阅读说明：本技术 含有d-阿洛糖和/或d-阿洛酮糖而成的腹膜透析液的渗透压调节剂 (Osmotic pressure regulator for peritoneal dialysis solution containing D-allose and/or D-psicose ) 是由 南野哲男 尾崎太郎 吉原明秀 何森健 于 2020-03-10 设计创作，主要内容包括：本发明要解决的技术问题在于：提供仅通过配合,即使用于长期治疗也能够抑制血糖值上升,还能够抑制感染症的经过改良的含有葡萄糖的腹膜透析液、眼科用组合物或输液剂。本发明的构成如下：一种渗透压调节剂,其特征在于,在含有D-葡萄糖的渗透压调节剂中,作为用于抑制由于葡萄糖向体内的持续吸收所引起的血糖值上升、并且用于抑制感染症的添加剂,配合有D-阿洛糖和/或D-阿洛酮糖；配合在腹膜透析液、眼科用组合物或输液剂中使用；一种腹膜透析法,其特征在于,使用含有D-阿洛糖和/或D-阿洛酮糖的有效量的透析液,抑制由于因腹膜透析导致的葡萄糖向体内的持续吸收所引起的血糖值上升,并且抑制感染症。(The technical problem to be solved by the invention is as follows: provided is an improved glucose-containing peritoneal dialysis solution, ophthalmic composition or infusion solution which can suppress an increase in blood glucose level even in long-term treatment and can suppress infection by simply blending. The invention comprises the following components: an osmotic pressure regulator containing D-glucose, characterized in that D-allose and/or D-psicose are blended as an additive for inhibiting the increase in blood glucose level due to the sustained absorption of glucose into the body and for inhibiting infection; used in peritoneal dialysis solution, ophthalmic composition or infusion solution; a peritoneal dialysis method characterized by using an effective amount of a dialysis solution containing D-allose and/or D-psicose to suppress an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis and to suppress infection.)

1. An osmotic pressure regulator, characterized in that,

in the osmotic pressure regulator containing D-glucose,

additives for suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body and/or for suppressing an infectious disease are blended.

2. The osmotic pressure regulating agent according to claim 1, wherein,

the additive is a rare sugar which is D-allose and/or D-psicose.

3. The osmotic pressure regulating agent according to claim 1 or 2, wherein,

it can be used in peritoneal dialysis solution, ophthalmic composition or infusion solution.

4. A peritoneal dialysis solution, an ophthalmic composition or an infusion solution, characterized in that,

comprising the osmotic pressure regulator according to any one of claims 1 to 3,

inhibit the increase of blood glucose level due to the continuous absorption of glucose into the body, and/or inhibit infection.

5. The peritoneal dialysis solution, ophthalmic composition, or infusion solution of claim 4,

also contains D-glucose and electrolyte.

6. The peritoneal dialysis solution, ophthalmic composition, or infusion solution of claim 5,

the concentration of the D-glucose is 1000-4500 mg/dl.

7. The peritoneal dialysis solution, ophthalmic composition, or infusion solution of claim 6,

the concentration of D-allose and/or D-psicose in the peritoneal dialysis solution is 0.1 wt% or more relative to D-glucose.

8. A peritoneal dialysis fluid, an ophthalmic composition, or an infusion solution according to any one of claims 4 to 7,

the total content of saccharides is 0.1-10 wt%.

9. A method for regulating osmotic pressure, wherein,

comprises a step of administering D-allose and/or D-psicose to a patient in need of osmotic pressure regulation, and suppresses increase in blood glucose level due to continuous absorption of glucose into the body and/or infection in the patient.

10. Use of an osmotic pressure regulator according to any of claims 1 to 3 for the manufacture of a peritoneal dialysis solution, an ophthalmic composition or an infusion solution,

the peritoneal dialysis solution, ophthalmic composition or infusion solution suppresses an increase in blood glucose level due to continuous absorption of glucose into the body and/or suppresses an infection.

Use of D-allose and/or D-psicose for the manufacture of a peritoneal dialysis solution, an ophthalmic composition or an infusion solution, wherein,

the peritoneal dialysis solution, ophthalmic composition or infusion solution is an electrolyte solution that is close to the composition of extracellular fluid, and suppresses an increase in blood glucose level due to continuous absorption of glucose into the body and/or suppresses an infection.

12. The use according to claim 10 or 11,

also contains D-glucose and electrolyte.

13. A peritoneal dialysis method characterized by comprising the steps of,

using an effective amount of a dialysate containing D-allose and/or D-psicose,

inhibit the increase of blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis, and/or inhibit infection.

14. The peritoneal dialysis method of claim 13,

into the peritoneum of a renal disease patient having a catheter implanted in the abdominal cavity, an effective amount of dialysate containing D-allose and/or D-psicose is infused through the catheter.

15. The peritoneal dialysis method of claim 13 or 14,

the concentration of D-allose and/or D-psicose in the dialysate is 0.1 wt% or more of D-glucose.

16. The peritoneal dialysis method of any one of claims 13-15,

the dialysate also contains D-glucose and electrolytes.

17. The peritoneal dialysis method of claim 16,

the concentration of the D-glucose is 1000-4500 mg/dl.

18. The peritoneal dialysis method of claim 17,

to the peritoneum of a renal disease patient in which a catheter is implanted into the abdominal cavity, a dialysate containing D-glucose at a physiological concentration and an effective amount of D-allose and/or D-psicose is injected via the catheter, followed by a dialysate containing D-glucose at a high concentration.

19. The peritoneal dialysis method of claim 18,

the physiological concentration of D-glucose is 0.08-0.16 wt%, and the high concentration of D-glucose is 1000-4500 mg/dl.

Technical Field

The invention relates to an osmotic pressure regulator of peritoneal dialysis solution. More specifically, the present invention relates to an osmotic pressure regulator containing D-allose and/or D-psicose, a method for regulating osmotic pressure, a peritoneal dialysis solution containing the regulator, and uses of the regulator for producing the same.

Background

As one of the effective therapies for patients with renal failure, peritoneal dialysis is known. Peritoneal dialysis is performed by storing a dialysis solution in an abdominal cavity for a certain period of time, transferring wastes in the body into the dialysis solution through the peritoneal membrane, and discarding them to the outside of the body. In order to remove water from the body, the peritoneal dialysis solution needs to be applied with an osmotic pressure higher than that of blood. Therefore, D-glucose (glucose) is now blended as an osmotic agent in peritoneal dialysis solutions commercially available from various companies.

However, when glucose is blended as an osmotic pressure agent, there are various problems caused by this. For example, there are problems associated with pH adjustment of the dialysate. In the conventional peritoneal dialysis solutions, it is necessary to adjust the dialysis solution to the acidic side because the decomposition of glucose in the dialysis solution is suppressed and the stability is maintained during autoclaving, but the method of making the solution frequently injected into the abdominal cavity acidic is not preferable because of the irritation to the abdominal cavity or the skin cells in the peritoneal cavity. In the method of neutralizing a solution by adding baking soda, it is necessary to overcome problems such as destruction of the electrolyte balance and increase of the possibility of bacterial infection.

Further, Glucose Degradation Products (GDP) increase due to the sterilization treatment of the dialysate, or glucose reacts with amino acids during storage of the dialysate to generate highly reactive compounds called advanced glycation end-products (AGEs). These compounds promote intermolecular crosslinking of proteins, and therefore, when the dialysate is used for a long period of time, peritoneal membrane deterioration such as peritoneal membrane sclerosis, thickening, and peritoneal sclerosis becomes a problem.

In order to solve this problem, patent document 1 discloses a glucose-containing peritoneal dialysis solution to which a reducing agent or an antioxidant (sodium or potassium salt of thiosulfuric acid or dithionous acid) is added as a substance for suppressing the crosslinking reaction of proteins or dissociation of binding.

In addition, there are problems associated with the absorption of glucose into the patient. In the case of a conventional glucose-containing dialysate, a large amount of glucose is absorbed into the body even if additives or the like are added to suppress the crosslinking reaction of proteins. As described above, in peritoneal dialysis, in order to remove excess water contained in body fluid, the osmotic pressure difference between body fluid and dialysate is used, and therefore, it is necessary to maintain the osmotic pressure of the peritoneal dialysis dialysate higher than the osmotic pressure of plasma of a patient, and an osmotic pressure regulator, which is a solute for making the osmotic pressure hypertonic, is further added to the peritoneal dialysis dialysate.

As the osmotic pressure regulator, the ones mentioned above are knownD-glucose is then generally used. The solute contained in the dialysate for peritoneal dialysis as an osmotic pressure regulator is added to the old waste metabolites contained in the body fluid, typically Na⁺Ions, Cl^-Electrolytes such as ions and solutes such as urea and creatinine are diffused into the peritoneal dialysis solution through the peritoneal membrane by the same mechanism, and diffused into the body fluid through the peritoneal membrane.

As described above, when D-glucose is used as an osmotic pressure regulator of a dialysate for peritoneal dialysis, glucose is continuously absorbed into the body by peritoneal dialysis. Such high calorie intake of sugar by peritoneal dialysis is potentially dangerous in various aspects such as obesity, abnormal carbohydrate and lipid metabolism, progression of lode, problems of maintaining the blood system of a diabetic patient, and progression of complications.

