomposition, 5-hydroxymethylfurfural (5-HMF), formic acid, aldehydes, and the like increase, and the pH value decreases with the passage of time. These decomposition products are cytotoxic and may be associated with the progression of complications such as amyloidosis and progressive arteriosclerosis.

In order to suppress the above reaction, the pH of the peritoneal dialysis solution is lowered to about 5.0, but at this low pH, patients undergoing peritoneal dialysis are often exposed to an acidic solution of high glucose concentration. Since glucose reacts with free amino acids, polypeptides, and proteins or membrane phospholipids via its carbonyl group, the peritoneum may be damaged by long-term use of a high-concentration glucose solution, leading to peritoneal membrane deterioration and peritoneal sclerosis.

To solve these problems, an osmotic pressure substance has also been proposed as an alternative to glucose. For example trehalose, which is a stable disaccharide widely distributed in the animal kingdom, readily metabolized in the body, and used for surgical repair and adhesion prevention. Patent document 2 discloses a peritoneal dialysis solution containing trehalose as an osmotic pressure substance. Patent document 3 discloses a peritoneal dialysis solution containing trehalose as an osmotic pressure substance and glucose as an energy source.

One of the inventors of the present application discloses a peritoneal dialysis solution in which taurine is selected as an osmotic pressure substance (patent document 4). Taurine is a non-proteinogenic amino acid that has been found to increase intracellular concentrations to counteract and protect cells when the osmotic pressure of body fluids changes. In addition, it is extremely safe to humans in a load test. In addition, in peritoneal dialysis patients, the concentration of taurine in plasma and muscle is reduced due to synthesis failure, and it is effective to replenish taurine with a dialysate. Taurine is expected to have secondary effects such as improvement of circulatory function, improvement of lipid metabolism, and diuretic effect, in addition to the effects suitable for peritoneal dialysis.

Patent document 2: japanese laid-open patent publication No. 7-323084

Patent document 3: japanese laid-open patent publication No. 2002-282354

Patent document 4: japanese patent laid-open publication No. 2005-531630

However, the peritoneal dialysis solutions of patent documents 2 to 4 have a problem of remaining: it has not been considered that this is a complete alternative to peritoneal dialysis solutions which have been the main stream of glucose. In the peritoneal dialysis solution of patent document 3, trehalose is used in combination with glucose used in conventional peritoneal dialysis solutions, but there is still a problem that damage to the peritoneal membrane and hyperglycemia may occur due to the use of glucose.

In addition, although the peritoneal dialysis solutions of patent documents 2 and 4 do not contain glucose, when only one substance is used as an osmotic pressure substance to exert all the activities, it is necessary to use these osmotic pressure substances at a high concentration. In this case, if the dialysate suddenly flows into the blood due to frequent dialysis and the peritoneum becomes fragile, it cannot be denied that these high-concentration substances may disturb the metabolism of the solid. In addition, when a substance is responsible for all activities, the possibility of causing a dangerous situation to a dialysis patient due to a change in pH or a reaction of the substance contained therein caused by other unpredictable situations, accidental factors from the outside, or factors coming from the inside during dialysis cannot be completely denied. In general, peritoneal dialysis solutions using osmotic pressure substances other than glucose have a problem that safety of the living body cannot be sufficiently confirmed after long-term use, and thus have not been sufficiently used so far.

Disclosure of Invention

The following problems are essential for peritoneal dialysis solutions that can be safely used by patients with renal failure: the composition does not cause various hazards due to the inclusion of glucose, has characteristics optimal for peritoneal dialysis including osmotic pressure design, can sufficiently contribute to the treatment of patients with renal failure, and ensures sufficient safety. In order to ensure safety in vivo, conditions of optimum osmotic pressure and pH are defined, and excellent stability that can further maintain the osmotic pressure and pH is also required.

