JP2008031164A - Pharmaceutical composition for preventing or treating hyperuricemia or disease caused thereby - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition for preventing or treating hyperuricemia through searching a new pharmacological activity of loxoprofen. <P>SOLUTION: The pharmaceutical composition for preventing or treating hyperuricemia or diseases caused thereby contains loxoprofen. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for preventing or treating hyperuricemia containing loxoprofen or a disease caused thereby.

  Hyperuricemia is a condition in which the concentration of uric acid in the blood is high. As a result of the breakdown of the balance between uric acid production and excretion, the blood uric acid concentration abnormally increases, and inflammation that is caused by crystallization of those that could not be dissolved in the blood locally occurs in the body. For example, gout attacks (gout arthritis) with severe pain when crystals of uric acid accumulate in the joints, gout nodules when accumulated under the skin, kidney stones and urinary tract stones with severe pain in the urine, renal tubules and renal interstitium Causes kidney damage.

  In recent years, reports that hyperuricemia itself is an independent risk factor for cardiovascular disorders are increasing (see Non-Patent Document 1), and gout patients often have arteriosclerotic patients. This is a fact that has been well known since ancient times (for example, see Non-Patent Document 2). It has also been found that there is a very good correlation between the blood uric acid level and risk factors for metabolic syndrome (see Non-Patent Document 3).

  Thus, prevention and treatment of hyperuricemia and diseases caused thereby are extremely important.

  Currently, uric acid biosynthesis inhibitors such as allopurinol and uric acid excretion promoting agents such as benzbromarone are used as therapeutic agents for hyperuricemia, but analgesics are administered because of severe pain during gout attacks. Yes.

  Colchicine was the first-line drug for the treatment of gout attacks, but colchicine was used at the time of the prediction of gout attacks as the anti-inflammatory effect and the serious side effects of high-dose administration became apparent. Only the minimum amount was set. Instead of this, a nonsteroidal antipyretic analgesic / anti-inflammatory agent (hereinafter referred to as NSAID) has been used (Non-patent Document 4).

  On the other hand, loxoprofen, a type of NSAID, is a prodrug-type drug that is converted into an active metabolite in the body and exhibits antipyretic analgesic / anti-inflammatory action. Therefore, gastrointestinal disorders, which are the main side effects of the same drug, are reduced and safe. It is known that the property is high (see, for example, Non-Patent Document 5) and has relatively quick action (see, for example, Non-Patent Document 6). However, since the indication of gout attack (gout arthritis) has not been approved, other NSAIDs (indomethacin etc.) having this indication are administered (for example, see Non-Patent Document 4).

  In addition, more than 100 years before the synthesis of aspirin, salicylic acid preparations are known to promote uric acid excretion from the kidney and have been used as a therapeutic agent for gout. However, aspirin, which reduces the blood uric acid level by a uric acid absorption inhibitory action in a large dose of 5 to 10 g, whereas it causes hyperuricemia on the basis of the usual antipyretic analgesic dose (1 to 2 g). This is known as a paradox, and at present, aspirin is not used for gout treatment (see, for example, Non-Patent Document 7).

  Moreover, there is no report that NSAIDs other than aspirin have the same phenomenon as aspirin paradox, and there is no report that NSAID was administered for the purpose of lowering blood uric acid level in recent years.

As described above, the action of NSAID in reducing the blood uric acid concentration has not been elucidated, and it has been unclear about loxoprofen.
Progress in Medicine Vol.14 No.12, 1994 p.50-53 Tokyo Metropolitan Medical Association Magazine Vol.57 No.5, 2004 p.35-42 Pharmaceutical Journal Vol.42 No.6, 2006 p.125-132 Clinical and Research Vol.65 No.12, 1988 p.61-66 Pharmacology and Treatment Vol.16 No.2, 1988 p.611-619 CLINICA Vol.31 No.1, 2004 p.38-41 Hyperuricemia and gout Vol.6 No.2, 1998 p.136-139

  The first object of the present invention is to search for a new pharmacological action of loxoprofen, and the second object is to investigate whether or not aspirin paradox exists in loxoprofen, and thus loxoprofen for the treatment of hyperuricemia. It is to examine whether the administration of is realistic.

