JPH01242523A - Renal ischemia improving agent - Google Patents

Abstract

PURPOSE:To obtain a renal ischemia improving agent containing dichloroacetic acid and/or salt thereof as an active ingredient, capable of effectively improving renal blood flow in ischemia state and useful in prevention of renal failure. CONSTITUTION:At least one kind of dichloroacetic acid and/or salt thereof is added as an active ingredient and formulated according to a conventional method to provide the aimed product. The aimed product can be prepared in form of injection, tablet, granule, inhalant, ointment, suppository, etc. In the case of the injection, dichloroacetic acids are blended with distilled water for injection, diluent, stabilizing agent, etc. The amount of active ingredient contained in the injection is 0.5-20w/v% and dose thereof is 60-2500ml/adult.day. In the case of the oral agent, dichloroacetic acids are blended with diluting agent, binder, disintegrator, etc., and an amount of active ingredient contained in the agent is 1-70wt.% and dose thereof is 2-100mg/kg/day.

Description

[Detailed description of the invention] Industrial applications The present invention relates to an agent for improving renal ischemia.

DISCLOSURE OF THE INVENTION It is known that the kidney has a low resistance to tissue hypoxia and can become ischemic due to various causes.When such ischemia occurs, the excretion of nitrogen metabolites becomes insufficient and the internal environment of the body becomes unstable. The patient becomes unable to maintain sex and develops what is called renal failure.

Specifically, when kidney failure occurs, blood urea nitrogen (BUN) and creatinine concentrations persistently increase, and as this condition progresses, other renal functions deteriorate, leading to deterioration in torpedo-removal metabolism, regulation of acid-base balance, This causes disorders such as the production of prostaglandins and renal hematopoietic factors, and the activation of vitamin D, and research into prevention and treatment is still being actively conducted.

By the way, the ischemic state of the kidney (renal ischemia), which is the cause of renal failure, is caused by, for example, blood vessel ligation, massive bleeding, thrombosis caused by blood components coagulating within the blood vessel, or part of a dislodged thrombus or blood outside the blood vessel. It is said that various foreign substances that have entered the body are carried by the bloodstream and reach small blood vessels, causing embolism and the like that occur when the lumen of the blood vessels is occluded.

As a result of extensive research aimed at providing a drug that can improve the above-mentioned renal ischemic condition, the present inventors have found that dichloroacetic acid and its pharmacologically acceptable salts are highly effective as the intended renal ischemia improving agent. They discovered that it has excellent medicinal effects and completed the present invention.

That is, the present invention relates to a renal ischemia improving agent characterized by containing at least one kind of dichloroacetic acid and/or a pharmacologically acceptable salt thereof as an active ingredient.

Dichloroacetic acid (hereinafter referred to as DCA) used as an active ingredient of the renal ischemia improving agent in the present invention is a known compound, and is described, for example, in Merck Index 10th edition p4443.

Further, in the present invention, pharmacologically acceptable salts of the above-mentioned DCA can also be used. Examples of the groups include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and non-toxic salts such as ammonium salts. Furthermore, DCA or a pharmacologically acceptable salt as an active ingredient in the present invention can be used alone, or two or more types of pharmacologically acceptable salts can be used alone. It is also possible to use a combination of at least one pharmacologically acceptable salt.

The renal ischemia improving agent of the present invention is used when it is necessary to immediately improve an ischemic state that has already occurred, or for the purpose of preventing ischemic state that may occur after vascular ligation due to surgery or the like. , are required to be fast-acting and are therefore most often used as injections (solutions, emulsions, suspensions) for intravenous administration;
For example, oral preparations such as tablets, granules, powders, gunpowder, suppositories, etc. It can also be used in various forms other than injections.

The preparation method for the above injection is not substantially different from that for conventional injections. For example, typically, active ingredients such as DCA are mixed and dissolved in distilled water for injection, etc., and diluents such as salt, glucose, glycerin, other ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, and polyoxylated It is preferably prepared to be isotonic with blood using isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, or the like. Furthermore, if necessary, stabilizers such as cyclodextrin, EDTA, thioglycolic acid,
Adding sodium bisulfite, etc., pH adjusters such as hydrochloric acid, acetic acid, lactic acid, malic acid, phosphoric acid, citric acid, sodium hydroxide, etc., and appropriate additives such as solubilizing agents, buffering agents, and sterilizing agents, It can also be prepared by a method in which the resulting aqueous solution is sterilized by heat sterilization, sterile filtration, or the like.

The pH of the injection thus prepared is usually 3.0 to 8.0.
The seed content is preferably about 5.0 to 7.5, and the amount of active ingredient is usually about 0.5 to 20 w/y%, preferably about 2.0 to 10 w/v%. is appropriate.