Accordingly, the inventors of the present invention have studied to solve the above problems by using taurine and trehalose together as an osmotic pressure substance. Even if the blood concentration of taurine and trehalose temporarily increases due to, for example, the weakening of the peritoneal membrane, the safety can be ensured by the metabolic activity present in the blood. In this case, if one substance is used at a high concentration instead of a single substance, and the respective concentrations can be reduced, the impact on metabolism is reduced, and safety is improved. Since these two substances are equivalent as osmotic pressure substances, they participate in osmotic pressure additively, but since they are different in metabolism, safety and stability can be synergistically improved by maintaining each at a low concentration.

The present invention has been made in view of the above-mentioned findings, and an object of the present invention is to provide a peritoneal dialysis solution which is not only low in peritoneal membrane damage, neutral (pH 6.5 to 7.5), extremely excellent in physicochemical stability, hardly causes irritation to the body, and has few side effects, but also sufficiently satisfies the blood purification effect and the water removal effect of removing urea or nitrogen-containing compounds derived from urea for therapeutic purposes, by using a plurality of harmless natural materials other than glucose as osmotic pressure substances.

In order to achieve the above object, the peritoneal dialysis solution of the present invention employs the following means.

That is, the peritoneal dialysis solution of the present invention is characterized in that: contains 0.05-3.5W/V% of taurine and 0.1-6.5W/V% of trehalose, and has a pH value of 6.5-7.5.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: taurine and trehalose are used as osmotic pressure substances, and the osmotic pressure is 300-680 mOsm/L based on extracellular fluid.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: comprises taurine, trehalose, amino acids, minerals, vitamins and alkalinizing agent.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: the amino acid contains at least 6 amino acids selected from the group consisting of L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, and L-carnitine, and the total concentration of these amino acids is 0.4 to 5.0 wt%.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: the minerals comprise more than 3 of iron ion, copper ion, calcium ion, magnesium ion, zinc ion, chromium ion, selenium ion, and manganese ion.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: the vitamins include at least 4 kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, nicotinic acid, vitamin B6 and its derivatives, folic acid, vitamin B12, pantothenic acid, and vitamin C or its derivatives, and the total amount is 10-40 mg.

In addition, the peritoneal dialysis solution of the present invention is characterized in that: the alkalizer contains bicarbonate, and the pH value is adjusted to 6.5-7.5 when the alkalizer is used.

The present invention is configured as described above, and therefore, the following effects can be achieved.

That is, according to the peritoneal dialysis solution of the present invention, the osmotic pressure can be arbitrarily adjusted within a range suitable for the peritoneal dialysis solution, that is, within a range in which a water removal amount sufficient for dialysis and a degree not causing water loss can be obtained by mixing while adjusting the concentration ratio so that the concentrations of the two osmotic pressure substances are set within the ranges of 0.05 to 3.5W/V% for taurine and 0.1 to 6.5W/V% for trehalose. In addition, the peritoneal dialysis solution obtained by mixing two substances at a concentration ratio within this range exhibits the osmotic pressure effect of each substance in addition, and synergistically protects and maintains the peritoneal tissue by the tissue and cell protecting and repairing effects obtained by utilizing different mechanisms, thereby inhibiting the occurrence of damage. In addition, a more stable and safer osmotic pressure can be ensured as compared with an accidental damage that occurs when only one substance is allowed to take full activity as an osmotic pressure substance.

Further, since glucose is not added as an osmotic pressure substance, it is not necessary to make the pH acidic in order to suppress the chemical reaction of glucose, and the pH can be set to 6.5 to 7.5 which is a pH close to physiological conditions, and therefore shock due to an acidic solution is not given to the dialysis patient. Further, damage caused by chemical reaction products of glucose and increase of blood glucose level are not caused. This enables peritoneal dialysis to be performed more safely for a long period of time.

In addition, according to the peritoneal dialysis solution of the present invention, by setting the minimum limit value of osmotic pressure to 300mOsm/L, it is possible to provide safety that is more than the range setting of the dialysis solution of the prior art. The maximum limit value is set to 680mOsm/L as a limit that water removal does not proceed rapidly, and a safe water removal rate optimum for peritoneal dialysis can be obtained by setting the maximum limit value within this range of osmotic pressure.