In response to this problem, it has been proposed to use substances other than glucose as an osmotic pressure agent. For example, patent document 2 discloses trehalose as an osmotic agent. However, it has not been put to practical use for reasons such as insufficient confirmation of biological safety in long-term use. Further, a substance containing an aminosugar and L-ascorbic acid as an osmotic pressure agent has been proposed (patent document 3), but these substances may be decomposed during autoclaving or the like, or may react with other components to produce browning substances or the like, which causes a problem in the storage stability of the peritoneal dialysis solution, and therefore development of a peritoneal dialysis solution using an osmotic pressure agent having further excellent properties has been desired.

Documents of the prior art

Patent document

Patent document 1: japanese patent No. 4882054

Patent document 2: japanese patent No. 3589701

Patent document 3: japanese laid-open patent publication No. 11-71273

Patent document 4: japanese patent No. 5330976

Patent document 5: japanese patent No. 5317055

Patent document 6: japanese patent No. 5158779

Patent document 7: japanese patent No. 4943839

Patent document 8: japanese patent No. 4724824

Patent document 9: japanese patent laid-open publication No. 2009-269887

Patent document 10: japanese laid-open patent publication No. 2002-17392

Patent document 11: WO2004/063369

Patent document 12: WO2006/022239

Patent document 13: japanese patent No. 4609845

Patent document 14: japanese patent No. 5171249

Patent document 15: japanese patent No. 5633952

Patent document 16: japanese patent No. 4888937

Patent document 17: japanese patent No. 4473980

Patent document 18: japanese patent No. 5421512

Patent document 19: japanese patent No. 4648975

Patent document 20: japanese patent No. 5997693

Non-patent document

Non-patent document 1: J.Ferment.Bioeng. (1998) Vol.85, p.539-541

Non-patent document 2: asia Pac.J.Clin.Nutr (2001) Vol.10, p.233-237

Non-patent document 3: asia Pac.J.Clin.Nutr. (2004) Vol.13, S127

Non-patent document 4: biosci.Biotech.biochem. (1993) Vol.57, p.1037-1039

Disclosure of Invention

Technical problem to be solved by the invention

Peritoneal dialysis has the advantage of causing less influence on the circulatory system or the internal environment of the living body than hemodialysis. In comparison with hemodialysis, peritoneal dialysis has been widely used in recent years because it has advantages such as not requiring mechanical or human assistance, being able to be performed without going to a hospital, being able to stabilize the physical condition due to slow progress of dialysis, having no fatigue feeling due to hypotension or discomfort after dialysis, and having no time constraint like hemodialysis. In addition to such advantages as less influence on the circulatory system and the internal environment of the living body, there are also advantages such as less frequency of going to a hospital, capability of going at home or at a company, and less time for restraining the patient. Therefore, if membrane dialysis can be continued for a long period of time while deterioration of the peritoneum is suppressed and increase of the blood glucose level is suppressed, an irreducible benefit can be brought to a patient whose renal function has deteriorated or lost.

The present invention relates to a peritoneal dialysis solution that can be used for a long period of time without causing peritoneal disorders, and a peritoneal dialysis method using the same, that is, it is not proposed to use substances other than D-glucose as an osmotic pressure regulator of the peritoneal dialysis solution, but to provide an improvement in peritoneal dialysis solutions containing D-glucose and an osmotic pressure regulating method for suppressing the increase in blood glucose level due to the continuous absorption of glucose into the body of a patient who needs to regulate the osmotic pressure, further, the present invention provides a method for producing a peritoneal dialysis solution, which can be used alone by blending with a glucose-containing peritoneal dialysis solution currently commercially available from various companies, the peritoneal dialysis method can inhibit the improvement of a peritoneal dialysis solution containing glucose, which has an increased blood glucose level, and the increase in blood glucose level caused by the continuous absorption of glucose into the body by peritoneal dialysis, even when the peritoneal dialysis solution is used for a long-term treatment.

Complications of peritoneal dialysis include peritonitis, infection at the catheter outlet, and tunnel infection. The reasons are thought to be errors in exchange of dialysate (not keeping clean), infection from the outlet portion, breakage of the catheter or loosening of the connection portion, invasion of bacteria into the abdominal cavity from the patient's own intestinal tract, and the like. Infection impairs the peritoneum and reduces the function of the peritoneum, which can also lead to a reduction in the period during which peritoneal dialysis can be continued. The causative bacteria of infection are, at best, Staphylococcus aureus, and, secondly, Staphylococcus epidermidis. Daily care of patients and family members is required, and an effective countermeasure is not established.

Accordingly, an object of the present invention is to develop a peritoneal dialysis solution having an infection-suppressing function, and to provide a peritoneal dialysis solution having an infection-suppressing effect, thereby solving an important problem in peritoneal dialysis.

Technical solution for solving technical problem

The inventors of the present invention first focused on the function of the rare sugar D-allose. With respect to D-allose, it is known that: a pharmaceutical composition for treating a renal disease selected from the group consisting of acute renal failure and uremia, which contains the compound as an active ingredient (patent document 4); a drug for delaying the onset or progression of dyskinesia caused by amyotrophic lateral sclerosis (patent document 5); blood pressure increase inhibitors (patent document 6); a preparation characterized by being used for inhibiting angiogenesis (patent document 7); t lymphocyte proliferation inhibitor (patent document 8). In addition, it is also known that rare sugars have a peritoneal membrane deterioration inhibitory effect. It has been reported that a peritoneal membrane deterioration inhibitor containing a rare sugar selected from the group consisting of D-allulose, L-allulose, D-allose, L-sorbose, D-fructose, L-tagatose, D-sorbose, L-fructose and D-tagatose, and further containing D-glucose, used in combination with a peritoneal dialysis solution, can prevent peritoneal membrane disorders, and can also prevent cell disorders due to a high concentration of sugar, particularly peritoneal endothelial cell disorders (peritonitis, sclerosing cystic peritonitis, refractory persistent peritonitis, secondary peritonitis, etc.) (patent document 9). However, it has not been confirmed whether or not the increase in blood glucose level due to the absorption of D-glucose can be suppressed even if glucose absorption into the body is continued by peritoneal dialysis when D-allose is blended with D-glucose as an osmotic pressure regulator for peritoneal dialysis solution.

It is considered that if D-glucose is blended as an osmotic pressure regulator of a peritoneal dialysis solution, both of peritoneal membrane deterioration such as peritoneal membrane sclerosis and hypertrophy, which are problems of long-term peritoneal dialysis caused by this and an increase in blood glucose level due to absorption of D-glucose, can be inhibited, long-term treatment can be performed only by peritoneal dialysis, and the present invention relating to D-allose has been achieved by attempting to use a rare sugar, because it is useful in terms of medical economy and improvement in "quality of life" (QOL) of patients.

Furthermore, the present invention related to D-psicose has been achieved by focusing attention on D-psicose known as a blood glucose lowering agent, an antidiabetic agent (patent document 13), a composition for suppressing an abnormal increase in plasma glucose concentration in the day (patent document 14), and a promoter for promoting the migration of glucokinase from the nucleus to the cytoplasm (patent document 15) which contain D-allulose as an active ingredient.

As for the use of rare sugars (D-allulose, D-allose) for inhibiting the growth of microorganisms, more specifically, the use and method of inhibiting the growth of harmful microorganisms as a microbe inhibitor against plant pathogenic bacteria and miscellaneous bacteria that cause adverse effects on food manufacturing processes, medical sites, living environments, air conditioning facilities, and the like have been reported (patent document 16). Therefore, it is considered that the present invention is useful for preventing bacterial infection by peritoneal dialysis, and the present invention related to D-allose and the like has been achieved by attempting to use a rare sugar.

The gist of the present invention resides in the following osmotic pressure controlling agents for peritoneal dialysis solutions (1) to (3).

(1) An osmotic pressure regulator, characterized in that, in an osmotic pressure regulator containing D-glucose,

additives for suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body and/or for suppressing an infectious disease are blended.

(2) The osmotic pressure regulator according to the above (1), wherein the additive is a rare sugar which is D-allose and/or D-psicose.

(3) The osmotic pressure regulator according to (1) or (2), wherein the osmotic pressure regulator is used in combination with a peritoneal dialysis solution, an ophthalmic composition or an infusion solution.

The present invention also resides in peritoneal dialysis solutions, ophthalmic compositions, or infusion solutions of the following (4) to (8).

(4) A peritoneal dialysis solution, an ophthalmic composition or an infusion solution, which comprises the osmotic pressure regulator according to any one of (1) to (3) above, and which is characterized by inhibiting an increase in blood glucose level due to the sustained absorption of glucose into the body and/or inhibiting an infectious disease.

(5) The peritoneal dialysis solution, ophthalmic composition or infusion solution according to (4) above, which further comprises D-glucose and an electrolyte.

(6) The peritoneal dialysis solution, ophthalmic composition, or infusion solution according to (5) above, wherein the D-glucose concentration is 1000 to 4500 mg/dl.

(7) The peritoneal dialysis solution, ophthalmic composition, or infusion solution according to (6) above, wherein the concentration of D-allose and/or D-psicose in the peritoneal dialysis solution is 0.1% by weight or more relative to D-glucose.