  As a result of intensive studies to search for a new pharmacological action of loxoprofen, the present inventor has found that when loxoprofen is orally administered within an appropriate range, it has an excellent blood uric acid level lowering action.

  In detail, it was completely unexpected before the present invention was carried out, but in loxoprofen, blood uric acid level increased in large doses, and blood uric acid level decreased in medium and small doses As a result, it was found that a phenomenon opposite to the phenomenon (ie, aspirin paradox) inferred from the prior art appears, and the present invention has been completed.

This indicates that loxoprofen, which has been used in antipyretic analgesic / anti-inflammatory applications, has been used in diseases caused by hyperuricemia, i.e. gout, kidney damage, urolithiasis, cardiovascular disorder, arteriosclerotic disease, and metabolic syndrome. Is the first time that it is effective. Therefore,
The present invention is (1) a pharmaceutical composition for preventing or treating hyperuricemia containing loxoprofen or a disease caused thereby,
(2) The pharmaceutical composition according to (1), wherein 0.01 to 70 mg of loxoprofen per 1 kg body weight is orally administered;
(1) the pharmaceutical composition according to (1), wherein loxoprofen (0.1 to 10 mg per 1 kg body weight) is orally administered;
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the disease caused by hyperuricemia is gout, renal disorder or urinary calculus,
(5) The pharmaceutical composition according to any one of (1) to (3), wherein the disease caused by hyperuricemia is cardiovascular disorder, arteriosclerotic disease or metabolic syndrome,
(6) A pharmaceutical composition containing loxoprofen for reducing the cause of hyperuricemia or a disease caused thereby,
(7) The pharmaceutical composition according to any one of (1) to (6), wherein the loxoprofen is loxoprofen sodium,
(8) A method for preventing or treating hyperuricemia caused by loxoprofen or a disease caused thereby,
(9) A method for reducing the cause of hyperuricemia caused by loxoprofen or a disease caused thereby, and (10) hyperuricemia or a disease caused by administration of an effective amount of a composition containing loxoprofen to a mammal Is a method of preventing or treating.

  In the present invention, “loxoprofen” is loxoprofen or a salt thereof, preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

  The “salt” in the present invention indicates a salt because loxoprofen, which is an active ingredient of the present invention, has a carboxylic acid group and can be converted into a salt by reacting with a base.

  The “salt” is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; N-methylmorpholine salt, triethylamine salt, tributylamine. Salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salt such as picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, An amino acid salt such as aspartate, and more preferably an alkali metal salt.

  The active ingredient of the present invention may absorb moisture by adhering to the atmosphere or recrystallize, and may adsorb water or become hydrate. Are also used in the present invention.

  In the present invention, the “disease caused by hyperuricemia” is not particularly limited as long as it is a disease caused by a state in which the blood uric acid concentration becomes too high to be dissolved in the blood. Examples thereof include gout, renal disorder, urinary calculus, cardiovascular disorder, arteriosclerotic disease, metabolic syndrome and the like.

  Here, the “arteriosclerotic disease” refers to a state in which the arterial wall is thickened and loses elasticity, and there are, for example, three types: atherosclerosis, Menkeberg-type arteriosclerosis, and microarteriosclerosis.

  Metabolic syndrome is also called visceral fat syndrome, and is well known to have a strong correlation with hyperuricemia and gout.

  In the present invention, “reducing the cause of a disease caused by hyperuricemia” means reducing the cause of the above-mentioned disease by lowering the blood uric acid level.

  In the present invention, “treatment” means to cure or ameliorate a disease or symptom or suppress a symptom, and “prevention” means to prevent the onset of illness or symptom.

  Since the pharmaceutical composition of the present invention has an excellent blood uric acid level lowering action, hyperuricemia or diseases caused thereby, such as gout, kidney damage, urolithiasis, cardiovascular disease, arteriosclerosis, Useful for prevention or treatment of metabolic syndrome.

  In addition, the pharmaceutical composition of the present invention is effective for analgesia / anti-inflammation during a ventilation attack based on the blood uric acid concentration lowering action, and is also suitable for the treatment of diseases caused by a ventilation attack. Furthermore, it is also useful for the treatment or prevention of stiff shoulders, neck streaks, numbness of limbs and coldness of limbs due to peripheral blood flow disorders caused by arteriosclerotic diseases.