In addition, according to the peritoneal dialysis solution of the present invention, by adding all or a part of amino acids, minerals, and vitamins to the dialysis solution, nutrition can be supplemented by dialysis, and the patient can be relieved from the occurrence of nutritional and metabolic disorders due to dialysis. In particular, since glucose is not used as an osmotic agent, there is no fear that glucose is bonded to various amino acids, polypeptides, and various proteins (various membrane proteins including blood cell membranes) via a carbonyl group. In addition, the osmotic pressure substance can be kept stable without mutual reaction with these additional nutrients by the stability of the pH value by the alkalizer.

In addition, according to the peritoneal dialysis solution of the present invention, since both osmotic pressure substances do not react with amino acids, amino acids for nutrition supplementation can be added. The amino acid profile (amino acid profile) to be supplemented in the peritoneal dialysis solution is not limited to only amino acids such as essential amino acids added for the purpose of supplementing and supplementing protein nutrients, but is more important for coping with the bias of amino acid metabolism due to the functional failure of organs such as renal failure. Leucine, isoleucine and valine, which are branched chain amino acids, are components of muscles and can supplement physical strength loss caused by low protein diet in renal failure, and histidine is a component of hemoglobin as well as being synthesized into myoprotein, and thus is suitable for anemia. Arginine, whose synthesis is reduced in renal failure, is important for maintaining immune activity, is also indispensable for nitrogen metabolism, and has vasodilator action, insulin secretion stimulating action. Tyrosine, a precursor of neurotransmitters, complements the central system. By adding an appropriate amount of amino acids to the peritoneal dialysis solution, it is possible to improve metabolism, maintain and preserve the nephron function by performing active therapy with the same dialysis solution while performing dialysis, and therefore, it is possible to exert an effect of marking a new level in dialysis therapy for renal failure. Thus, no prior example has been found in which an amino acid is added to a peritoneal dialysis solution for the purpose of supplementing nutrients and exerting a specific function depending on the therapeutic use.

In addition, according to the peritoneal dialysis solution of the present invention, essential trace minerals such as copper, zinc, manganese, chromium, and selenium may be added to the peritoneal dialysis solution of the present invention in addition to calcium, magnesium, and iron. Since minerals are indiscriminately removed from the dialysate by the peritoneal dialysis treatment, the load on the patient receiving the dialysis treatment due to the deficiency of nutrients is increased, and the fatigue of the whole body may be aggravated. The iron ions and copper ions in the present technical solution are substances that cope with iron ion and copper ion-deficient anemia that frequently occurs in dialysis patients, and calcium ions are added to prevent the occurrence of osteoporosis. Magnesium ions are added for maintenance of a biofilm, energy metabolism, or normalization of muscular movement; zinc ions are added for the purpose of preventing the occurrence of dermatitis and for immune maintenance; chromium ions are added to prevent peripheral nerve disorders and to prevent impaired glucose tolerance. Selenium is a substance having an effect of inhibiting the occurrence of cardiomyopathy and the occurrence of lower limb myalgia. Peritoneal dialysis solutions to which these essential trace minerals are added have not existed so far.

In addition, according to the peritoneal dialysis solution of the present invention, since vitamins can be added by making the pH of the dialysis solution neutral and by making the composition of the dialysis solution free of glucose and the like, the dialysis patient can be protected from vitamin deficiency due to dietary restrictions. In particular, since the vitamin B6 derivative can be added, various harmful substances such as GDP (glucose degradation Products) derived from glucose and AGE (Advanced glycation end Products) can be eliminated, and the risk of peritoneal sclerosis can be expected to be reduced. In the conventional peritoneal dialysis solutions, the addition of vitamins has not been considered.

In addition, according to the peritoneal dialysis solution of the present invention, the pH value is stably maintained at a neutral pH value close to physiological conditions by using the alkalizing agent bicarbonate. The peritoneal dialysis solutions according to aspects 1 to 6 of the present invention do not require a reduction in pH during dissolution to ensure stability, and can be adjusted to a neutral region and be stable, so that there is little concern over an extreme exceeding of a range of physiological conditions, and by including an alkalizer for adjusting pH in advance, even if there are unpredictable factors during use, the peritoneal dialysis solutions can be further maintained in a safe pH region. In addition, by selecting bicarbonate, which functions as a pH buffer for blood in the body, as an alkalizing agent, the dialysate becomes a system closer to the body environment.

