WO2009123029A1 - Blood ammonia level regulator - Google Patents

Abstract

Disclosed is a blood ammonia level regulator comprising α-cyclodextrin as an active ingredient. The blood ammonia level regulator can be used as a therapeutic agent for hyperammonemia or hepatic encephalopathy. The blood ammonia level regulator can also be used as a prophylactic agent for hyperammonemia or hepatic encephalopathy. The blood ammonia level regulator may be prepared in the form of a preparation for oral administration or enteral administration.

Description

Blood ammonia regulator

The present invention relates to a blood ammonia adjusting agent used for lowering the blood ammonia concentration or for suppressing an increase in blood ammonia concentration. More specifically, the present invention relates to a blood ammonia adjusting agent which contains α-cyclodextrin as an active ingredient and is used, for example, by administration to hyperammonemia patients or hepatic encephalopathy patients.

Generally, most of the ammonia in the blood is derived from ammonia generated in the intestine. Protein or amino acid taken orally ingests ammonia by being metabolized by the action of intestinal bacteria. Normally, ammonia generated in the intestinal tract is absorbed into the portal blood from the intestinal wall and transported to the liver. Ammonia carried to the liver is detoxified to urea in the urea cycle. However, if the liver function decreases due to liver disease such as cirrhosis, blood ammonia cannot be metabolized and blood ammonia increases. Furthermore, as cirrhosis progresses, the effective blood flow to the liver decreases, and a bypass (portal vein-aortic shunt path, PC shunt) is formed outside the liver. Therefore, ammonia absorbed from the intestinal wall flows directly into the systemic circulation without being metabolized by the liver. Hyperammonemia develops as a result of the increased ammonia concentration in the blood. Ammonia easily breaks through the cerebral blood barrier, and when it falls into hyperammonemia, it causes cerebral damage (hepatic encephalopathy) such as consciousness disorder, movement disorder and language disorder. Sometimes.

Ammonia is considered to be a typical encephalopathy-inducing factor together with lower fatty acids and mercaptans. Examples of the treatment aimed at lowering the blood ammonia concentration include diet therapy centered on a low protein diet and medication treatment. Examples of pharmaceuticals used in medication include pharmaceuticals intended to suppress the production of ammonia in the intestinal tract, such as antibiotics, lactulose (see Non-Patent Document 1) and lactitol, and pharmaceuticals intended to remove ammonia, such as Amino acid formulations are known. Among these, lactulose and lactitol are often used as therapeutic agents for hyperammonemia. When taken, lactulose and lactitol reach the large intestine without being absorbed in the stomach and small intestine, and are decomposed into organic acids such as acetic acid, propionic acid and butyric acid by intestinal bacteria. As a result, the pH in the intestine decreases, and ammonia changes to an ionic form that is difficult to be absorbed. Lactulose and lactitol also have an action of promoting intestinal transport ability and shortening the residence time of intestinal contents serving as an ammonia source.

However, lactulose has a problem that it frequently causes digestive symptoms such as diarrhea. In addition, there is a problem that discomfort and nausea are caused at the time of taking due to strong sweetness, and portability and storage are not good. On the other hand, although lactitol is easy to drink because it has a lower sweetness than lactulose, it has an insufficient effect of lowering the blood ammonia concentration, and diarrhea occurs not a little.
Bircher J. et al., Lancet 1, 890-893, 1966

Therefore, an object of the present invention is to provide a blood ammonia adjusting agent which is less likely to cause side effects and is useful for lowering the blood ammonia concentration. The present inventors have sought a substance that has a high effect of reducing blood ammonia concentration and has few side effects. As a result, the present inventors have found that α-cyclodextrin conventionally used as a food additive is excellent in the action of lowering the ammonia concentration in blood and has no side effects, thereby completing the present invention.