(8) The peritoneal dialysis solution, ophthalmic composition, or infusion solution according to any one of the above (4) to (7), wherein the saccharide is contained at a concentration of 0.1 to 10 wt% in the whole.

The gist of the present invention is also an osmotic pressure adjusting method described in the following (9).

(9) A method for regulating osmotic pressure, which comprises a step of administering D-allose and/or D-psicose to a patient in need of osmotic pressure regulation, and which inhibits an increase in blood glucose level and/or an infection of the patient due to the sustained absorption of glucose into the body.

The gist of the present invention is also the following applications (10) to (12).

(10) Use of the osmotic pressure regulator according to any one of (1) to (3) above for producing a peritoneal dialysis solution, an ophthalmic composition or an infusion solution for inhibiting an increase in blood glucose level due to continuous absorption of glucose into the body and/or inhibiting an infectious disease.

(11) Use of D-allose and/or D-psicose for the manufacture of a peritoneal dialysis solution, an ophthalmic composition or an infusion solution, wherein the peritoneal dialysis solution, the ophthalmic composition or the infusion solution is an electrolyte solution that is close to the composition of an extracellular fluid and suppresses an increase in blood glucose level due to the continuous absorption of glucose into the body and/or suppresses an infection.

(12) The use according to (10) or (11) above, which further comprises D-glucose and an electrolyte.

The gist of the present invention is also the peritoneal dialysis methods (13) to (19) below.

(13) A peritoneal dialysis method characterized by using an effective amount of a dialysis solution containing D-allose and/or D-psicose to suppress an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis and/or to suppress an infection.

(14) The peritoneal dialysis method according to (13) above, wherein the peritoneal membrane of the patient with renal disease, to which a catheter has been implanted in the peritoneal cavity, is infused with an effective amount of a dialysate containing D-allose and/or D-psicose via the catheter.

(15) The peritoneal dialysis method according to (13) or (14) above, wherein the concentration of D-allose and/or D-psicose in the dialysate is 0.1% by weight or more of D-glucose.

(16) The peritoneal dialysis method according to any one of (13) to (15) above, wherein the dialysate further contains D-glucose and electrolytes.

(17) The peritoneal dialysis method according to (16) above, wherein the D-glucose concentration is 1000 to 4500 mg/dl.

(18) The peritoneal dialysis method according to (17) above, wherein the peritoneal membrane of the patient with renal disease in which a catheter is implanted into the peritoneal cavity is infused with a dialysate containing D-glucose at a physiological concentration and an effective amount of D-allose and/or D-psicose via the catheter, and then the dialysate containing D-glucose at a high concentration is infused.

(19) The peritoneal dialysis method according to (18) above, wherein the physiological concentration of D-glucose is 0.08 to 0.16% by weight, and the high concentration of D-glucose is 1000 to 4500 mg/dl.

ADVANTAGEOUS EFFECTS OF INVENTION

The osmotic pressure regulator of the present invention has excellent biocompatibility and no problem in safety, and exhibits an effect that it can be used even for patients with diabetes or the like, such as preventing an increase in blood glucose level and/or inhibiting infection. Further, since the osmotic pressure regulator of the present invention is a stable substance without reacting with or decomposing into other components, a peritoneal dialysis solution, an ophthalmic composition or an infusion solution containing the regulator can be in a form that does not require a pharmaceutical measure such as blending with other components immediately before use.

Therefore, according to the present invention, there is an effect of improving a peritoneal dialysis solution containing D-glucose, which can suppress an increase in blood glucose level and/or can suppress infection, even when the peritoneal dialysis solution is used for a long-term treatment, only by blending the peritoneal dialysis solution with a glucose-containing peritoneal dialysis solution currently commercially available from a plurality of companies. Further, it is possible to provide a peritoneal dialysis solution, an ophthalmic composition or an infusion solution which can suppress an increase in blood glucose level due to the continuous absorption of glucose into the body and/or can suppress infection.

Further, it is possible to provide an osmotic pressure regulating method for inhibiting an increase in blood glucose level due to the continuous absorption of glucose into the body of a patient who needs to regulate osmotic pressure and/or inhibiting an infection. Further, it is possible to provide a peritoneal dialysis method for suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis and/or suppressing an infection. Since it is important to suppress infection in peritoneal dialysis as well as to suppress an increase in blood glucose level, the present invention can provide a peritoneal dialysis solution having an infection suppression effect, and can solve an important problem in peritoneal dialysis.

Drawings

FIG. 1 is a diagram illustrating an experimental method of a normal rat model of test example 1 (using D-allose).

FIG. 2 is a graph showing the change in blood glucose level when peritoneal dialysis solution is administered intraperitoneally in the normal rat model in test example 1. The unit on the Y, X axis is that Y is mg/dl and X is min (min).

Fig. 3 is a graph in which AUC (area under the blood concentration-time curve) of each group is plotted based on the results of fig. 2.

FIG. 4 is a diagram showing an experimental method of a diabetic model rat in test example 1.

FIG. 5 is a graph showing the change in blood glucose level when peritoneal dialysis solution was administered intraperitoneally to a diabetic model rat in test example 1. The unit on the Y, X axis is that Y is mg/dl and X is h (time).

Fig. 6 is a graph in which AUC (area under the blood concentration-time curve) of each group is plotted based on the results of fig. 5.

FIG. 7 is a diagram illustrating an experimental method of a normal rat model of test example 2 (using D-allose).

Fig. 8 is a graph (left side) showing changes in blood glucose values when peritoneal dialysis solution is administered intraperitoneally in the normal rat model in test example 2, and a graph (right side) showing AUC (area under the blood concentration-time curve) of each group based on the results.

FIG. 9 is a diagram showing an experimental method of a diabetic model rat in test example 2.

Fig. 10 is a graph (left side) showing changes in blood glucose values when peritoneal dialysis solutions were administered intraperitoneally to diabetic model rats in test example 2, and a graph (right side) showing AUC (area under the blood concentration-time curve) of each group based on the results.

FIG. 11 is a diagram illustrating an experimental method of a normal rat model of test example 3 (using D-psicose).

Fig. 12 is a graph (left side) showing changes in blood glucose values when peritoneal dialysis solutions were administered intraperitoneally in the normal rat model in test example 3 (using D-psicose), and a graph (right side) plotting AUC (area under the blood concentration-time curve) of each group based on the results.

Detailed Description

[ additive for inhibiting increase in blood glucose level due to continuous absorption of glucose into the body, and/or additive for inhibiting infectious diseases ]

When glucose is blended as an osmotic pressure agent, there are various problems caused by this. One of them is the problem associated with the absorption of glucose into the body of the patient. The osmotic pressure regulator of the present invention is used in combination with a peritoneal dialysis solution, an ophthalmic composition or an infusion solution, and the following description will be given by taking a peritoneal dialysis solution as an example. When D-glucose is used as an osmotic pressure regulator in peritoneal dialysis solution, glucose is continuously absorbed into the body by peritoneal dialysis. Such high calorie intake of sugar by peritoneal dialysis is potentially dangerous in various aspects such as obesity, abnormal carbohydrate and lipid metabolism, progression of lode, maintenance of the blood system of a diabetic patient, and progression of complications.

In order to solve this problem, it has been proposed to use substances other than glucose as an osmotic pressure agent, but in the present invention, an additive is used for suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis. The additive can inhibit blood sugar increase and infection of peritoneal dialysis. Inhibition of infection by peritoneal dialysis is also important as inhibition of blood glucose level elevation. The present invention can provide a peritoneal dialysis solution having an infection-inhibiting effect, and can solve the problems of inhibiting the increase in blood glucose level due to the continuous absorption of glucose into the body and/or inhibiting infection, which are important problems in peritoneal dialysis.

[ D-allose ]

The additive is D-allose which is a rare sugar used as an osmotic pressure regulator. D-allose may be a derivative thereof, or a salt thereof. Hereinafter, the term "D-allose" may be abbreviated as "D-allose".

D-allose is a rare sugar which has been confirmed to have various physiological activities in particular in rare sugar studies. The rare sugar is defined as a monosaccharide or a sugar alcohol which is present only in a trace amount in nature. The monosaccharides abundantly present in nature include 7 kinds of monosaccharides, i.e., D-glucose, D-fructose, D-galactose, D-mannose, D-ribose, D-xylose, and L-arabinose, and the others are rare sugars. Sugar alcohols are obtained by reducing monosaccharides, but since D-sorbitol is relatively abundant in nature and the amount of sugar alcohols other than D-sorbitol is small, these are considered to be rare sugars.

D-allose (D-allohexose) which is the subject of the present invention is a D-form of allose classified as aldose (aldohexose), is a six-carbon sugar having a melting point of 178 ℃, and is one of monosaccharides. Is represented by the chemical formula C₆H₁₂O₆The structure of the D-glucose is slightly different from that of D-glucose, i.e., the shape of the sugar. In addition, many molecules of substances that are the basis of life, such as amino acids and sugars, have "mirror image isomers". It has the same relationship as the right hand and the left hand of a person, and has a symmetrical structure. Most of the saccharides existing in nature are D-form, and are now high inAllose in form D is efficiently produced and studied, and therefore D is mostly omitted for convenience as allose.