Detailed Description

The present invention will be described in detail below.

The trehalose includes α, β -trehalose and β, β -trehalose in isomeric forms, and in the present invention, natural α, α -trehalose is used as an osmotic pressure substance. Since both of the osmotic pressure substances taurine and trehalose do not react with each other, they can be mixed at an arbitrary concentration and an arbitrary concentration ratio designed as a peritoneal dialysis solution. Since trehalose is a disaccharide, a 2-fold concentration of monosaccharide such as glucose is required as an osmotic pressure substance.

The contents of the two osmotic pressure substances are 0.05-3.5W/V% for taurine and 0.1-6.5W/V% for trehalose. If the concentration is higher than this range, the amount of water removed is too large, and various symptoms associated with water loss may occur. In addition, excessive water removal may cause peritoneal sclerosis due to chronic osmotic stress. The concentration at which sufficient dialysis effect can be obtained and osmotic pressure is not excessively removed is more preferably 0.1 to 3.0W/V% for taurine and 0.2 to 6.0W/V% for trehalose, and the ranges of 0.3 to 2.5W/V% for taurine and 0.6 to 5.0W/V% for trehalose are particularly preferable for obtaining an appropriate amount of water removed.

The adjustment of the osmotic pressure of the peritoneal dialysis solution is mainly performed according to the concentrations of the osmotic pressure substances taurine and trehalose and by adjusting the concentration ratio of the two substances. After deducting the contribution of all other solutes to osmotic pressure, the osmotic pressure of the dialysate generated by two osmotic pressure substances, taurine and trehalose, can be determined, and the mixing ratio (molar concentration ratio) of the two substances can be 10: 1 to 1: 10. It is more preferable to maintain the concentrations of the two substances at about the equimolar concentration ratio.

The final value of the osmotic pressure to which all the components are added must be in the range of 300 to 680 mOsm/L. If the osmotic pressure is less than 300mOsm/L, the amount of water removed is too low to achieve the desired amount, and if an osmotic pressure mixture having a concentration of 680mOsm/L or more is used, the amount of water removed is too high, and various symptoms associated with water loss may occur. More preferably, in order to obtain a sufficient water removal amount, the amount of water is set to 320mOsm/L or more and less than 650mOsm/L, which contributes to avoiding rapid water removal associated with acute physiological shock and preventing peritoneal sclerosis due to chronic osmotic stress. Particularly preferably 330 to 530mOsm/L, which can maintain the water removal slowly.

The amino acids added into the dialysate are selected from L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, L-proline and L-carnitine. Particularly preferred amino acids and concentrations thereof include at least 6 kinds selected from the group consisting of 0.02 to 0.13W/V% of L-histidine, 0.085 to 0.50W/V% of L-isoleucine, 0.07 to 0.8W/V% of L-leucine, 0.05 to 0.5W/V% of L-valine, 0.02 to 0.15W/V% of L-tyrosine, 0.025 to 0.6W/V% of L-arginine, 0.02 to 0.20W/V% of L-tryptophan, 0.02 to 0.3W/V% of L-methionine, and 0.05 to 0.5W/V% of L-carnitine. The concentration of each amino acid represents a concentration that is preferable for returning an amino acid map (amino gram) of a patient who is undergoing dialysis therapy to a normal region. In case of a significant excess of this concentration, attention is paid to the increased risk of acidosis. The results of various studies with regard to the concentration of amino acids that should be added are: the total amount of amino acids is 0.4 to 5.0W/V%, and more preferably 0.7 to 3.0W/V% in order to further reduce the risk of metabolic acidosis.

As minerals, the dialysate used 1 time preferably contains iron ions (0.1 to 3mg), copper ions (0.1 to 0.7mg), chromium ions (0.1 to 50. mu.g), manganese ions (0.1 to 0.5mg), selenium ions (0.1 to 20. mu.g), calcium ions (1.0 to 10.0mg), magnesium ions (0.2 to 4.0mg), and zinc ions (0.2 to 2.0 mg). In the peritoneal dialysis method, water-soluble essential trace minerals in blood are lost together with the discharged fluid, and the amounts of various metals to be added to the dialysate are based on "the nutritional requirement of japanese (revision 6) [ required amount of japanese Eiken (6 ) ]".