That is, in order to achieve the above object, in one embodiment of the present invention, a blood ammonia adjusting agent containing α-cyclodextrin as an active ingredient is provided.
The above blood ammonia adjusting agent can be used as a therapeutic agent for hyperammonemia or hepatic encephalopathy. Alternatively, the blood ammonia adjusting agent can also be used as a preventive agent for hyperammonemia or hepatic encephalopathy. The blood ammonia adjusting agent is preferably formed as a preparation for oral administration or enteral administration. The blood ammonia adjusting agent may be formed as a solid agent. In that case, the blood ammonia adjusting agent preferably contains α-cyclodextrin in an amount of 10 to 100% by mass.

Alternatively, the blood ammonia adjusting agent can be used as a food or drink for hyperammonemia patients or hepatic encephalopathy patients. The blood ammonia regulator may be formed as a solid food, and in that case, it preferably contains α-cyclodextrin in an amount of 10 to 100% by mass.

Hereinafter, an embodiment of the present invention will be described.
The blood ammonia regulator of this embodiment contains α-cyclodextrin as an active ingredient. Cyclodextrin is a cyclic oligosaccharide in which a plurality of glucose molecules are linked cyclically by α-1,4 glycosidic bonds, and is also present in nature. Cyclodextrin molecules are generally known to have an inclusion action of incorporating molecules into a central cavity (hole). Since the inside of the cavity of cyclodextrin is hydrophobic, cyclodextrin tends to include a hydrophobic substance. For this reason, for example, in the field of food additives, cyclodextrins are used for the purpose of enhancing the solubility of hydrophobic substances or protecting substances that easily react with water and oxygen.

The cyclodextrin formed by combining six glucose molecules is called α-cyclodextrin and is produced from starch by the action of α-cyclomaltodextrin glucanotransferase. Cyclodextrin formed by combining seven glucose molecules is called β-cyclodextrin and is produced from starch by the action of β-cyclomaltodextrin glucanotransferase. Cyclodextrin formed by combining eight glucose molecules is called γ-cyclodextrin and is produced from starch by the action of γ-cyclomaltodextrin glucanotransferase. Of the cyclodextrins, only α-cyclodextrin specifically suppresses an increase in blood ammonia concentration. α-Cyclodextrin is a water-soluble dextrin that dissolves in about 14 g in 100 mL of water at 25 ° C., and is also an indigestible dextrin that is not degraded by digestive enzymes.

The blood ammonia regulator exerts the action of reducing the ammonia concentration in the blood or the action of suppressing the increase in the blood ammonia concentration by the action of α-cyclodextrin when taken into the body. The blood ammonia adjusting agent is preferably used as a therapeutic agent for hyperammonemia in patients with hyperammonemia, but is not limited thereto. For example, the blood ammonia adjusting agent may be used as a preventive agent for hyperammonemia. Alternatively, it may be used for hepatic encephalopathy patients as a therapeutic agent for hepatic encephalopathy, which is a brain disorder caused by hyperammonemia, or as a prophylactic agent for hepatic encephalopathy.

The blood ammonia regulator can be used as a medicine or a food or drink. It is considered that the decrease in blood ammonia concentration or the suppression of increase in blood ammonia concentration by α-cyclodextrin is exhibited by the action of α-cyclodextrin in the intestinal tract. Therefore, the blood ammonia regulator is preferably formed as a preparation for oral administration or enteral administration if used as a pharmaceutical product. Since α-cyclodextrin is water-soluble and indigestible as described above, it reaches the intestine without being decomposed and absorbed in the stomach by ingestion.

The dosage form of the blood ammonia regulator is not particularly limited, and may be any of solid, liquid and gel. Examples of the solid preparation include tablets, pills, powders, powders, granules, and fine granules. Liquid agents include, for example, solutions, suspensions and emulsions. The powder of α-cyclodextrin can also be used for administration as a blood ammonia adjusting agent. Moreover, the blood ammonia adjusting agent may be filled into a capsule and formed as a capsule.