D-allose derivatives are illustrated. A compound in which a molecular structure is changed by a chemical reaction from a certain starting compound is referred to as a derivative of the starting compound. As derivatives of six-carbon sugars including D-allose, sugar alcohols (polyols having the same number of carbon atoms as that of aldehyde groups and ketone groups when monosaccharides are reduced to alcohol groups), uronic acids (products obtained by oxidizing alcohol groups of monosaccharides, and known as D-glucuronic acid, galacturonic acid, and mannuronic acid) and aminosugars (compounds obtained by oxidizing OH groups of sugar molecules with NH) are widespread₂Examples of the substituent include glucosamine, chondrosamine, and glycoside), but the present invention is not limited thereto.

When the rare sugar or a derivative thereof is used in the form of a salt, an alkali metal salt such as a sodium salt, an alkaline earth metal salt such as a magnesium salt or a calcium salt, or the like is preferable.

As the method for producing D-allose, there are a method of reducing D-allose lactone with sodium amalgam and a method of synthesizing D-allose from D-allose using L-rhamnose isomerase as described in non-patent document 1 of Shakhawat Hossain Bhuiyan et al. In recent years, patent document 10 discloses a process for producing D-allose from D-allulose by allowing D-xylose isomerase to act on a solution containing D-allulose. According to the production method described in this publication, when D-allose is produced, the enzyme reaction mixture is obtained so as to contain newly produced D-allose together with unreacted D-allose.

Recently, regarding enzymes used for converting a substrate convertible to D-allose into D-allose by an enzymatic reaction, patent document 11 uses an enzyme derived from Pseudomonas stutzeri LL172(IPOD FERM BP-08593) as an enzyme capable of producing D-allose from D-allose, and patent document 12 uses an L-rhamnose isomerase derived from Bacillus pallidus strain 14a (IPOD FERM BP-20172). For example, D-allose can be efficiently obtained as a solution containing D-allose by using a substrate-containing solution as a raw material and performing an enzymatic reaction at 60 to 80 ℃ by using a protein having L-rhamnose isomerase activity derived from Bacillus pallidus strain 14a (IPOD FERM BP-20172). Further, D-allose can be separated and recovered from the solution containing D-allose, and the above reaction can be continuously performed.

D-allose and/or its derivatives can be used. D-allose is a monosaccharide feedstock that can be stably obtained. The monosaccharide is a monosaccharide that is naturally derived and widely used as a food or an edible material, and therefore is safe to the human body. Examples of the method for directly administering D-allose into the abdominal cavity include a method of mixing a peritoneal dialysis solution and administering the solution into the abdominal cavity during peritoneal dialysis, and a method of directly administering D-allose in liquid form into the abdominal cavity via a catheter for peritoneal dialysis.

[ D-psicose ]

The additive is D-psicose which is a rare sugar used as an osmotic pressure regulator. The D-psicose may be a derivative thereof, or a salt thereof. Hereinafter, the term "D-allose" may be abbreviated as "D-allose".

Recently, a mass production technique of D-allulose (D-psicose) which becomes a base material capable of producing all rare sugars (monosaccharides present only in a trace amount in nature) has been established, and production of rare sugars which are originally difficult to obtain has been achieved. D-psicose (D-allulose), also known as D-allulose (D-psicose), is an epimer of D-fructose, has approximately 70% of the sweetness of granulated sugar, and is similar to D-fructose in terms of sweetness quality. However, it is known that D-psicose, unlike D-fructose, is hardly metabolized when absorbed in the body and has almost zero calorie, and has a function of reducing abdominal fat by inhibiting the activity of lipid synthase. D-psicose has been reported to be useful as a low-calorie sweetener (patent document 17) or as a sweetener effective for weight reduction (non-patent documents 2 and 3), and patent document 18 discloses a low-calorie sweetener, a diet for diabetic patients, a diet for reducing weight, and the like, focusing on the blood sugar increase-suppressing effect of D-psicose.

For derivatives of D-psicoseAnd (6) explaining. A compound in which a molecular structure is changed by a chemical reaction from a certain starting compound is referred to as a derivative of the starting compound. As derivatives of six-carbon sugars including D-psicose, sugar alcohols (in the case of reducing a monosaccharide, an alcohol group is formed by changing an aldehyde group and a ketone group into an alcohol group, and a polyhydric alcohol having the same number of carbon atoms) and uronic acids (substances obtained by oxidizing an alcohol group of a monosaccharide, and D-glucuronic acid, galacturonic acid, and mannuronic acid are known naturally), amino sugars (an OH group of a sugar molecule is replaced by NH)₂Examples of the substituent include glucosamine, chondrosamine, and glycoside), but the present invention is not limited thereto.

When the rare sugar or a derivative thereof is used in the form of a salt, an alkali metal salt such as a sodium salt, an alkaline earth metal salt such as a magnesium salt or a calcium salt, or the like is preferable.

As a method for producing D-psicose, a method using isomerase has been used for producing a rare sugar containing D-psicose, and this is a result of finding a useful enzyme reaction. A ketose 3-epimerase that is one of these isomerases can use a plurality of ketoses as a substrate, and sometimes, ketoses having the highest epimerization activity at the 3-position among ketoses that are substrates are named, and for example, an enzyme having the highest epimerization activity at the 3-position of D-tagatose is called D-tagatose 3-epimerase. A technique for producing D-psicose, which is a rare sugar, from D-fructose by using the D-tagatose 3-epimerase (DTE) has been established.

For example, non-patent document 4 discloses a D-ketose 3-epimerase derived from Pseudomonas cichorii (Pseudomonas cichorii) ST-24 strain, and describes that D-psicose can be produced from D-fructose by using the enzyme. Further, patent document 19 reports a method for producing D-allulose (D-psicose) using D-allulose 3-epimerase derived from Agrobacterium tumefaciens (Agrobacterium tumefaciens), and patent document 20 reports a method for producing D-psicose using ketose 3-epimerase derived from Arthrobacter globiformis (Arthrobacter globiformis).

[ osmotic pressure controlling agent for peritoneal dialysis solution ]

The invention is characterized in that D-glucose and D-allose and/or D-psicose are used as osmolytes. In the present specification, the term "osmotic pressure regulation" means that a desired osmotic pressure is regulated or maintained.

The osmotic pressure is proportional to the solute molarity of the solution, and since D-glucose and D-allose and/or D-psicose are monosaccharides and represent the same degree of osmotic pressure at the same amount of use, the osmotic pressure regulating effect is not changed by the mixing ratio.

D-allose is absorbed into the body together with D-glucose, but has been confirmed to have an effect of suppressing the increase in blood glucose level or neutral fat level in blood, for example, in postprandial hyperglycemia, postprandial hyperlipidemia, and the like due to D-glucose. D-psicose was also found to have the same effect as D-psicose.

Since the 1 st disease of dialysis-induced disease in recent years is diabetic nephropathy and the number thereof tends to increase year by year, a dialysate capable of controlling blood glucose is desired. Since a dialysate containing glucose raises the blood glucose level and causes disorders such as abnormal lipid metabolism, it cannot be used for patients with diseases requiring blood glucose control, such as diabetic nephropathy. However, it is suggested that a dialysate containing D-glucose and D-allose and/or D-psicose is useful as a dialysate capable of controlling blood glucose because it exerts the above-mentioned effects. The invention therefore also provides mixtures of D-glucose and D-allose and/or D-psicose for regulating the osmotic pressure.

The osmotic pressure regulator of the present invention is preferably in a liquid state, i.e., a state of being dissolved in a liquid. This enables efficient transfer of the peritoneal dialysis solution containing the osmotic pressure regulator of the present invention into the peritoneal tissue (target site). Examples of the liquid in which the osmotic pressure regulator is dissolved include a drug solution (e.g., isotonic solutions such as physiological saline, Locke solution, Ringer solution, Tyrode solution, Earle solution, Krebs solution, Dulbecco solution, PBS, etc., peritoneal dialysis solution, peritoneal rinse solution, etc.), water (e.g., pure water, distilled water, sterilized water, etc.), and the like.

The tonicity modifier may be dissolved in a liquid upon administration to a patient. That is, the form of the dialysate is not particularly limited, and is a known form such as a one-dose form, a two-dose form, and the like, because D-allose and/or D-psicose are stable monosaccharides like D-glucose, and do not react with other components or are decomposed due to liquidity, and therefore, there is no need for a pharmaceutical measure such that D-allose and/or D-psicose are mixed with other components immediately before use.

Examples of the method for directly administering D-allose and/or D-psicose into the abdominal cavity include a method of mixing D-allose and/or D-psicose into a peritoneal dialysis solution and administering D-allose into the abdominal cavity during peritoneal dialysis, and a method of directly administering D-allose and/or D-psicose in a liquid form into the abdominal cavity via a catheter for peritoneal dialysis. When D-allose is dissolved in an isotonic solution such as Ringer's solution, the load on the living tissue can be minimized because the osmotic pressure of the isotonic solution is close to that of the living body. In addition, when D-allose and/or D-psicose are dissolved in the peritoneal dialysis solution, they can be administered to a patient simultaneously with the peritoneal dialysis. In addition, the D-allose and/or D-psicose of the present invention can be provided in the form of a drug (powder, liquid, etc.) in a form to be mixed and injected into the peritoneal dialysis solution, for example, in the case of peritoneal dialysis.