The drug in the form of an injection prepared as described above can be administered intravenously in the form of a sterile aqueous solution, thereby effectively improving renal ischemic conditions. The above-mentioned drug of the present invention (injection)
The dosage is generally about 60 to 250 per adult per day.
The dosage can be adjusted as appropriate depending on the pathological condition, age, body weight, concomitant drugs, etc. of the patient to whom it is administered, with 0 mQ, preferably about 100 to 650 mQ as a guide.

In addition, when forming tablets for oral administration, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, and ethanol can be used as carriers. , propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbylan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch , disintegrants such as lactose, disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, Adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, if necessary, the tablets may be coated with a conventional coating, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets, etc.

When forming into granules, carriers include excipients such as glucose, lactose, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, and binders such as gum arabic powder, tragacanth powder, gelatin, hydroxypropyl cellulose, and ethanol. Disintegrants such as , starch, agar, etc. can be used.

When molding into a fully expanded form, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers.

The active ingredient compound to be contained in the above-mentioned oral preparations and all preparations is not particularly limited and can be appropriately selected from a wide range, but it is usually preferable to contain about 1 to 70% by weight in the preparation. In addition, the dosage for oral administration or full dosage is usually about 2 to 1000 mg/kg of body weight per day.
The preparation may be administered in 1 to 4 divided doses per day.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to representative examples of the renal ischemia improving agent of the present invention, with reference to their production examples.

<Production Example-1> Sodium dichloroacetate 2500mg Distilled water for injection Appropriate amount Add an appropriate amount of activated carbon to the above solution, filter aseptically, fill in a 50mQ vial, and sterilize it in an autoclave at 105℃ for 40 minutes. to obtain the renal ischemia improving agent (2) of the present invention in the form of an injection.
, 5 w/v%).

<Production Example-2> Dichloroacetic acid 5000 mg Distilled water for injection Appropriate amount To the above solution, add an appropriate amount of activated carbon, further add sodium hydroxide to adjust the pH, filter aseptically, fill in a 50 mQ vial, This was sterilized in an autoclave at 105°C for 40 minutes, and the renal ischemia improving agent of the present invention in the form of an injection (50W
/V%) was obtained.

<Production Example-3> Dichloroacetic acid 2000 mg Sodium chloride 500 mg Distilled water for injection Appropriate amount To the above formulation, add disodium hydrogen phosphate and sodium hydroxide to adjust the pH, filter aseptically, and place in a 50 mQ vial. This was sterilized in an autoclave at 105°C for 40 minutes to obtain the renal ischemia improving agent (1,O
w/v%) was obtained.

Production Example-4 Sodium dichloroacetate 1000 mg Cyclodextrin 200 mg Distilled water for injection Appropriate amount To the above formulation, add disodium hydrogen phosphate and sodium hydroxide to adjust the pH, filter aseptically, and place in a 50 mQ vial. Fill and
This was sterilized in an autoclave at 105°C for 40 minutes, and the renal ischemia improving agent of the present invention in the form of an injection (2.5 w
/v%) was obtained.

Production example-5> Sodium dichloroacetate 100g lactose powder
70g Potato Starch 50g Hydroxypropyl Cellulose 2g Avicel pH 10153g Stearic Acid Talc 5□ Lactose Fine Granules 20g Sieved lactose powder and sodium dichloroacetate are mixed with a 10% ethanol solution of hydroxypropylcellulose, and then granulated. dry.

Potato starch, talc stearate, lactose fine granules, and Avicel were added to this mixture and the mixture was compressed to obtain a renal ischemia improving agent of the present invention in tablet form.

Production Example-6> Sodium dichloroacetate 400g Corn starch 120g Lactose
272g Magnesium Stearate 8g All amounts except magnesium stearate were finely powdered and mixed, and 4% starch paste was added and mixed to prepare granules for tableting. After drying, 1% magnesium stearate based on the total amount of the granules was added and tableted to obtain the renal ischemia improving agent of the present invention in tablet form.

Production Example-7> Sodium dichloroacetate 900g Hydroxypropylcellulose 25g Ethanol
After sieving and mixing 25001Ω sodium dichloroacetate, adding 250 mQ of 10% ethanol solution of hydroxypropyl cellulose and kneading,
Granulate, dry, and size. In this way, the renal ischemia improving agent of the present invention in the form of granules was obtained.

Production Example-8> Sodium dichloroacetate 50g Witepsol (H-15) 100g Witepsol (E75) 100g Sodium dichloroacetate, which was ground into fine particles by grinding in a mortar, was heated and melted with H-
15 and E75 were added little by little and stirred to obtain a homogeneous suspension, which was then filled into a fully opened plastic container at 40 to 45°C and molded to obtain a semi-open form of the renal ischemia improving agent of the present invention. .

