JP2009102248A - Pharmaceutical composition for rapidly decreasing uric acid in blood and package, and use of anserine for rapidly decreasing uric acid in blood - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition for rapidly decreasing a uric acid level in blood of a subject useful for treating gout and/or alleviating symptoms related to a high uric acid level in blood that contains anserine in an amount of more than 50 mg up to about 600 mg. <P>SOLUTION: The pharmaceutical composition for rapidly decreasing a uric acid level in blood of a subject contains anserine in an amount of more than 50 mg up to about 600 mg. The package includes a label and/or an insert indicating that administration to a subject of the composition provides anserine in an amount of more than 50 mg up to about 600 mg per dose. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to administering anserine in an amount greater than 50 mg and up to about 600 mg so as to rapidly reduce a subject's blood uric acid level.

  Uric acid is the end product of purine metabolism in humans. Blood uric acid levels are a function of the balance between purine degradation and the rate of uric acid excretion. For many years, hyperuricemia has been considered to be associated with or the same as gout. However, uric acid is currently recognized as a marker for several metabolic and hemodynamic abnormalities. High blood uric acid levels induce gout and are usually associated with symptoms such as muscle spasms, localized swelling, inflammation, joint pain, muscle fatigue, feeling of stress, and myocardial infarction.

  Many over-the-counter drugs, such as benzbromarone (urinome), probenecid, allopurinol, bucolome, cinchophene, and colchicine are used for the treatment of gout. These drugs, for example, inhibit the formation of uric acid, remove excess uric acid, act on the kidneys to help excrete uric acid, inhibit the activity of xanthine oxidase, which converts xanthine to uric acid, and reduce uric acid excretion Acts by promoting. However, these drugs are known to have hepatotoxicity and cause many side effects such as urinary calculi, gastrointestinal obstruction, jaundice, and anemia. There are no reports that these drugs can rapidly reduce blood uric acid levels in subjects.

  Several dipeptides are known to be useful in reducing blood uric acid levels. For example, ROC (Taiwan) Patent No. I280136 (ROC (Taiwan) Patent Application No. 092114798) discloses a composition for reducing uric acid in a subject. The composition comprises an effective amount of one or more dipeptides consisting of histidine or a functional equivalent thereof and alanine or a functional equivalent thereof. Examples of dipeptides described in this ROC patent include carnosine, anserine, calcinin, and ofphidin. The ROC patent only teaches that the composition is administered orally to give dipeptides in an amount of about 8 mg to about 50 mg, preferably about 10 mg to about 45 mg per day. It does not disclose, suggest, or suggest any route that can rapidly reduce blood uric acid levels.

  Anserine (β-alanyl-1-methyl-L-histidine) is a very stable dipeptide having a pK value of about 7.1 and does not degrade even at low pH (<3.0). Anserine exists naturally in vertebrate skeletal muscle tissue and brain tissue and is formed by peptide bonds between β-alanine and 1-methyl-L-histidine (Tolkachevskaya, NF. 1929. Z Physiol Chem. 185: 28-32). In 1938, there is a report that anserine is an ideal physiological acid-base buffer. Due to its physiological acid-base buffering capacity, anserine is effective in eliminating lipid peroxidation promoted by changing the pH value of biological systems. For an acidemia subject suffering from gout, the administration of anserine acting as an acid-base buffer is beneficial in helping to regulate blood pH values and lowering blood uric acid levels. 40% of the fast muscle fiber buffer capacity is due to the contribution of dipeptides in the mobile phase, while the remaining percentage of fast muscle fiber buffer capacity is essentially due to the contribution of muscle proteins in the stationary phase (Bate- Smith, EC. 1938, “Stiffening Muscle Buffering: Proteins, Phosphate, and Carnosine (see The buffering of mouse in protein: phosphate, phosphate and carriage)” J Physiol. 92: 336-43). This document shows that in highly structured myocytes, a local acid-base gradient is composed of mobile phase buffering support and stationary phase buffering suppression.

  In addition, anserine has various antioxidant properties and is useful as a free radical scavenger or metal chelator. Subjects who have suffered from inflammation for a long time usually show higher in vivo free radical concentrations. Administration of anserine, which acts as a free radical scavenger, is advantageous for removing free radicals.

Anserine is also effective in inhibiting lipid peroxidation promoted by iron, hemoglobin, lipid peroxidase, and singlet oxygen (Babizhayev MA et al., 1994, “Natural with hydroxyl radical scavenging activity and lipid peroxidase activity. L-carnosine (beta-alanyl-L-histidine) and calcinin (beta-alanylhistamine) acting as antioxidants
(L-carinosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities) "Biochem J. 304 (Pt 2): 509-516, And Kohen R. 1988, "Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain" Proc Natl Acad Sci USA. 85 (9): 3175-3179).