[ peritoneal dialysis solution containing glucose ]

The dialysate used for peritoneal dialysis differs in details depending on the method of peritoneal dialysis such as CAPD (continuous movable peritoneal dialysis) and IPD (intermittent peritoneal dialysis), but basically similarly contains Na⁺Ion, Ca²⁺Ions, Mg²⁺Ions, Cl^-Electrolytes represented by ions and the like, alkalinizing agents centered on lactate, acetate and the like, and osmotic pressure regulators represented by D-glucose.

The composition of the peritoneal dialysis solution containing D-glucose is not particularly limited, and a generally known composition can be used.

[ D-psicose and/or D-psicose added to peritoneal dialysis solution containing glucose ]

Peritoneal dialysis solution is a solution stored in the abdominal cavity and having a high osmotic pressure, and is intended to remove solutes such as excess water and waste in the body. In the peritoneal dialysis solution of the present invention, D-allose and/or D-psicose is added to the peritoneal dialysis solution in order to prevent the peritoneal dialysis solution from being disturbed and to suppress the increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis.

In the peritoneal dialysis solution of the present invention, the mixing method is not limited, and for example, D-allose and/or D-psicose may be mixed at a concentration of 100. mu.g to 10mg/ml or 0.5 to 50mOsm/L at the time of mixing the two solutions immediately before use, or may be mixed in advance in one solution. The peritoneal dialysis solution can be used in which the concentration of D-psicose and/or a derivative thereof, or a salt thereof, and/or D-psicose and/or a derivative thereof, or a salt thereof in the peritoneal dialysis solution is 0.1 wt% or more relative to D-glucose.

[ peritoneal dialysis solution containing glucose and D-allose and/or D-psicose ]

The osmotic pressure regulator of the present invention has excellent biocompatibility, is safe, and does not increase the blood glucose level, and therefore the present invention also provides a peritoneal dialysis solution containing the osmotic pressure regulator of the present invention.

If the peritoneal dialysis solution of the present invention contains D-allose and/or D-psicose, it can be prepared according to a known method of a peritoneal dialysis solution containing glucose. The obtained peritoneal dialysis solution needs to be sterilized, and D-allose and/or D-psicose are stable even at high temperature, and thus any method of heat sterilization or filtration sterilization can be used.

The osmotic pressure of the peritoneal dialysis solution is preferably 300-700 mOsm/L, and more preferably 300-500 mOsm/L. In the present specification, the osmotic pressure can be measured using a known osmometer (for example, model MARK3 manufactured by FISK).

The pH (25 ℃) of the peritoneal dialysis solution is preferably 3 to 9, more preferably 5 to 8, still more preferably 6 to 8, and most preferably 6.8 to 7.5.

The amount of the active ingredient contained in the peritoneal dialysis solution containing D-glucose is not particularly limited. In the peritoneal dialysis solution of the present invention, D-allose andand/or a derivative thereof, or a salt thereof, and/or D-psicose and/or a derivative thereof, or a salt thereof, and further contains D-glucose and an electrolyte. The composition of the peritoneal dialysis solution containing D-glucose is not particularly limited, and a commonly known composition, for example, a D-glucose-containing peritoneal dialysis solution having a D-glucose concentration of 1000 to 4500mg/dl can be used. That is, the D-glucose concentration is preferably 1000 to 4500mg/dl, and particularly preferably 1200 to 3600 mg/dl. In addition, Na may be used as the electrolyte⁺、Ca²⁺、Mg²⁺And Cl^-。Na⁺Preferably 100 to 200 milliequivalents (mEq/L) of Ca²⁺Preferably 4 to 5mEq/L, Mg²⁺Preferably 1 to 2mEq/L, Cl^-Preferably 80 to 120 mEq/L. In addition, preferably also contains lactic acid and other organic acid 30 ~ 50 mEq/L. Further, the osmotic pressure of the peritoneal dialysis solution is desirably adjusted to 300 to 700 milliosmol (mOsm/L). And the balance being water.

More specifically, for example, a dialysis solution (pH6.3 to 7.3) of 135mEq/L Na, 2.5mEq/L (or 4mEq/L) Ca, 0.5mEq/L Mg, 98mEq/L Cl, 40mEq/L lactic acid, or 2.5g/dl (or 1.35g/dl or 4g/dl) D-glucose can be used.

In the preparation, a solution (pH5.0) prepared by mixing D-glucose and sodium lactate, KCl and MgCl are mixed₂The sodium lactate solution (pH adjusted to pH9.0 with NaCl) is sterilized by high-pressure steam heating and then mixed at a ratio of 4: 1 just before use, but the method of mixing in the peritoneal dialysis solution of the present invention is not limited, and for example, D-allose and/or D-psicose may be mixed at a concentration of 100. mu.g to 10mg/ml or 0.5 to 50mOsm/L just before use when mixing the two solutions, or may be mixed in one solution. The peritoneal dialysis solution can be used in which the concentration of D-psicose and/or a derivative thereof, or a salt thereof, and/or D-psicose and/or a derivative thereof, or a salt thereof in the peritoneal dialysis solution is 0.1 wt% or more relative to D-glucose.

The glucose-containing peritoneal dialysis solution of the present invention is a known peritoneal dialysis solution containing electrolytes in addition to D-glucose, and as the peritoneal dialysis solution of the present invention, a dialysis solution prepared by combining the osmotic pressure regulating agent of the present invention with components contained in a known peritoneal dialysis solution and formulating the same can be mentioned. Specifically, cations such as sodium ion, calcium ion, potassium ion, and magnesium ion, and anions such as chloride ion and acetate ion may be combined as the electrolyte. In addition, as other components that can be used for the same purpose as D-glucose and D-psicose and/or D-psicose, there may be contained D-psicose and/or rare sugars other than D-psicose and sugars other than D-glucose.

Examples of the rare sugar other than D-allose and/or D-psicose include L-allulose, L-sorbose, D-fructose, L-tagatose, D-sorbose, L-fructose, and D-tagatose.

Examples of the saccharide other than the rare sugar and the D-glucose include monosaccharides such as galactose, mannose and fructose, disaccharides such as sucrose, maltose, lactose and trehalose, polysaccharides such as glycogen, maltooligosaccharide, isomaltooligosaccharide, oligo-glucose sucrose, fructo-oligosaccharide and galacto-oligosaccharide, and sugar alcohols such as maltitol, erythritol and xylitol.

[ D-glucose and D-allose and/or D-psicose concentrations of peritoneal dialysis solutions ]

The peritoneal dialysis solution can contain D-glucose and D-allose and/or D-psicose, a rare sugar other than D-allose and/or D-psicose, and a saccharide other than D-glucose. In this case, the concentration of the saccharide in the peritoneal dialysis solution is preferably about 0.1 to 10W/V% (weight volume percentage), and more preferably about 1 to 4.5W/V%. Furthermore, 1000 to 4500mg/dl is equivalent to 1 to 4W/V%. When the sugar concentration is within this range, if the amount of D-allose and/or D-psicose in the peritoneal dialysis solution is 0.1 wt% or more relative to D-glucose, an increase in blood glucose level due to continuous absorption of glucose into the body by peritoneal dialysis can be suppressed.

[ peritoneal dialysis method for inhibiting increase in blood glucose level due to continuous absorption of glucose into the body by peritoneal dialysis ]

The peritoneal dialysis solution containing an osmotic pressure regulating agent of the present invention is preferably administered directly into the abdominal cavity. When directly administered into the abdominal cavity, the peritoneal dialysis solution of the present invention can be selectively and efficiently delivered to the peritoneal tissue as the target site. Further, when the drug is administered directly into the abdominal cavity, the drug effect can be obtained effectively without using a special delivery method to deliver the peritoneal dialysis solution. Moreover, the loss of HGF (hepatocyte growth factor) until reaching the affected part after administration was very small. HGF is a regeneration factor responsible for controlling physiological functions necessary for the regeneration of many organs and tissues including the liver, the kidney, the lung, and the digestive tract. Further, when the peritoneal dialysis solution is administered directly into the abdominal cavity, since the peritoneal dialysis solution stays in the abdominal cavity for a certain period of time, it is less invasive to the patient and the dose of the peritoneal dialysis solution can be small. In addition, the influence on other organs and living tissues can be minimized.

The peritoneal dialysis solution of the present invention is not limited in use because it is not likely to cause disorders such as an increase in blood glucose level or abnormal lipid metabolism, and the amount thereof is not always set as appropriate depending on the purpose of use and the age, weight, or symptoms of the patient to whom the peritoneal dialysis solution is administered. The period of use is also arbitrary.

When the peritoneal dialysis solution is administered directly into the abdominal cavity, it is equivalent to direct administration to the affected part of the peritoneum, and there is no loss of the active ingredient until the affected part is reached after administration as in the case of oral or venous injection. Therefore, the concentration of the active ingredient of the present invention can be adjusted to the minimum optimum concentration effective in the peritoneum. That is, the drug can be directly administered to the affected part at the minimum concentration required, and has the characteristics of little side effect and the like.