In addition to α-cyclodextrin, blood ammonia regulators include excipients (bulking agents), binders, disintegrants, surfactants, disintegration inhibitors, adsorbents, lubricants, gelling agents, etc. An agent may be further contained. Examples of excipients include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and potassium phosphate. Examples of binders include, for example, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, and polyvinylpyrrolidone. Examples of the disintegrant include, for example, sodium carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, and calcium carbonate. Examples of the surfactant include polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and stearic acid monoglyceride. Examples of disintegration inhibitors include, for example, sucrose, stearin, cocoa butter, and hydrogenated oil. Examples of adsorbents include, for example, starch, lactose, kaolin, bentonite, and colloidal silicic acid. Examples of lubricants include purified talc, stearate, boric acid powder, and polyethylene glycol. Examples of gelling agents include agar, gelatin, carrageenan, gellan gum, xanthan gum, locust bean gum, pectin, sodium alginate, and potassium alginate.

Blood ammonia regulators are tablets coated with a known coating to mask the sweetness derived from α-cyclodextrin, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, and film-coated tablets. Also good. The coating may be a single layer or a multilayer of two or more layers. The blood ammonia adjusting agent having a capsule dosage form is filled in capsules such as hard gelatin capsules and soft capsules after mixing α-cyclodextrin with an arbitrary pharmaceutical carrier according to the usual method of capsule preparation. Manufactured.

Liquid dosage forms of blood ammonia, such as liquids, emulsions, and suspensions, contain a diluent used as a solvent. Examples of the diluent include water and alcohols. From the viewpoint of safety and solubility, a preferred diluent is water. The liquid ammonia adjusting agent in the liquid dosage form may further contain at least one of a solubilizing agent and a buffer (pH adjusting agent). Moreover, you may further contain at least one chosen from a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, and a corrigent as needed. The blood ammonia regulator can also be used by mixing with other drugs that do not inhibit the action of the blood ammonia regulator.

If the blood ammonia regulator is used as a food or drink, it is prepared by mixing it with a food or drink material. Of the foods and drinks used as the blood ammonia regulator, particularly preferred are foods and drinks for hyperammonemia patients or hepatic encephalopathy patients. The form of the blood ammonia regulator used as a food or drink is not particularly limited. For example, it may be a jelly-like, cream-like, jam-like or gel-like semi-fluid food, solid food, or beverage. Good.

In addition to α-cyclodextrin, blood ammonia regulators used as semi-fluid foods or beverages include sugars, electrolytes, nutrients, amino acids (eg, branched chain amino acids), vitamins, minerals (eg, zinc and Serine), flavoring agents, coloring agents, and flavoring substances may be further contained. Examples of branched chain amino acids include, for example, isoleucine, leucine and valine. Examples of vitamins include, for example, retinol palmitate, tocopherol, thiamine, riboflavin, pyridoxine hydrochloride, cyanocobalamin, sodium ascorbate, cholecalciferol, nicotinamide, calcium pantothenate, folic acid, biotin, and choline bitartrate It is done. In addition, blood ammonia adjusting agents used as semi-fluid foods are, for example, thickening polysaccharides such as agar, gelatin, carrageenan, gellan gum, xanthan gum, locust bean gum, pectin, sodium alginate, potassium alginate and the like as gelling agents. You may contain.

The amount of α-cyclodextrin contained in the blood ammonia regulator is not particularly limited. However, when formed as a solid agent or a solid food, the amount of α-cyclodextrin contained in the blood ammonia regulator is preferably 10 to 100% by mass, more preferably 50 to 100% by mass. When the blood ammonia regulator contains α-cyclodextrin in an amount of 10% by mass or more, the blood ammonia concentration can be sufficiently reduced by ingesting a relatively small amount of blood ammonia regulator, or blood An increase in the ammonia concentration can be sufficiently suppressed. In the case of being formed as a liquid agent or beverage, the amount of α-cyclodextrin contained in the blood ammonia regulator is appropriately within the range where α-cyclodextrin is dissolved in the blood ammonia regulator. Is set.

The dosage of the blood ammonia regulator is appropriately set according to, for example, the dosage form, patient age, sex, disease severity, and administration method, and is usually 0.01 to 7 in terms of α-cyclodextrin. 5 g / kg (body weight) / day, preferably 0.05 to 3 g / kg (body weight) / day, more preferably 0.05 to 2 g / kg (body weight) / day. The blood ammonia regulator may be administered either by single dose or once or several doses per day.