Hereinafter, the results of animal experiments on the renal ischemia improving agent of the present invention prepared in the above production example will be described in detail.

1. Toxicity (LD5o) value The renal ischemia improving agent of the present invention (prepared according to Production Example 1 and adjusted to 10 w/v%) using 7 Wistar rats (4 retired males) per group. intravenously administered a predetermined amount (10 mg/kg/min), and orally administered a predetermined amount of the renal ischemia improving agent of the present invention (prepared according to Production Example 1 to 50 w/v%), Acute toxicity values were determined for each route of administration.

As a result, the LD5o value for intravenous administration was 3500.
~5000mg/kg, LDs for oral administration
o value was 5000 mg/kg or more.

2. Pharmacological effect Using 10 adult hybrids, anesthesia was induced with ketamine and suxamethonium chloride, and after endotracheal intubation, anesthesia was maintained with air-enflurane and pancuronium bromide. Breathing was controlled using a ventilator. Cannulate the femoral artery and vein, set up blood pressure measurement and infusion lines,
Swan Guns from the jugular vein
) A catheter was inserted to measure hemodynamics.

Thereafter, the test subject was placed in the right lateral position, and an incision was made along the body axis from the prominence of the external angle of the ilium to the lower costal end. After reaching the kidney transperitoneally, the left renal pedicle was dissected and an electromagnetic flowmeter probe was attached to the renal vein. Next, electrodes for measuring hydrogen gas clearance were inserted into the cortex and medulla of the kidney. An insensitive electrode was implanted subcutaneously on the inner side of the thigh, and the left ureter was cannulated to collect urine.

After the surgical procedure is completed and the condition stabilizes, blood pressure, pulse rate, central venous pressure, pulmonary artery wedge pressure, cardiac output, renal blood flow, and renal cortex are measured as values before DCA administration (hereinafter referred to as "previous values"). Blood flow, medullary blood flow, and urine output were measured.

Next, the renal ischemia improving agent of the present invention obtained in Production Example-1 was administered intravenously over 15 minutes at an active ingredient amount of 100 mg/kg (Experiment P3), and 15 minutes after the end of administration, a clamp was placed on the renal artery. The blood flow was blocked for 60 minutes. Unblocking 5
The above-mentioned measurements were carried out at respective times, one minute and one hour later.

In addition, in the above, a group to which the renal ischemia improving agent of the present invention was not administered was provided as a control group, and measurements were similarly performed at each period.

The renal blood flow rate obtained from the above test is shown in FIG. 1, the renal cortical blood flow rate is shown in FIG. 2, and the urine volume is shown in FIG. 3.

In each figure, the vertical axis shows renal blood flow% (relative value with the previous value as 100, Figure 1), renal cortical blood flow% (relative value with the previous value as 100, Figure 2), and urine volume (relative value with the previous value as 100, Figure 2). mQ/hrs 3rd
Figure), and the elapsed time from the start of the experiment is plotted on the horizontal axis, and the results of the experimental group (DCAC re-administration group and control R (DCA non-administration group) are plotted. In each figure, (1) is the experimental (2) shows the control group.

Examining the results shown in the figures above, the following becomes clear.

■ In the comparison of renal blood flow, in the control group (non-administered group), the blood flow was around 50% of the previous value, which was clearly decreased, but in the experimental group (DCA administration? 3), the blood flow was lower than the previous value. There was no difference, and blood flow was maintained even after ischemia.

■ A comparison of medullary blood volume showed that there was no major change due to ischemia between the experimental group (DCAC re-administration group and control group (non-administration group), and no difference was found; however, a comparison of cortical blood volume showed that hydrogen clearance The measured results showed that the control group had a decrease of about 60% compared to the previous value, whereas the DCAC
There was almost no difference from the value before the readministration group.

■ In a comparison of urine volume, the control group (non-administered group) decreased to 1/10 of the previous value, while the experimental group (DCAC
In the readministered group, the decrease was suppressed and urine output was maintained.

From these facts, it is clear that the renal ischemia improving agent of the present invention can effectively improve renal blood flow in ischemic conditions, and is an extremely useful drug as a renal ischemia improving agent and as a preventive drug for renal failure. is clear.

[Brief explanation of the drawing]

Figures 1 to 3 are graphs showing the results of subjecting the renal ischemia improving agent of the present invention to animal experiments, and Figure 1 shows renal blood flow,
Figure 2 shows the renal cortical blood flow, and the third representative, patent attorney Eiji Saegusa, 7E), shows the renal cortical blood flow.
5 minutes 1 hour R I J 5
Minutes IB41%'1 Fig. 3 front straight Clamp Ishibiki Xu 4 (1 examination)

Claims (1)

[Claims] (1) A renal ischemia improving agent characterized by containing at least one dichloroacetic acid and/or a pharmacologically acceptable salt thereof as an active ingredient.