The effective dose of the peritoneal dialysis solution is not particularly limited, and a dose of 10 to 10000mg, preferably 100 to 5000mg, per patient can be selected. The peritoneal dialysis solution of the present invention is used to cure or at least partially cure the symptoms of a subject patient. The peritoneal dialysis solution of the present invention can be used for therapeutic purposes after onset of symptoms, or can be used for prophylactic purposes for alleviation of symptoms at the onset of symptoms when the onset of symptoms can be predicted.

The present invention also provides a peritoneal dialysis solution characterized by containing D-allose and/or D-psicose, for suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis. When D-allose and/or D-psicose are contained in the peritoneal dialysis solution, the effect of suppressing the increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis is exerted. The peritoneal dialysis solution containing D-glucose contains D-allose and/or D-psicose in an amount disclosed in the present specification as an osmotic pressure regulator, thereby exhibiting an effect of inhibiting the increase in blood glucose level. It is not known at all that D-allose and/or D-psicose, which are used as an osmotic pressure regulator for peritoneal dialysis solutions in the present invention, have an effect of suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis.

The peritoneal dialysis solution of the present invention contains an effective amount of D-allose or a derivative or salt thereof, and/or D-psicose or a derivative or salt thereof. The concentration of D-allose and/or D-psicose or a salt thereof in the peritoneal dialysis solution is preferably 10 to 5000. mu.M, more preferably 50 to 3000. mu.M, and particularly preferably 50 to 2000. mu.M.

In this case, the concentration of D-allose and/or D-psicose in the peritoneal dialysis solution is 0.1% by weight or more relative to D-glucose. That is, it is effective that the concentration of D-allose and/or D-psicose in the peritoneal dialysis solution is 0.1% by weight or more of D-glucose, preferably 1% by weight or more of D-glucose, and more preferably 5% by weight or more. In addition, a high concentration may be considered as a concentration at which D-glucose is completely substituted.

The peritoneal dialysis solution of the present invention can be administered to a host (patient) in an effective amount for the purpose of prevention and/or prevention and treatment of renal failure diseases. The host to be administered is not particularly limited, and examples thereof include mammals, preferably humans, monkeys, mice, and livestock. The peritoneal dialysis solution of the present invention is not limited in the route of administration as long as the effect of the present invention is effectively exhibited in the affected part of the peritoneum, and is preferably administered intraperitoneally.

The peritoneal dialysis solution follows the usual peritoneal dialysis method. That is, a method of injecting a dialysate (usually 1.5 to 2.0L) containing D-allose and/or D-psicose and D-glucose into the peritoneum of a renal disease patient having a catheter implanted into the abdominal cavity via the catheter, or a method of injecting a physiological D-glucose-concentration solution containing D-allose and then injecting a conventional dialysate (for example, the above-mentioned high-concentration D-glucose solution) is performed, and the dialysate is stored for about 5 to 6 hours and drained. This operation is usually repeated 3 to 5 times for 1 day. Wherein the physiological concentration of the D-glucose is 0.08-0.16% (w/v).

[ exacerbation of diabetes by peritoneal dialysis ]

The description of the deterioration of diabetes by peritoneal dialysis is shown by the following data extracted from reference 1 (manual of peritoneal dialysis, department of medical science, china and foreign countries) and reference 2 (manual of PD, tokyo medical society).

50-69 years old male with low activity and 2100 kilocalories per 1 day

For sugar exposure:

(1) 1.5% D-glucose dialysate 15-22 g absorption

(2) 2.5% D-glucose dialysate absorbed 24-40 g

(3) 4.25% D-glucose dialysate 45-60 g absorption

Example (c): when 2.5% D-glucose dialysate was exchanged 4 times per 1 day, 110g of D-glucose (440 kcal) was absorbed

[ use as ophthalmic composition and infusion solution ]

Since the osmotic pressure regulator of the present invention has excellent biocompatibility and no problem in safety and does not increase the blood glucose level, the present invention also provides a peritoneal dialysis solution containing the osmotic pressure regulator of the present invention as described above, but can provide an ophthalmic composition and an infusion solution in addition to a peritoneal dialysis solution.

The ophthalmic composition is not particularly limited as long as it contains D-allose and/or D-psicose and, for example, a known component having an osmotic pressure regulating action, specifically, glucose, trehalose, and the like, and examples thereof include intraocular perfusion and cleansing solutions used in ophthalmic surgery, compositions directly applied to the eye such as eye drops and eye ointments, and compositions used in ophthalmic medical devices such as cleansing solutions and storage solutions for contact lenses. Further, since D-psicose and/or D-psicose are stable in a solution state, the composition may be a liquid or ointment, or may be a solid which is dissolved in the case of use. In these compositions, since D-psicose and/or D-psicose is a stable monosaccharide, other ingredients known in the art that can be used for the same purpose as D-psicose and/or D-psicose may be compounded without limitation.

The content of D-psicose and/or D-psicose in the ophthalmic composition is the same as that in the above-mentioned dialysate when the composition is a liquid. Also, the ophthalmic composition can be prepared according to a known method. Further, the composition to be directly applied to the eye is required to be sterilized, and D-allose and/or D-psicose are stable even at high temperature, and thus any method of heat sterilization or filtration sterilization may be used.

The osmotic pressure of the ophthalmic composition is preferably 100 to 700mOsm/L, and more preferably 200 to 500 mOsm/L. When the composition is a solid, the osmotic pressure of the solution after dissolution is preferably within the above range.

In addition, the ophthalmic composition has a pH (25 ℃) which is stable even in a neutral region, and D-allose and/or D-psicose are preferably 3 to 9, more preferably 6 to 8, and still more preferably 6.8 to 7.5. Also, in the case where the composition is a solid, it is desirable that the pH of the prepared solution is within the above range. Since D-allose and/or D-psicose are stable and the liquid properties of the ophthalmic composition can be made neutral, for example, irritation to the application site can be suppressed in an eye drop or the like, and the amount to be used is appropriately set depending on the purpose of use and the age, weight, and symptoms of a patient to which the ophthalmic composition is to be administered, and is not constant. The period of use is also arbitrary.

The infusion solution is not particularly limited as long as it contains D-allose and/or D-psicose, and may be any of an electrolyte infusion solution mainly for the purpose of electrolyte replenishment, a water infusion solution mainly for the purpose of water replenishment, a nutrient infusion solution mainly for the purpose of nutrient replenishment, and other infusion solutions (a plasma-increasing agent, an osmotic pressure diuretic, a cerebral pressure-lowering agent, etc.).

In the conventional commercially available infusion solutions, saccharides such as glucose, dextran, mannitol and the like are blended. Among these, glucose-containing infusion solutions are used as media for drip administration of medicines, for example, and energy is also taken in even infusion solutions other than infusion solutions contained at high concentrations for the purpose of energy replenishment. In such an infusion solution, since D-allose and/or D-psicose represent the same degree of osmotic pressure as glucose, it is possible to inhibit energy intake without changing the osmotic pressure by incorporating it as a part of or as a substitute for glucose.

In addition, an infusion solution of an osmotic diuretic which increases the osmotic pressure by adding mannitol for the purpose of prevention and treatment of acute renal failure, reduction of intraocular pressure or reduction of cerebral pressure is commercially available. It is also presumed that D-allose and/or D-psicose can exert a diuretic effect by being incorporated into an infusion solution so as to achieve a high osmotic pressure. As for the infusion solution, since D-psicose and/or D-psicose are stable monosaccharides, they can be compounded with components contained in a known infusion solution. Further, as other components that can be used for the same purpose as D-allose and/or D-psicose, for example, a known component having an osmotic pressure regulating action, specifically, glucose, trehalose, and the like may be blended. The content of D-psicose and/or D-psicose in the infusion solution is the same as that in the above dialysate. The infusion solution can be prepared by a known method. The infusion solution thus obtained is required to be sterilized, and D-allose and/or D-psicose are stable even at high temperatures, and thus any method of heat sterilization or filtration sterilization may be used.

In the form of an infusion solution, since D-allose and/or D-psicose is a stable monosaccharide, and is not colored by reaction with other compounding ingredients or decomposition, there is no need to take a pharmaceutical measure of mixing D-allose and/or D-psicose with other ingredients immediately before use, and there is no particular limitation on the known forms such as a single dosage form and a two-dosage form.

The osmotic pressure of the infusion solution is preferably 300-2500 mOsm/L, and more preferably 300-2000 mOsm/L. The pH (25 ℃) of the infusion solution is preferably 3 to 9, more preferably 4 to 8, and still more preferably 6.8 to 7.5.

Since the infusion solution of the present invention does not increase the blood glucose level, it is not limited to use even for patients who need to control blood glucose, and the amount of use is not constant, and is appropriately set depending on the purpose of use and the age, weight, and symptoms of the patient to whom the infusion solution is administered. The period of use is also arbitrary.

The subject to which the peritoneal dialysis solution, the ophthalmic composition, and the infusion solution of the present invention are administered is preferably a human who needs peritoneal dialysis treatment or eye drop treatment, or a human who needs replenishment or drip treatment with an infusion solution, but may be a pet animal or the like.

In addition, the present invention provides, as another embodiment, use of the osmotic pressure regulating agent of the present invention in the manufacture of a peritoneal dialysis solution, an ophthalmic composition and an infusion solution for use in the present invention.