According to the present embodiment, the following effects can be obtained.
(1) The blood ammonia regulator of this embodiment containing α-cyclodextrin as an active ingredient sufficiently reduces the blood ammonia concentration or sufficiently suppresses the blood ammonia concentration from rising without side effects.

(2) The blood ammonia adjusting agent is useful as a therapeutic or prophylactic agent for hyperammonemia, and is also useful as a therapeutic or prophylactic agent for hepatic encephalopathy.
(3) α-cyclodextrin, which is an active ingredient of a blood ammonia regulator, has a weaker sweetness than lactulose and lactitol. Therefore, the blood ammonia regulator is less likely to cause disgust or nausea when taken.

(4) The blood ammonia regulator is preferably formed as a preparation for oral administration or enteral administration. In this case, the α-cyclodextrin in the blood ammonia adjusting agent acts reliably in the intestinal tract, so that the blood ammonia concentration is efficiently reduced or efficiently suppressed.

(5) α-Cyclodextrin is safe enough to be evaluated by the World Food Additives Joint Expert Meeting (JECFA) as it is not necessary to specify an acceptable daily intake (ADI). Therefore, the blood ammonia adjusting agent can be used as a food and drink with high biological safety, and can be safely and continuously ingested.

(6) The blood ammonia regulator is preferably used as a food or drink for hyperammonemia patients or hepatic encephalopathy patients. In this case, daily intake of the blood ammonia regulator is useful for the treatment of hyperammonemia patients or hepatic encephalopathy patients.

(7) The blood ammonia adjusting agent formed as a solid agent or a solid food contains α-cyclodextrin in an amount of preferably 10 to 100% by mass, more preferably 50 to 100% by mass. In this case, the intake of a relatively small amount of blood ammonia regulator can sufficiently reduce the blood ammonia concentration or sufficiently suppress the blood ammonia concentration from rising.

In addition, you may change the said embodiment as follows.
The blood ammonia regulator is not limited to human administration, and may be administered to non-human animals. For example, domestic animals such as horses, cows and pigs, and domestic animals such as chickens, dogs and cats. It may be administered to pets such as rats and mice.

Next, the present invention will be described more specifically with reference to a production example of the blood ammonia regulator of the present invention and a test example using the blood ammonia regulator obtained in the production example.
Production Example 1
10 g of α-cyclodextrin (product name W6 manufactured by Cyclochem) was dissolved in purified water to prepare a blood ammonia adjusting agent in a liquid dosage form with a total volume of 100 mL.

Production Example 2
500 g of α-cyclodextrin, 25 g of anhydrous citric acid (Japanese pharmacopoeia product), and 15 g of hydroxypropylcellulose (Japanese pharmacopoeia product) were uniformly mixed, and 70 mL of distilled water was added and granulated. The obtained granules were dried at 60 ° C. for 2 hours and then passed through a 24-mesh sieve, and the granules passed through the sieve were collected to prepare a solid dosage form of a blood ammonia regulator. The obtained blood ammonia adjusting agent was filled and sealed in an aluminum laminated stick bag in an amount of 3.5 g.

Production Example 3
Α-Cyclodextrin, branched chain amino acid, gelatin hydrolyzate and pH adjuster (buffer) were added to 500 g of warm water in this order, and the mixture was prepared. Separately, agar as a gelling agent was added to 400 g of cold water and dissolved by heating and stirring at 95 ° C. The above mixture was mixed with this agar solution, and water was further added to make a total amount of 1 kg, and then 100 g each was filled in a heat-resistant synthetic resin container. And the blood ammonia regulator of gel-form dosage form was prepared by cooling after heating at 95 degreeC for 20 minutes and sterilizing. In Table 1 below, the content of each component in the blood ammonia adjusting agent is shown in terms of 1 kg of blood ammonia adjusting agent.

Production Example 4
5 g of α-cyclodextrin (product name W6 manufactured by Cyclochem) was dissolved in purified water to prepare a blood ammonia adjusting agent in a liquid dosage form with a total volume of 100 mL.