Vitamins are supplemented with vitamins that are lost with water removal by peritoneal dialysis therapy, as with other nutrients. Among them, the derivatives of vitamin B6 are useful for enhancing the antioxidant effect. The dialysate used once preferably contains 6 or more of vitamin A (100-2000 I.U.), vitamin D3 (10-200 I.U.), vitamin E (0.5-10 mg), vitamin B1 (0.2-5.0 mg), vitamin B2 (0.5-5 mg), nicotinic acid (2-10 mg), any 1 or 2 or more selected from vitamin B6 and derivatives thereof such as pyridoxine, pyridoxal, pyridoxamine, and pyridoxal phosphate (0.2-10 mg), folic acid (50-200 μ g), vitamin B12 (1.0-5.0 μ g), pantothenic acid (0.5-5 mg), vitamin C, and ascorbic acid-2-glucoside (20-100 mg), respectively. The amount shown here is an amount based on "nutritional requirement of japanese (revision 6)" which is sufficient to supplement the amount and quality lost by peritoneal dialysis.

The pH value of the peritoneal dialysis solution is set to be maintained within the range of 6.5-7.5. In the present invention, as the alkalizer, bicarbonate, which is a blood buffer material in the body, is used, but lactate or citrate may be used. As the electrolyte, sodium ions, calcium ions, magnesium ions, zinc ions, chloride ions, and the like generally used in peritoneal dialysis solutions are preferably used, and as the electrolyte component, sodium chloride, calcium chloride, magnesium chloride, zinc sulfate, and the like are preferably contained. By setting the pH value to this range, the osmotic pressure substances taurine and trehalose are maintained stable and do not react with other components of the dialysate, the composition in the abdominal cavity, or the peritoneal cells.

The amount of each component of the peritoneal dialysis solution is preferably in the following concentration range.

Sodium ion: 50 to 150mEq/L

Potassium ion: 0 to 3.0mEq/L

Chloride ion: 50 to 140mEq/L

An alkalizer: 2.0 to 45mEq/L

Total of trehalose and taurine: 0.6-9.0W/V%

Total of amino acids: 0.4-5.0W/V%

These peritoneal dialysis solutions are contained in, for example, a plastic container of polyethylene, polypropylene, polyvinyl chloride, polyester, ethylene-vinyl acetate copolymer, nylon, or the like, or a cutting material thereof. In the present invention, a stable neutral peritoneal dialysis solution free from peritoneal injury can be contained in a one-compartment container by containing a mixture of trehalose and taurine as an osmotic pressure substance instead of glucose, but a two-compartment or more preparation can be prepared as necessary.

The sterilization may be performed under the usual heat sterilization conditions of 108 ℃ and 60 minutes, which are generally performed, but if a heat-resistant container is used, all kill sterilization may be performed. Further, sterilization may be performed by aseptic filtration or irradiation with radiation such as UV or γ rays. In the present invention, CAPD dialysate is contained in an airtight plastic container, and the container may be packed with an airtight coating material or an airtight plastic container may be used as needed. The term "airtight" refers to a material having the property of being impermeable or hardly permeable to a gas such as oxygen, nitrogen, carbon dioxide, or water vapor. The airtight plastic is, for example, ethylene-vinyl alcohol copolymer, polyvinylidene chloride, airtight nylon, or other polymer, and an optimum material can be obtained by selecting an appropriate degree of overlapping. These resins may be laminated or coated with plastic, or may be laminated with aluminum, aluminum oxide, silicon oxide, or the like. Whether transparent or opaque.

When an airtight coating material is used as the outer packaging material, the space between the container containing the peritoneal dialysis solution and the outer packaging material may be filled with an inert gas such as nitrogen gas or carbon dioxide gas alone or mixed at an appropriate concentration, or may be subjected to deaeration packaging.