  In addition, anserine can improve in vivo oxidative stress caused by fatigue and enhance oxygen radical absorption capacity in vivo. Anserine also serves as a transmitter precursor in the central histaminergic nervous system. Through metabolism of histidine contained in anserine, anserine can effectively regulate histamine concentration in the central nervous system, reduce blood cortisol concentration, and reduce fatigue (Aoi W et al., 2006). , “Exercise and functional foods” Nutr J. 5: 15-22 and US Pat. No. 6,680,294).

  However, there are no reports that commercially available drugs for the treatment of gout containing anserine have the effect of rapidly reducing blood uric acid levels in subjects.

  There remains a need to develop new drugs that can rapidly reduce blood uric acid levels in subjects, thereby treating gout and alleviating symptoms associated with high blood uric acid levels.

  The inventors have surprisingly discovered that administration of anserine in an amount greater than 50 mg per dose and up to about 600 mg can rapidly reduce a subject's blood uric acid levels.

  Thus, the present invention relates to a pharmaceutical composition for rapidly reducing blood uric acid levels in a subject comprising an anserine in an amount greater than 50 mg and up to about 600 mg.

  The invention further includes a pharmaceutical composition of the invention and a label and / or package insert indicating that administration of the composition to a subject provides an amount of anserine greater than 50 mg per dose and up to about 600 mg. Related to the package containing.

  The present invention further relates to a method for rapidly reducing a subject's blood uric acid level comprising administering to the subject an anserine in an amount greater than 50 mg and up to about 600 mg.

  In addition, the present invention relates to the use of anserine in the manufacture of a medicament for rapidly reducing blood uric acid levels in a subject, the medicament comprising an anserine in an amount of more than 50 mg and up to about 600 mg.

  In a first aspect, the present invention provides a pharmaceutical composition for rapidly reducing blood uric acid levels in a subject comprising an amount of anserine greater than 50 mg and up to about 600 mg. The pharmaceutical composition of the present invention can rapidly reduce blood uric acid levels in a subject, thereby treating gout and / or ameliorating symptoms associated with high blood uric acid levels.

  In a second aspect, the invention provides a pharmaceutical composition of the invention and a label indicating that administration of the composition to a subject provides an anserine in an amount greater than 50 mg and up to about 600 mg per dose and / or Provide a package that includes the package insert. The packages of the present invention are useful for rapidly reducing a subject's blood uric acid levels, thereby treating gout and / or ameliorating symptoms associated with high blood uric acid levels.

  In a third aspect, the present invention provides a method for rapidly reducing blood uric acid levels in a subject comprising administering to the subject an amount of anserine greater than 50 mg and up to about 600 mg. The methods of the present invention can rapidly reduce a subject's blood uric acid levels, thereby treating gout and / or ameliorating symptoms associated with high blood uric acid levels.

  In a fourth aspect, the present invention provides the use of anserine in the manufacture of a medicament capable of rapidly reducing a subject's blood uric acid level, wherein the medicament comprises an anserine in an amount greater than 50 mg and up to about 600 mg. Including. The medicament can rapidly reduce a subject's blood uric acid levels, thereby treating gout and / or ameliorating symptoms associated with high blood uric acid levels.

  Anserine may be naturally occurring or synthesized. In the present invention, in order to obtain the effect of rapidly reducing the blood uric acid level of a subject, the amount per dose is more than 50 mg, up to about 600 mg, preferably about 100 mg to about 500 mg, more preferably An amount of about 150 mg to about 250 mg of anserine is administered to the subject.

  In this application, the term “rapidly reduces blood uric acid levels” means that the amount of decrease in blood uric acid levels in a subject within one hour of anserine administration is about 0.5 to about 4 mg / dL (dL is deciliter, Hereinafter the same). The term “subject” refers to a mammal, preferably a human. Furthermore, the term “symptom associated with high uric acid levels” refers to, for example, muscle spasms, localized swelling, inflammation, joint pain, muscle fatigue, feeling of stress, myocardial infarction, or a combination thereof.

  The pharmaceutical compositions and medicaments of the present invention can be prepared by any conventional method known in the art. In addition to the active ingredient, anserine, the pharmaceutical compositions and medicaments of the present invention may contain pharmaceutically or physiologically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, dextrin-maltose, lactose, sucrose, mannitol, starch, microcrystalline cellulose, carboxymethylcellulose, talc, and magnesium stearate.

  The pharmaceutical compositions and medicaments of the present invention can be formulated into suitable dosage forms such as tablets, powders, granules, capsules, solutions, and suspensions for various routes of administration. The pharmaceutical compositions and medicaments of the present invention can be administered via any suitable route, preferably the oral or parenteral route.