Test Example 1: Verification of blood ammonia lowering effect by α-cyclodextrin in normal rats (Part 1)
(1) Administration of blood ammonia regulator 6 weeks old SD male rats (purchased from Japan SLC) were acclimated for 3 days or more, and then into three administration groups: experimental group, comparative group, and control group. Separately, it was used for the administration experiment. The number of individuals in each group was 6-7. For rats in the experimental group, once between 8 am and 10 pm in the morning and once between 15 pm and 18 pm in the free drinking with the standard purified diet AIN-93G Twice per day, the blood ammonia adjusting agent obtained in Production Example 1 was orally administered using a rat oral sonde at a dose of 1.5 g / kg (body weight) per administration. For the rats in the control group, distilled water was administered in the same manner as in the experimental group at a dose of 15 mL / kg (body weight) per administration instead of the blood ammonia adjusting agent. For the rats in the comparative group, a distilled aqueous solution containing 10% lactitol (product name: Poltrac manufactured by Nippon Shinyaku Co., Ltd.) instead of blood ammonia regulator was added at 15 mL / kg (body weight) per administration. The dose was administered as in the experimental group.

(2) Measurement of blood ammonia concentration After anesthesia with somnopentyl (pentobarbital sodium) 4 hours after oral administration in the morning on the 4th day after the start of administration, about each from the portal vein and jugular vein of each rat. 0.3 mL of blood was collected. Each collected blood was transferred to a tube containing 10 μL of heparin (Japanese Pharmacopoeia Heparin Sodium Injection (Shimizu Pharmaceutical, Shimizu, Shimizu, 1000 units / mL)) in advance. The supernatant plasma was obtained by centrifugation. The ammonia concentration in the obtained plasma was measured by the dry chemistry method. The average value of the measured ammonia concentration in each group is shown in Table 2 below.

Regarding the results shown in Table 2, the ammonia concentration in portal vein plasma measured in the experimental group was lower than the ammonia concentration in portal vein plasma measured in the control group and the comparison group. On the other hand, the ammonia concentration in the jugular vein plasma measured in the experimental group was not different from the ammonia concentration in the jugular vein plasma measured in the control group and the comparative group. From the above, it was confirmed that the blood ammonia regulator has a function of selectively lowering the ammonia concentration in the portal vein plasma even when administered for a relatively short period of 3.5 days. Therefore, the blood ammonia regulator is expected to be effective for the treatment and prevention of hyperammonemia.

Test Example 2: Verification of blood ammonia lowering effect by α-cyclodextrin in normal rats (Part 2)
(1) Administration of blood ammonia regulator 9 weeks old SD male rats (purchased from Charles River Japan) after an acclimatization period of 3 days or more, experimental group, first comparative group, second comparative group, The administration experiment was divided into four administration groups of the control group. The number of individuals in each group was 7. For rats in the experimental group, once between 8 am and 10 am in the morning and 15:00 in the evening under free drinking with the mouse, rat and hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd. From 1 to 18 o'clock, using an oral sonde for rats at a dose of 1 g / kg (body weight) per administration of the blood ammonia adjusting agent obtained in Production Example 1 twice a day. And administered orally. For the rats in the control group, distilled water was administered in the same manner as in the experimental group at a dose of 10 mL / kg (body weight) per administration instead of the blood ammonia adjusting agent. For the rats of the first comparative group, a distilled aqueous solution containing 10% of methylated β-cyclodextrin (product name: W7M, manufactured by Cyclochem) instead of blood ammonia adjuster was added at 1 g / dose per administration. Administration was performed in the same manner as in the experimental group at a dose of kg (body weight). For the rats of the second comparative group, a distilled aqueous solution containing 10% of γ-cyclodextrin (product name W8 manufactured by Cyclochem) instead of the blood ammonia adjusting agent was added at 1 g / kg per administration ( (Body weight) was administered in the same manner as in the experimental group.