Thus, since a peritoneal dialysis solution, an ophthalmic composition and an infusion solution containing D-psicose and/or D-psicose have an effect of regulating osmotic pressure, the present invention also provides use of D-psicose and/or D-psicose for regulating osmotic pressure, and a method for regulating osmotic pressure in a subject comprising a step of administering D-psicose and/or D-psicose to the subject, particularly to a subject in need of regulation of osmotic pressure.

The method of administration or the amount of administration may be appropriately determined depending on the form, as long as D-allose and/or D-psicose can be taken into the living body.

The present invention will be described in more detail by way of examples. The present invention is not limited to this.

Examples

[ inhibitory Effect of D-allose on increase in blood sugar level when administered intraperitoneally to rats for study ]

(test example 1)

< preparation of sample >

A solution containing glucose in an amount (0.432g) consistent with the total amount of glucose contained in the solution was prepared, and D-allose was added to the solution at a given ratio to obtain 4 kinds of peritoneal dialysis solutions of a sugar concentration of 4 wt% and an osmotic pressure of 230mOsm/L as described below.

(1) Peritoneal dialysis solution (comparative example) wherein all sugars in the solution were D-glucose

(2) Peritoneal dialysis solution containing D-glucose 95 wt% and D-allose 5 wt% of sugar

(3) Peritoneal dialysis solution containing D-glucose 90 wt% and D-allose 10 wt% of sugar

(4) Peritoneal dialysis solution with D-glucose 75 wt% and D-allose 25 wt% of sugar in solution

< animal test >

As shown in the scheme of FIG. 1, normal rats (6-week-old male SD rat, body weight 155-170g/body) were measured for body weight and fasting blood glucose in a fasting state for 24 hours, and were divided into 4 groups at random.

Administration solutions 4 kinds of solutions were prepared in which only glucose was 4% in concentration, 5% of 4% of sugars was replaced with D-allose and 95% was glucose, 10% of the same 4% of sugars was replaced with D-allose and 90% was glucose, and 25% was replaced with D-allose, and the respective osmotic pressures were measured.

No difference in osmotic pressure, no significant difference, was confirmed by the same test.

Blood glucose (Blood sugar) was measured from the tail of a normal rat using a commercially available Blood glucose meter.

Table 1 shows the measurement results of body weight, blood glucose level, and osmotic pressure of 4 groups of glucose (glucose), 5% D-allose (allose), 10% D-allose (allose), and 25% D-allose (allose).

[ Table 1]

Osmotic pressure of all solutions. The osmotic pressure was not significantly poor.

Counting: one-way ANOVA (one-way analysis of variance)

FIG. 2 shows the results of measurement of blood glucose levels in 4 groups, i.e., a solution containing only glucose at a concentration of 4%, a solution containing 4% of sugars in which 5% of the sugars were replaced with D-allose and 95% of the sugars were glucose, a solution containing 4% of sugars in which 10% of the sugars were replaced with D-allose and 90% of the sugars were glucose, and a solution containing 25% of the sugars were replaced with D-allose.

In the 4 groups, experiments were performed with n being 6 to 8, and the blood glucose (glucose) group (a in the figure), 5% D-allose (allose) (B in the figure), 10% D-allose group (C in the figure), and 25% D-allose group (D in the figure) showed changes in blood glucose values when peritoneal dialysis solutions were administered intraperitoneally in a normal rat model. At this time, the duke-Kramer method (Tukey-Kramer test) was performed using the analysis software JMP, and it was confirmed that there was no significant difference.

Fig. 3 is a graph in which AUC (area under the blood concentration-time curve) of each group is plotted based on the results of fig. 2. In the course of blood glucose, the increase inhibitory effect was significantly poor at 30 minutes and 60 minutes, and AUC also showed a significant decrease in the D-allose by the duke-Kramer method (Tukey-Kramer test).

As shown in the scheme of fig. 4, 12-13 week-old male SDT obese (fat) rats (body weight 360-. Administration solution 2 solutions were prepared in which only glucose was 4% concentrated and 10% of the 4% sugars were replaced with D-allose and 90% glucose, and the respective osmotic pressures were measured.

No difference in osmotic pressure, no significant difference, was confirmed by the same test.

Fig. 5 shows the measurement results of blood glucose levels in 2 groups, i.e., a solution containing only 4% glucose, and a solution containing 4% glucose, 10% of which was replaced with D-allose and 90% of which was glucose. In the 2 groups, experiments were performed with n being 6 to 8, and the blood glucose (glucose) group (G in the figure) and the 10% D-allose group (a in the figure) showed changes in blood glucose values when peritoneal dialysis solutions were administered to the diabetic model rats intraperitoneally.

In the diabetic model rats, the weight was heavier than that of the normal rats, and the fasting blood glucose was also high. In diabetic rats, blood was collected from the tail, and from the neck, followed by pulsation, and blood glucose was measured using the same blood glucose meter. In this case, the blood glucose level was increased more slowly than in normal rats due to diabetes. Therefore, blood glucose measurements were performed at 4 points of 0, 2, 4, and 6h for a long period of time.

The AUC among the 2 groups was investigated, and the effect of inhibiting the increase in blood glucose level due to D-allose, which was significantly poor in t-test, is shown in FIG. 6.

[ conclusion of the results of test example 1]

Normal rats showed results of significantly inhibiting the blood glucose rise in AUC (area under the blood concentration-time curve) as shown in fig. 2 at 30, 60 and 120 minutes, and as shown in the bar graph of fig. 3.

In the diabetes model rats, as shown in fig. 5 and 6, a significant increase in blood glucose level was observed in the peritoneal dialysis solution containing only glucose, whereas the increase in blood glucose level was suppressed in the peritoneal dialysis solution containing D-allose.

As summarized above, the 100% glucose solution and the glucose solution mixed with the D-allose as a rare sugar showed the same osmotic pressure. The increase in blood glucose level in normal rats can be inhibited by adding the rare sugar D-allose. The addition of D-allose, a rare sugar, can inhibit the increase of blood glucose level in diabetic rats.

From these results, it was found that the peritoneal dialysis solution containing D-allose can be safely used as a dialysis solution capable of controlling blood glucose by suppressing an increase in blood glucose level due to the continuous absorption of glucose into the body by peritoneal dialysis.

(test example 2)

< preparation of sample >

Next, a Peritoneal Dialysis solution (PDF: Peritoneal Dialysis Fluid) was prepared so that the total amount of glucose (0.432g) contained in the solution was uniform, and D-allose was added to the solution at a constant ratio to obtain 2 kinds of Peritoneal Dialysis solutions of a sugar concentration of 4 wt% and an osmotic pressure of 500mOsm/L as described below.

The composition of the PDF is shown in table 2.

(1) Peritoneal dialysis solution (comparative example) wherein all sugars in the solution were D-glucose

(2) Peritoneal dialysis solution containing D-glucose 90 wt% and D-allose 10 wt% of sugar

[ Table 2]

PDF composition table
		Glucose	13.5g/L
Sodium chloride	5.55g/L
		L-sodium lactate	8.96g/L
Hydrated calcium chloride	0.183g/L
		Magnesium chloride	0.0508g/L
pH	5.2-6.2
		Osmotic pressure	350mOsm

< animal test >

As shown in the scheme of FIG. 7, normal rats (6-week-old male SD rat, body weight 155-175g/body) were randomly divided into 2 groups by measuring body weight and fasting blood glucose in a fasting state for 24 hours. Administration solution a solution with 4% concentration of glucose alone, a solution in which 10% of the 4% sugar was replaced with D-allose and 90% was glucose, and the osmotic pressure of each was measured.

No difference in osmotic pressure, no significant difference, was confirmed by the same test.

Blood glucose (Blood sugar) was measured from the tail of a normal rat using a commercially available Blood glucose meter.

FIG. 8 shows the results of measurement of blood glucose levels in 2 groups, i.e., a solution containing only 4% glucose and a solution containing 4% glucose, 10% of which was replaced with D-allose and 90% of which was glucose. In 2 groups, experiments were carried out with n being 8 to 10, and the blood glucose (glucose) group and the 10% D-allose group showed changes in blood glucose values when peritoneal dialysis solutions were administered intraperitoneally in a normal rat model.

At this time, it was confirmed by t-test that there was no significant difference using the analysis software JMP.

Fig. 8 also shows a graph obtained by plotting AUC (area under the blood concentration-time curve) of each group based on the results.

In addition, as shown in the scheme of FIG. 9, male SDT obese (fat) rats (body weight 380-. The administration solution was prepared by changing the original solution to PDF and changing the sugar content to a 4% concentration solution of glucose alone and a 4% concentration solution of glucose in which 10% of the sugars were replaced with D-allose and 90% was glucose, and the osmotic pressure was measured for each of the solutions.

No difference in osmotic pressure, no significant difference, was confirmed by the same test.

FIG. 10 shows the results of measurement of blood glucose levels in 2 groups, i.e., a solution containing only 4% glucose and a solution containing 4% glucose, 10% of which was replaced with D-allose and 90% of which was glucose. In the 2 groups, the test was performed with n-5, and the blood glucose (glucose) group and the 10% D-allose group showed changes in blood glucose values when peritoneal dialysis solutions were administered intraperitoneally to rats as a model of diabetes.