Examples

The present invention will be described in detail below with reference to examples. However, the scope of the present invention is not limited to these examples.

Example 1: (stability against Heat Sterilization)

107.8g of sodium chloride, 5.14g of calcium chloride dihydrate, 1.016g of magnesium chloride hexahydrate, 5.4g of sodium acid carbonate, 5.6g of L-histidine, 3.8g of L-tryptophan, 15.0g of L-isoleucine, 12.4g of L-leucine, 9.4g of L-valine, 4.3g of L-tyrosine and 9.4g of L-arginine are dissolved in a proper amount of distilled water for injection, the pH value is adjusted to 7 by using sodium hydroxide, and water is added to 20L. The solution is used as a basic solution. In this example, a solution to which no vitamin was added was used as a base solution. Test solutions TT-1, TT-2, TT-3, TT-4, and gluc are shown in the lower column of Table 1.

TABLE 1

Basic liquid: contains only salts and amino acids, has pH of 7.4, and is adjusted to 20L with distilled water for injection.

TT-1: 1L of basic solution, 10.0g of taurine and 10.0g of trehalose

TT-2: 1L of basic solution, 15.0g of taurine and 15.0g of trehalose

TT-3: basic solution 1L + taurine 30.0g

TT-4: basic solution 1L + trehalose 30.0g

Gluc.: basic solution 1L + glucose 38.0g

And (3) sterilization conditions: at 108 ℃ for 60 minutes

Storage conditions after sterilization: standing at 60 deg.C

As shown in the results in Table 1, the test solutions TT-1 to TT-4 were stable in appearance, pH, and osmotic pressure without change even after autoclaving and after storage at 60 ℃ for 2 weeks. On the other hand, the comparative solution containing glucose showed significant browning reaction after autoclaving, and the pH was lowered. And the brown color increased after 2 weeks of storage, showing a tendency to further decrease in pH.

Example 2: (relationship between concentration and amount of dewatering)

Sodium chloride (5.38g), sodium bicarbonate (2.52g), magnesium chloride hexahydrate (34mg), calcium chloride dihydrate (370mg), and zinc sulfate heptahydrate (86mg) were dissolved in distilled water, the pH was adjusted to 7.2, and distilled water was added to adjust the solution volume to 1L. This liquid was used as a base liquid.

A solution obtained by adding 2.0g of L-arginine, 0.5g of L-histidine, 3.0g of L-leucine, 2.0g of L-isoleucine, 2.0g of L-valine and 0.5g of L-tyrosine to 1L of the base solution and adding taurine and trehalose thereto was TTA-3 to TTA-6, and a control solution was prepared by dissolving glucose in the base solution and was GLU-1, GLU-2 and GLU-3. The amino acid concentration of the TTA-1 and TTA-2 solutions is 1/2 of TTA-3-6.

30ml of each of these solutions was injected into the abdominal cavity of an SD male rat, and the difference between the measured intra-abdominal liquid volume and the administered liquid volume (30ml) was defined as the water removal volume.

The results are shown in Table 2.

TABLE 2

As shown in example 2, the peritoneal dialysis solution containing taurine, trehalose, and a mixture of 6 kinds of amino acids as an osmotic pressure substance can obtain an osmotic pressure that is concentration-dependent, and can obtain a good water removal effect by adjusting the concentration, as in the case of a solution containing glucose as an osmotic pressure substance.

Example 3: (action of peritoneal injury)

Even if repeated operations of filling, retaining and draining the peritoneal dialysis solution into the peritoneal cavity are performed for a plurality of times, the peritoneal membrane is not damaged, and the drainage function can be normally maintained for a long time, which is a basic condition that the peritoneal dialysis solution should have.

For comparative study of the effect of peritoneal injury, the following experimental conditions were set. Specifically, a predetermined amount (30ml) of the peritoneal dialysis solution to be tested was injected into the abdominal cavity of the rat, and the whole volume was discharged after the solution was left for a predetermined time (4 hours). The same new peritoneal dialysis solution was then introduced into the peritoneal cavity in the same amount, left for 4 hours and then drained in full. This operation was performed 3 times a day for 7 days.