  Any known packaging and printing method can be used to make the package of the present invention.

  The present invention will become apparent by reference to the following examples, which are to be construed as purely illustrative and limit the scope of the invention as claimed. is not.

(Example 1)
Anserine (GL Biochem Ltd., Shanghai, China) and dextrin-maltose were filled into gelatin capsules (total weight 400 mg). The capsule contained 50 mg of anserine. Subjects suffering from gout and having high blood uric acid levels took 3 capsules (total amount 150 mg of anserine) twice a day and 5 capsules (total amount of 250 mg of anserine) once a day. Therefore, the total dose of anserine taken by the subject per day was 550 mg. Blood uric acid levels were monitored by UroSpeed (Apex Biotechnology Co., Inc. Hsinchu, Taiwan, ROC), a rapid serum uric acid test strip. The results are shown in Table 1 and further illustrated in FIG.

  As shown in Table 1 and FIG. 1, the range of decrease in blood uric acid levels is 0.9 mg / dL to 1.5 mg / dL 1 hour after administration of capsules containing anserine. One hour after administration of 150 mg of anserine at 10:35, blood uric acid level decreased by 1.5 mg / dL. After the subject ingested beef noodles at noon, the subject's blood uric acid level increased to 11.9 mg / dL. One hour after administration of 150 mg of anserine at 13:15, the subject's blood uric acid level decreased by 0.9 mg / dL. One hour after ingesting 250 mg of anserine at 17:17, the subject's blood uric acid level dropped by 1.3 mg / dL. The data in Table 1 shows that administration of anserine can rapidly reduce a subject's blood uric acid levels within 1 hour.

(Example 2)
This oral administration study was conducted on 15 adult volunteers (9 men and 6 women from age 28 to 53) with chronic hyperuricemia. These subjects discontinued normal medication for at least 3 days. These subjects had blood uric acid levels higher than 9.3 mg / dL. These subjects were randomly divided into 5 groups, each consisting of 3 subjects, taking the following doses of anserine. The doses were 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg, respectively. After 1 hour, the subject's blood uric acid level was measured. The subject's blood uric acid level was found to drop from 1.1 mg / dL to 1.3 mg / dL. Among the 5 groups, the decrease in blood uric acid level of the group taking 150 mg of anserine was the most remarkable. The results are shown in Table 2.

It is a figure which shows the influence of orally administered anserine on the blood uric acid level.

Claims (14)

  A pharmaceutical composition for rapidly reducing a subject's blood uric acid level, comprising an anserine in an amount greater than 50 mg and up to about 600 mg.   2. The pharmaceutical composition according to claim 1 comprising anserine in an amount of about 100 mg to about 400 mg.   The pharmaceutical composition according to claim 2, comprising anserine in an amount of about 150 mg to 250 mg.   4. The pharmaceutical composition according to any one of claims 1 to 3, useful for the treatment of gout and / or the alleviation of symptoms associated with high blood uric acid levels.   The pharmaceutical composition according to claim 4, wherein the symptom is selected from muscle spasm, localized swelling, inflammation, joint pain, muscle fatigue, feeling of stress, myocardial infarction, and combinations thereof. A pharmaceutical composition comprising anserine;
Administration of said composition to a subject provides an amount of anserine of greater than 50 mg per dose and up to about 600 mg to treat gout and / or alleviate symptoms associated with high blood uric acid levels Package including label and / or package insert.   7. The package of claim 6, wherein the label and / or the package insert indicates that administering the composition to the subject provides an amount of about 100 mg to about 500 mg of anserine.   8. The package of claim 7, wherein the label and / or the package insert indicates that administering the composition to the subject provides an amount of about 150 mg to about 250 mg of anserine.   The package according to claim 6, wherein the symptom is selected from muscle spasm, localized swelling, inflammation, joint pain, muscle fatigue, feeling of stress, myocardial infarction, and combinations thereof.   Use of anserine in the manufacture of a medicament comprising an anserine in an amount greater than 50 mg and up to about 600 mg to rapidly reduce a subject's blood uric acid level.   11. Use according to claim 10, wherein the medicament comprises anserine in an amount of about 100 mg to about 400 mg.   12. Use according to claim 11, wherein the medicament comprises anserine in an amount of about 150 mg to about 250 mg.   11. Use according to claim 10, wherein the medicament is useful for the treatment of gout and / or alleviation of symptoms associated with high blood uric acid levels.   14. The use according to claim 13, wherein the symptom is selected from muscle spasm, localized swelling, inflammation, joint pain, muscle fatigue, feeling of stress, myocardial infarction, and combinations thereof.

Images