(2) Measurement of blood ammonia concentration After anesthesia with pentobarbital sodium 4 hours after the morning oral administration on the 8th day after the start of administration, about 0.3 mL each from the portal vein and jugular vein of each rat Blood was collected. Each collected blood was transferred to a tube containing 10 μL of heparin (Japanese Pharmacopoeia Heparin Sodium Injection (Heparin Sodium “Shimizu” manufactured by Shimizu Pharmaceutical Co., Ltd., 1000 units / mL)) in advance. The supernatant plasma was obtained by centrifugation. The ammonia concentration in the obtained plasma was measured by the dry chemistry method. The average value of the measured ammonia concentration in each group is shown in Table 3 below.

Regarding the results shown in Table 3, the ammonia concentration in the portal vein plasma measured in the experimental group was lower than the ammonia concentration in the portal vein plasma measured in the control group, the first comparison group and the second comparison group. It was. On the other hand, the ammonia concentration in the jugular vein plasma measured in the experimental group was not different from the ammonia concentration in the jugular vein plasma measured in the control group, the first comparison group and the second comparison group. Based on the above, methylated β-cyclodextrin and γ-cyclodextrin belonging to the same cyclodextrin as α-cyclodextrin contained in the blood ammonia regulator have the function of reducing the ammonia concentration in portal vein plasma. Not confirmed.

Test Example 3: Verification of blood ammonia lowering effect by α-cyclodextrin in rats with porto-caval shunt (PCS) (Part 1)
(1) Preparation of PCS rats 6-week-old Crl: CD (SD) male rats (purchased from Charles River Japan) were fasted overnight after 3 days of acclimatization period, and the day after ether anesthesia An incision was made in the abdomen to the sphenoid process. A part of the liver was turned over and taken out on the chest, and the gastrointestinal tract was taken out on the left ventral side. The abdominal vena cava was peeled from the upper branch of the right renal vein to the lower branch of the left renal vein, and a suture for cigarette suture (drawstring suture) was put on the anastomosis near the portal vein. On the other hand, the portal vein portion of about 2 cm was completely peeled from the liver inflow side. The part of the detached portal vein and the splenic vein were clipped, and the portal vein on the liver side was ligated. In addition, the site of the portal vein 1 to 2 mm away from the ligation part toward the digestive tract was lightly ligated. The portal vein was blocked between the two ligatures, and the intestinal portal vein was passed through the anastomosis button. The portal vein that came out on the groove side of the anastomosis button was fixed to the groove of the button with a suture. Arterial clips were applied between the abdominal vena cava and the right renal vein, and between the abdominal vena cava and the left renal vein, respectively, and the central part of the tobacco suture was incised to insert an anastomosis button. Thereafter, the anastomosis button was anastomosed and fixed to the abdominal vena cava with a suture thread that had been put in advance. The blood in the abdominal cavity was washed and removed, ampicillin solution was dropped into the anastomosis, the digestive tract and the liver were returned to the abdominal cavity, and then the abdominal muscle and skin were sutured back to the original. Finally, ampicillin (titer 50 mg) was injected intramuscularly for the purpose of preventing infection.

(2) Administration of blood ammonia regulator PCS rats prepared as described above were subjected to administration experiments in 2 to 4 days after the operation, divided into two administration groups, an experimental group and a control group. The number of individuals in each group was 3. For the rats in the experimental group, the blood ammonia adjusting agent obtained in Production Example 4 was used as drinking water under free feeding of the mouse / rat / hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd. It was given in a drinking bottle with a nozzle set. For the rats in the control group, distilled water was given as drinking water instead of the blood ammonia regulator.

(3) Measurement of blood ammonia concentration At the same time on the 7th and 12th days immediately after the start of the administration experiment and at the same time on the 7th and 12th day, the rat was kept awake and blood was collected from the left jugular vein. Each collected blood was transferred to a tube containing heparin, mixed and ice-cooled, and immediately centrifuged to obtain supernatant plasma. The ammonia concentration in the obtained plasma was measured by the dry chemistry method. The average value of the measured ammonia concentration in each group is shown in Table 4 below.