  Loxoprofen is listed in the 15th revised Japanese Pharmacopoeia.

  Further, other salts and hydrates of loxoprofen can be produced by known methods.

  The single dose of loxoprofen varies depending on the indication and age, but is usually 20 to 180 mg, and this is administered 1 to 3 times a day.

  In the case of a solid preparation, the content of loxoprofen contained in a single dose is usually 10 to 400 mg, preferably 20 to 180 mg.

  The content of loxoprofen contained in the case of a liquid preparation is usually 0.1 to 200 mg / mL, and preferably 1 to 100 mg / mL.

  In the present invention, in addition to the above active ingredients, if necessary, a uric acid production inhibitor (such as allopurinol), a uric acid excretion promoter (such as benzbromarone), an HMG-CoA reductase inhibitor, various vitamins or vitamin-like substances Further, herbal medicines and the like can be contained within a range not impairing the effects of the present invention.

  Specific examples of these dosage forms include tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and additives and base materials suitable for each dosage form. Can be used according to the usual methods described in the Japanese Pharmacopoeia and the like.

For example, in the case of tablets, lactose, crystalline cellulose or the like as an excipient, magnesium metasilicate aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant Can be used,
In the case of fine granules and capsules, lactose or purified sucrose is used as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, corn starch or the like as an adsorbent, hydroxypropylcellulose or the like as a binder As can be used.

  In each of the above dosage forms, a disintegrant such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a colorant such as iron sesquioxide and caramel; a stabilizer such as sodium benzoate; A pH adjuster; a fragrance, etc. can also be added.

  Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope of the present invention is not limited thereto.

Example 1 Tablet (1) Ingredient (Table 1)
1 or 2 tablets (mg)
------------------------
Loxoprofen sodium dihydrate 60
Lactose 120
Magnesium stearate 2
Corn starch 50
Low substituted hydroxypropyl cellulose appropriate amount ----------------------------
(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.

(Example 2) Fine granule (1) component (Table 2)
In 1 packet (mg)
------------------------
Loxoprofen sodium dihydrate 60
Lactose 100
Magnesium stearate 4
Low substituted hydroxypropyl cellulose appropriate amount ----------------------------
(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.

Example 3 Capsule (1) Ingredient (Table 3)
In 1 or 2 capsules (mg)
------------------------
Loxoprofen sodium dihydrate 60
Lactose 25
Magnesium stearate 3
Corn starch 40
Hydroxypropylcellulose Suitable amount -------------------------
(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.

(Example 4) Syrup (1) component (Table 4)
In 60 mL (mg)
-------------------------
Loxoprofen sodium dihydrate 60
Sodium benzoate 100
Glycerin 150
Polyvinyl alcohol 80
Sucrose 1200
Purified water remainder --------------------------.
(2) Manufacturing method Take the above ingredients and quantities, and manufacture a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to manufacture a syrup.

(Test Example 1)
(1) Test substance Loxoprofen sodium dihydrate was manufactured by Sankyo Co., Ltd.
(2) Animals As test animals, Covance Research Products Inc. Beagle dogs were purchased at 5 months of age and used after approximately one month of quarantine and acclimatization.
(3) Dosage Form, Preparation Method and Preservation Method The required amount of the test substance calculated based on the body weight of each test animal was filled into a gelatin capsule (1/2 ounce) manufactured by TORPAC. After filling, the capsules were placed in cases separated by animal and stored refrigerated until administration.
(4) Administration route and administration period Capsules filled with the test substance were orally administered by gavage to test animals once a day between 9:00 and 12:30. The test animals were fasted for 2-3 hours before administration.

The administration period was 11 days.
(5) Preparation of test sample About 10 mL of blood was collected from the cephalic vein on -14 and -7 days before capsule administration (second week and first week before administration start) and on days 4, 8 and 12 after administration. The test animals were fasted for about 18 hours before blood collection.