Since the drainage ability of the peritoneum is reduced depending on the degree of damage when the peritoneum is damaged, the peritoneal membrane damage effect of the peritoneal dialysis solution to be tested can be detected by injecting a detection solution (30ml) containing xylitol at a predetermined concentration into the abdominal cavity on the 8 th day of the test, draining the whole volume after a predetermined time (4 hours), and measuring the amount of the drained liquid and the concentration of xylitol.

As the test peritoneal dialysis solution, the peritoneal dialysis solution TTA-3 solution of the present invention (see example 2) was used, and as the comparative solution, a commercially available peritoneal dialysis solution containing 2.27% glucose was used.

After repeatedly injecting and discharging 30ml of the test peritoneal dialysis solution and an equivalent amount of the comparative peritoneal dialysis solution 3 times 7 days and 1 day using 5 male SD rats (body weight: 250 to 300g), 30ml of the test 1.9W/V% xylitol solution (and pure pharmaceutical grade xylitol) was injected into the abdominal cavity on day 8. The sample was collected immediately after injection and again after leaving for 4 hours, and the total amount of the solution was discharged after measuring the xylitol concentration, and the solution amount was measured.

When the amount of xylitol immediately after injection was denoted as D0 and the amount after leaving for 4 hours was denoted as D4, a smaller ratio of D4/D0 indicates more diffusion of xylitol out of the peritoneum, indicating significant peritoneal damage.

TABLE 3

D4/D0 xylitol ratio (N ═ 5)

As shown in Table 3, the D4/D0 xylitol amount ratio of TTA-3 of the present invention showed significantly higher value (P < 0.001) compared to the commercial dialysate (containing 2.27% glucose).

That is, even when the TTA-3 peritoneal dialysis solution is repeatedly injected into and discharged from the peritoneal cavity many times, the amount of the solution that flows out of the peritoneal cavity through the peritoneal membrane and flows into the blood vessel is significantly smaller than when a glucose-containing peritoneal dialysis solution is used, and thus the damage to the peritoneal membrane is small.

The peritoneal dialysis solution of the present invention is not only extremely excellent in physicochemical stability, hardly causes irritation to the body, does not cause deterioration of the peritoneal membrane, and has few side effects, but also can achieve a blood purification effect and a water removal effect for the purpose of treatment to remove urea or nitrogen-containing compounds derived from urea, and thus can continuously and safely perform dialysis treatment on a patient with renal failure for a long period of time.

Claims (33)

1. A peritoneal dialysis solution which is characterized by containing 0.05-3.5W/V% of taurine and 0.1-6.5W/V% of trehalose and having a pH value of 6.5-7.5.

2. A peritoneal dialysis solution is characterized in that taurine and trehalose are used as osmotic pressure substances, and the osmotic pressure is 300-680 mOsm/L based on extracellular fluid.

3. The peritoneal dialysis solution of claim 1 or 2, which contains amino acids, minerals, and vitamins.

4. The peritoneal dialysis solution of claim 1 or 2, which contains an amino acid selected from the group consisting of L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, L-proline and L-carnitine, and at least 6 of the group consisting of L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine and L-arginine, and the total concentration of these amino acids is 0.4 to 5.0W/V%.

5. The peritoneal dialysis solution of claim 3, which contains amino acids selected from the group consisting of L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, L-proline, and L-carnitine, and contains at least 6 of L-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, and L-arginine, and the total concentration of these amino acids is 0.4 to 5.0W/V%.

6. The peritoneal dialysis solution according to claim 1 or 2, characterized by containing 3 or more of iron ions, copper ions, calcium ions, magnesium ions, zinc ions, chromium ions, selenium ions, and manganese ions as minerals.

7. The peritoneal dialysis solution of claim 3, which contains 3 or more of iron ions, copper ions, calcium ions, magnesium ions, zinc ions, chromium ions, selenium ions, and manganese ions as minerals.

8. The peritoneal dialysis solution of claim 4, which contains 3 or more of iron ions, copper ions, calcium ions, magnesium ions, zinc ions, chromium ions, selenium ions, and manganese ions as minerals.