Regarding the results shown in Table 4, the ammonia concentration in the jugular vein plasma measured in the control group increased with time. On the other hand, the ammonia concentration in the jugular vein plasma measured in the experimental group hardly changed over time. From the above, it is expected that the blood ammonia regulator is effective for the treatment and prevention of hyperammonemia.

Test Example 4: Verification of blood ammonia lowering effect of α-cyclodextrin in the portal vein cava (porto-caval shunt (PCS)) rat (Part 2)
(1) Preparation of PCS rat In the same manner as in Test Example 3, except that a 6-week-old SD male rat purchased from Japan SLC was used instead of a rat purchased from Charles River Japan. PCS rats were created.

(2) Administration of blood ammonia regulator The PCS rat prepared as described above was subjected to administration experiments 14 days after the operation, divided into two administration groups, a first experimental group and a second experimental group. The number of individuals in each group was 3. For rats in the first experimental group, distilled water was used until 11 am on the 6th day after the start of the administration experiment under free feeding with the mouse / rat / hamster feed CRF-1 manufactured by Oriental Yeast Co., Ltd. Thereafter, the blood ammonia adjusting agent obtained in Production Example 4 was given as drinking water in a drinking bottle with a nozzle set in a breeding cage. The rats in the second experimental group were given the blood ammonia adjusting agent obtained in Production Example 4 until 11 am on the sixth day after the start of the administration experiment, and thereafter distilled water as drinking water.

(3) Measurement of blood ammonia concentration Rats were kept awake at the same time on the 4th, 7th, 9th, and 14th days immediately before and after the start of the administration experiment, and blood was collected from the left jugular vein. Each collected blood was transferred to a tube containing heparin, mixed and ice-cooled, and immediately centrifuged to obtain supernatant plasma. The ammonia concentration in the obtained plasma was measured by the dry chemistry method. The average value of the measured ammonia concentration in each group is shown in Table 5 below.

Regarding the results shown in Table 5, the ammonia concentration in the jugular vein plasma measured in the first experimental group was at a relatively high level during the period when the first distilled water was administered. It decreased immediately after the start of administration of the conditioning agent. On the other hand, the ammonia concentration in the jugular vein plasma measured in the second experimental group was kept at a relatively low level during the period when the first blood ammonia adjusting agent was administered. After finishing the administration of the drug, it started to increase after a while. From the above, it is expected that the blood ammonia regulator is effective for the treatment and prevention of hyperammonemia.

Claims (13)

1. A blood ammonia regulator characterized by containing α-cyclodextrin as an active ingredient.
2. The blood ammonia adjusting agent according to claim 1, which is used as a therapeutic agent for hyperammonemia or hepatic encephalopathy.
3. The blood ammonia adjusting agent according to claim 1, which is used as a preventive agent for hyperammonemia or hepatic encephalopathy.
4. The blood ammonia adjusting agent according to any one of claims 1 to 3, which is formed as a preparation for oral administration or enteral administration.
5. The blood ammonia adjusting agent according to any one of claims 1 to 4, which is formed as a solid agent and contains α-cyclodextrin in an amount of 10 to 100% by mass.
6. The blood ammonia regulator according to claim 1, which is used as a food or drink for a patient with hyperammonemia or hepatic encephalopathy.
7. The blood ammonia regulator according to claim 1 or 6, which is formed as a solid food and contains α-cyclodextrin in an amount of 10 to 100% by mass.
8. Use of α-cyclodextrin to produce a blood ammonia regulator.
9. Use of α-cyclodextrin as a blood ammonia regulator.
10. A method of using a blood ammonia regulator containing α-cyclodextrin in order to reduce the blood ammonia concentration.
11. A method of using a blood ammonia adjusting agent containing α-cyclodextrin in order to suppress an increase in blood ammonia concentration.
12. A method of treating hyperammonemia or hepatic encephalopathy by administering a blood ammonia regulator containing α-cyclodextrin.
13. A method for preventing hyperammonemia or hepatic encephalopathy by administering a blood ammonia regulator containing α-cyclodextrin.