In the diabetic model rats, the weight was heavier than that of the normal rats, and the fasting blood glucose was also high. Since it is difficult to take blood from the tail of a diabetic rat, blood is taken from the neck and from the vein, and blood glucose is measured using the same blood glucose measuring instrument. In this case, the blood glucose level was increased more slowly than in normal rats due to diabetes. Therefore, blood glucose measurements were performed at 4 points of 0, 2, 4, and 6h for a long period of time.

AUC among the 2 groups was investigated, and it was shown that there was a significantly poor inhibitory effect of D-allose on the increase in blood glucose in t-test.

[ conclusion of the results of test example 2]

Normal rats also showed a result of significantly suppressing the increase in blood glucose in the PDF solution as in the usual sugar solution in AUC (area under the concentration-time curve in blood) as shown in fig. 8 at 30, 60 and 120 minutes and as shown in the bar graph of fig. 8.

In addition, as shown in fig. 10, in the diabetes model rat, a significant increase in blood glucose level was observed in the peritoneal dialysis solution containing only glucose, whereas the increase in blood glucose level was suppressed in the case of the peritoneal dialysis solution containing D-allose.

As summarized above, the 100% glucose solution and the glucose solution mixed with the rare sugar D-allose showed the same osmotic pressure even when PDF was used as a base. The increase in blood glucose level in normal rats can be inhibited by adding the rare sugar D-allose. The addition of D-allose, a rare sugar, can inhibit the increase of blood glucose level in diabetic rats.

(test example 3)

Considering that dialysis patients with end-stage renal failure are still on the increase, diabetic nephropathy is the most basic disease of end-stage renal failure, peritoneal dialysis patients can work in the daytime, patient QOL is high, peritoneal dialysis utilizes osmotic pressure difference generated by glucose to remove water and toxins, glucose in peritoneal dialysis solution is absorbed into the body through the peritoneum, blood glucose level is increased, and prognosis of diabetic dialysis patients is deteriorated, university of xiangchu is the only world organization capable of producing all kinds of rare sugars, and the rare sugar most suitable for a target dialysis solution can be searched. Therefore, the effect of suppressing the increase in blood glucose by replacing a part of glucose in the normal rat model peritoneal dialysis solution with D-psicose or by applying a load to the control was also examined for D-psicose at n 6 to 10, in the same manner as for D-psicose in test example 2. Further, the effect of D-psicose, which is a rare sugar different from D-psicose, was investigated, and the effect of significantly suppressing the increase in blood glucose was obtained as with D-psicose.

In addition to D-psicose, which shows a blood glucose suppressing effect as a food, was investigated in test example 3 in order to select a more suitable rare sugar.

Examples of D-psicose include alternatives and additions. An alternative example is an example in which D-psicose (D-allose) of FIG. 7 is replaced with D-psicose (D-allolose). For example, as shown in fig. 11, two sets of data, i.e., a control set and a substitution set, were added, in which D-psicose (D-allose) was replaced with D-psicose (D-allose) in the same configuration as in fig. 7 and 8, and the recipe and the data were set as shown in fig. 8, respectively.

Fig. 12 shows the experimental results of D-psicose (D-allolose) produced with the configuration shown in fig. 11.

Male SD rats were used, and a solution obtained by mixing glucose in peritoneal dialysis solution (PDF) was used as a control solution, a solution obtained by replacing 10% (by weight) of the mixed glucose with D-psicose was used as a 10% replacement solution, a solution obtained by adding 10% of D-psicose in terms of the weight ratio of glucose to the control solution was used as a 10% loading solution, the same amount of the solution was administered into the abdominal cavity, and the blood glucose level was measured over time. In each group, n was 6 to 10, and in the D-psicose-substituted group and the D-psicose-added group, the increase in blood glucose level (BS, left in fig. 12) and the area under the blood glucose level time curve (AUC, right in fig. 12) were significantly suppressed as compared with the control group.

(test example 4)

[ MIC test (minimum development arrest concentration test) ]

The minimum growth-arrested concentration of a specimen was determined with reference to the agar plate dilution method of the Japanese society for chemotherapy (1981). The samples were added at arbitrary concentrations, and after the test bacterial liquid was smeared on an agar plate medium and cultured, the minimum concentration at which the growth of the bacteria was inhibited was set as the minimum growth-inhibiting concentration.

1. The subject bacterium: the causative bacteria commonly found in peritoneal infections were selected (pick up).

(1) Coagulanse-negative Staphylococcus (Coagulase-negative Staphylococcus epidermidis)

(2) Pseudomonas aeruginosa (Pseudomonas aeruginosa)

(3) Enterococcus faecalis

(4) Escherichia coli (E.coli)

(5) Staphylococcus aureus MSSA

(6) Staphylococcus Aureus (MRSA)

(7) Corynebacterium strain (Corynebacterium striatum)

2. Use of rare sugars: (4) and (5) as a control

(1) D-psicose

(2) L-psicose

(3) D-allose

(4) D-glucose

(5) D-fructose

3. Test method

A10-fold dilution of the specimen was prepared using purified water, and 1/10 amounts were added to the agar medium.

The concentration was measured from the upper limit of the concentration to around 100. mu.g/ml by 2-stage dilution.

(1) Preparation of 70% solution (14 g to 20ml)

The peritoneal dialysis solution has an upper limit of 4.5% sugar concentration and is used clinically.

It has been experimentally verified that by warming, the sugar can be dissolved to a concentration of 70%.

(2) The 70% solution was diluted 2-fold in stages. 7 to 8 stages

(3) The amount of each solution 1/9 was added to the agar medium, poured into a petri dish and solidified (sample concentration in agar 7% -)

Sample 14g is used 1 time. 2 times of the amount of the test sample was prepared so that the test could be performed as quickly as possible.

The bacteria were cultured in a liquid medium for 16 to 20 hours and then prepared to have a concentration of about 10 to the power of 6/ml.

Total of 5 strains of bacteria: rare sugar about 30g

Total of 7 strains of bacteria: rare sugar about 37g

4. Determination of test

The Minimum Inhibitory Concentration (MIC) of the test bacteria for the test specimens is shown in tables 3 and 4.

[ Table 3]

Minimum development arrest concentration (MIC) of test body to test bacterium

70: this indicates that the development of the test bacteria was not prevented at 70 mg/mL.

[ Table 4]

Minimum development arrest concentration (MIC) of test body to test bacterium

70: this indicates that the development of the test bacteria was not prevented at 70 mg/mL.

The results are summarized below.

The concentration of the medicament is 128 mu g/ml of the developing bacteria A + B-C-

64 mu g/ml developing bacteria A + B + C-

Developed bacterium A + B + C + of 32 μ g/ml

MIC A＞128μg/ml B：128μg/ml C：64μg/ml

(1) D-psicose → A

(2) L-psicose → B

(3) D-allose → C

(4) D-glucose → D

(5) D-fructose → E

5. Evaluation of the results

As shown in tables 3 and 4 of the test reports from the food analysis center of Japan, the specimen 1 was tested for D (D-glucose ) sugar,

Detecting body 2) sugar E (D-Fructose),

Detecting body 3) sugar A (D-allolose, D-psicose),

Detecting body 4) sugar B (L-allolose, L-psicose),

Detecting body 5) sugar C (D-allose )

After 7 test bacteria solutions including coryneform bacteria were applied to agar plate media added at arbitrary concentrations and cultured, the minimum growth-inhibitory concentration at which the growth of the bacteria was inhibited was defined as the minimum growth-inhibitory concentration.

As shown in tables 3 and 4, the development of Staphylococcus epidermidis was prevented only when D-allose (D-allose) was 70 mg/mL. In addition, the development of test bacteria was not inhibited at 70mg/mL in all specimens and test bacteria. Infection is a major problem in peritoneal dialysis practices. D-allose (D-allose) was demonstrated to significantly inhibit the development of S.epidermidis, the upper cause of peritoneal dialysis-related infections. Further, patent document 16 reports the use and method of inhibiting the growth of harmful microorganisms that are D-allulose and D-allose, which are rare sugars, as plant pathogens and miscellaneous fungi that cause adverse effects on food production and processing, medical sites, living environments, air conditioning equipment, and the like, and the ability to inhibit infectious diseases in osmoregulators containing D-glucose can be expected.

Industrial applicability of the invention

The osmotic pressure regulator containing D-allose of the present invention has excellent biocompatibility, no problem in safety, and no in vivo accumulation, and therefore, can be suitably used in a composition requiring osmotic pressure regulation, such as a peritoneal dialysis solution, an ophthalmic composition, and an infusion solution.

In the near future, peritoneal membrane degradation can be prevented and blood glucose can be controlled by a dialysate containing D-allose, and thus peritoneal dialysis can be expected to be performed for a long period of time. The Peritoneal Dialysis (PD) rate in renal replacement therapy for chronic renal failure is very low on a global basis, and is pressing medical economy in japan. As a large reason why PD therapy cannot be widely used, there are serious problems that deterioration of the peritoneum for a long period of time cannot be avoided, and blood glucose level rises, and infection cannot be suppressed, and peritoneal dialysis cannot be a permanent renal replacement therapy at present. Peritoneal Dialysis (PD) patients are gospel if the rare sugar D-allose can be used to safely and efficiently perform peritoneal dialysis and also prevent long-term peritoneal deterioration.