9. The peritoneal dialysis solution of claim 5, which contains 3 or more of iron ions, copper ions, calcium ions, magnesium ions, zinc ions, chromium ions, selenium ions, and manganese ions as minerals.

10. The peritoneal dialysis solution of claim 1 or 2, which contains at least 4 of vitamin a, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, and derivatives thereof, as vitamins, and the total amount thereof is 10 to 40 mg.

11. The peritoneal dialysis solution of claim 3, which contains at least 4 of vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, and derivatives thereof, and the like, as vitamins, and the total amount thereof is 10 to 40 mg.

12. The peritoneal dialysis solution of claim 4, which contains at least 4 of vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, and derivatives thereof, and the like, as vitamins, and the total amount thereof is 10 to 40 mg.

13. The peritoneal dialysis solution of claim 5, which contains at least 4 of vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, and derivatives thereof, and the like, as vitamins, and the total amount thereof is 10 to 40 mg.

14. The peritoneal dialysis solution of claim 6, which comprises at least 4 vitamins selected from vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, and vitamin C or derivatives thereof, and the total amount of these vitamins is 10 to 40 mg.

15. The peritoneal dialysis solution of claim 7, which contains at least 4 of vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, or derivatives thereof, as vitamins, and the total amount thereof is 10 to 40 mg.

16. The peritoneal dialysis solution of claim 8, which comprises at least 4 vitamins selected from vitamin A, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, and vitamin C or derivatives thereof, and the total amount of these vitamins is 10-40 mg.

17. The peritoneal dialysis solution of claim 9, which contains at least 4 of vitamin a, vitamin D3, vitamin E, vitamin B1, vitamin B2, niacin, vitamin B6 and derivatives thereof, folic acid, vitamin B12, pantothenic acid, vitamin C, and derivatives thereof, and the like, as vitamins, and the total amount thereof is 10 to 40 mg.

18. The peritoneal dialysis solution of claim 1 or 2, wherein bicarbonate is included as an alkalizer, and the pH at the time of use is adjusted to 6.5 to 7.5.

19. The peritoneal dialysis solution of claim 3, which contains bicarbonate as an alkalizer and has a pH adjusted to 6.5-7.5 in use.

20. The peritoneal dialysis solution of claim 4, which contains bicarbonate as an alkalizing agent and has a pH adjusted to 6.5-7.5 in use.

21. The peritoneal dialysis solution of claim 5, which contains bicarbonate as an alkalizer and has a pH adjusted to 6.5-7.5 in use.

22. The peritoneal dialysis solution of claim 6, which contains bicarbonate as an alkalizer and has a pH adjusted to 6.5-7.5 in use.

23. The peritoneal dialysis solution of claim 7, which contains bicarbonate as an alkalizing agent and has a pH adjusted to 6.5-7.5 in use.

24. The peritoneal dialysis solution of claim 8, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5-7.5 in use.

25. The peritoneal dialysis solution of claim 9, which contains bicarbonate as an alkalizing agent and has a pH adjusted to 6.5-7.5 in use.

26. The peritoneal dialysis solution of claim 10, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5 to 7.5 in use.

27. The peritoneal dialysis solution of claim 11, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5 to 7.5 in use.

28. The peritoneal dialysis solution of claim 12, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5 to 7.5 in use.

29. The peritoneal dialysis solution of claim 13, wherein bicarbonate is included as an alkalizer and the pH is adjusted to 6.5 to 7.5 in use.

30. The peritoneal dialysis solution of claim 14, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5 to 7.5 in use.

31. The peritoneal dialysis solution of claim 15, wherein bicarbonate is included as an alkalizer, and the pH is adjusted to 6.5 to 7.5 in use.

32. The peritoneal dialysis solution of claim 16, wherein bicarbonate is included as an alkalizing agent and the pH is adjusted to 6.5 to 7.5 in use.

33. The peritoneal dialysis solution of claim 17, wherein bicarbonate is included as an alkalizer and the pH is adjusted to 6.5 to 7.5 in use.