The obtained blood was placed in a test tube, allowed to stand at room temperature for 30 minutes to 1 hour, and then serum obtained by centrifugation (about 1600 × g, 10 minutes) was used.
(6) Test method The uric acid level in the blood was measured using the Uricase-POD method used normally.
(7) Test results The fluctuation rate of the blood uric acid level in loxoprofen administration was determined by converting the average of the blood uric acid level two weeks before and one week before administration to 100.

  The results obtained are shown in Table 5. Each value is an average value of 5 animals per group.

(Table 5)
Test substance% change in blood uric acid level
(Mg / Kg) 4 days after administration 8 days after administration 12 days after administration ――――――――――――――――――――――――――――――――― ―――――
Loxoprofen sodium dihydrate (10) 97.8 89.5 72.4 *
――――――――――――――――――――――――――――――――――――――
*: P = 0.009 (paired t test)
Administration of loxoprofen sodium dihydrate significantly reduced blood uric acid levels.

(Test Example 2)
(1) Test substance Loxoprofen sodium dihydrate was manufactured by Sankyo Co., Ltd.
(2) Animals As test animals, CD (SD) male rats 5 weeks old were purchased from Charles River Japan and used after acclimation for 1 week.
(3) Dosage form and administration route The test drug was used after dissolving in 0.5% CMC solution. The test drug was orally administered about 30 minutes after blood collection. The dose of the test drug containing the solvent (0.5% CMC solution) was 5 mLg / Kg.
(4) Test method The carotid artery was exposed by incising the right neck under ether anesthesia, and approximately 0.3 mL of blood was collected with a Terumo syringe (for 1.0 mL). Blood was collected four times, 30 minutes before administration of the test drug, 1 hour, 2 hours and 3 hours after administration. As blood collected at each time point, serum obtained by centrifugation (11,000 rpm, 5 minutes) was used.

The uric acid level in serum was measured using uric acid C-Test Wako (Uricase-TOOS method, manufactured by Wako Pure Chemical Industries).
(5) Test results FIG. 1 shows the results obtained by converting the blood uric acid level at 3 hours after loxoprofen administration into an average of 100 blood uric acid levels before administration. Each value is an average value of 5 animals per group.

  From FIG. 1, it was found that loxoprofen has a blood uric acid level lowering effect in the range of 0 to 70 mg / Kg. In particular, it was found that a significant blood uric acid level lowering effect was exhibited at a low dose of 10 mg / Kg or less.

  Since the pharmaceutical composition of the present invention has an excellent blood uric acid level lowering action, hyperuricemia or diseases caused thereby, such as gout, kidney damage, urolithiasis, cardiovascular disease, arteriosclerosis, Useful for prevention or treatment of metabolic syndrome.

  In addition, the pharmaceutical composition of the present invention is effective for analgesia / anti-inflammation during a ventilation attack based on the blood uric acid concentration lowering action, and is also suitable for the treatment of diseases caused by a ventilation attack. Furthermore, it is also useful for the treatment or prevention of stiff shoulders, neck streaks, numbness of limbs and coldness of limbs due to peripheral blood flow disorders caused by arteriosclerotic diseases.

FIG. 1 shows the effect of lowering blood uric acid level by administration of loxoprofen.

Claims (10)

A pharmaceutical composition for preventing or treating hyperuricemia or a disease resulting therefrom comprising loxoprofen. The pharmaceutical composition according to claim 1, wherein 0.01 to 70 mg of loxoprofen per 1 kg body weight is orally administered. The pharmaceutical composition according to claim 1, wherein 0.1 to 10 mg of loxoprofen is orally administered per 1 kg body weight. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disease caused by hyperuricemia is gout, kidney damage or urinary calculus. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disease caused by hyperuricemia is cardiovascular disorder, arteriosclerotic disease or metabolic syndrome. A pharmaceutical composition comprising loxoprofen for reducing the cause of hyperuricemia or a disease caused thereby. The pharmaceutical composition according to any one of claims 1 to 6, wherein loxoprofen is loxoprofen sodium. A method for preventing or treating hyperuricemia caused by loxoprofen or a disease caused thereby. A method for reducing the cause of hyperuricemia caused by loxoprofen or a disease caused thereby. A method for preventing or treating hyperuricemia or a disease caused thereby, wherein an effective amount of a composition containing loxoprofen is administered to a mammal.