WO2010022581A1 - Medical composition for treating hyperuricemia and the use thereof - Google Patents

Abstract

The present invention provides a medical composition for treating hyperuricemia or correlative diseases thereof, including febuxotat or derivatives thereof, probenecid and pharmaceutically acceptable carriers, wherein the weight ratio of febuxotat or derivatives thereof, probenecid and pharmaceutically acceptable carriers is 1:10~200:0.5~100. The present invention also provides the use of the medical composition and a method for treating hyperuricemia or correlative diseases thereof.

Description

 Pharmaceutical composition for treating hyperuricemia and use thereof

Technical field

 The present invention relates to a pharmaceutical composition for treating hyperuricemia, febuxostat and a uric acid excretion agent for the treatment of hyperuricemia, and more particularly to the treatment of febuxostat or a derivative thereof with probenecid. A pharmaceutical composition for treating a condition associated with hyperuricemia and gout. Background technique

 With the development of the economy and the improvement of people's living standards, the lifestyle and diet structure have changed, and many diseases have caused hyperuricemia, and its incidence has increased year by year, and there is a trend of aging. Hyperuricemia, like other metabolic diseases, has increased in recent years and has increased the mortality rate of cardiovascular and cerebrovascular diseases. Hyperuricemia includes primary and secondary hyperuricemia. When hyperuricemia reaches a certain high value, urate is formed, and crystallization accumulates in tissues and joints, causing gout attacks. Hyperuricemia can also cause gouty arthritis, gouty nephropathy, and kidney stones. At the same time, there is evidence that hyperuricemia is closely related to hypertension, coronary heart disease, diabetes, hyperlipidemia, hypercoagulability, obesity, etc., and is an important component of metabolic syndrome. They can influence each other and form a vicious circle, which is a serious threat to people's health and safety.

 Reducing plasma and tissue uric acid levels is a key component in the prevention of gout and the development of these diseases. There are two main types of drugs for the treatment of gout with uric acid:

 (1) Drugs that reduce uric acid production, such as allopurinol, febuxostat, etc., which reduce uric acid production by inhibiting xanthine oxidase activity, thereby reducing uric acid content in blood and urine. The important difference between febuxostat and allopurinol is that it has a specific inhibitory effect on xanthine oxidase, while allopurinol is only competitive inhibition. There is data showing that high doses of febuxostat have a significant detrimental effect on liver function.

(2) Drugs that promote uric acid excretion, such as probenecid, benzbromarone, sulfinpyrazone, etc., but they all have varying degrees of side effects and toxicity, especially When used in larger doses, it can cause harm to the human body. Inventive day, , · -1, inch -, p, gate, 〕, - ^ 舒 I: 10-200 ratio of the pharmaceutical composition has an unexpected synergy, which is They can rapidly and significantly reduce the concentration of uric acid in serum by using a much lower dose, thereby effectively treating hyperuricemia. Therefore, such pharmaceutical compositions are particularly suitable for the treatment of hyperuricemia and diseases associated therewith, such as acute and chronic gout.

 It is an object of the present invention to provide a pharmaceutical composition for the treatment of hyperuricemia.

 Another object of the present invention is to provide use of the pharmaceutical composition for the preparation of a medicament for the treatment of hyperuricemia and its associated various diseases, particularly acute and chronic gout.

 Accordingly, the present invention provides a pharmaceutical composition for treating hyperuricemia, the composition comprising febuxostat or a derivative thereof and probenecid and a pharmaceutically acceptable carrier; wherein febuxostat or The ratio by weight of the derivative to probenecid is 1: 10-200, preferably 1: 20-100, particularly preferably 1: 30-75; the febuxostat or its derivative and the drug in the pharmaceutical composition of the invention The weight ratio of the carrier used is 1: 0.5-100.

 The febuxostat derivative of the present invention includes not only a pharmaceutically acceptable salt of febuxostat with an alkali metal and with ammonia or an organic amine, such as a sodium salt, a potassium salt, a calcium salt, an ammonium salt, etc.; Solvents of febuxostat and its pharmaceutically acceptable salts, such as hydrates, alcoholates, and polycrystals of febuxostat and its pharmaceutically acceptable salts, such as febuxostat polycrystals, butethatin sodium salt Polycrystalline, febuxostat potassium salt polycrystalline^ The inventive pharmaceutical composition may be in the form of enteral and parenteral administration. The enteral administration forms include: various oral solid and liquid preparations, and the parenteral administration forms include sublingual preparations, transdermal preparations, injections, films or aerosols, and the like. Preferably, the active ingredient is intimately mixed with any one or several pharmaceutically acceptable carriers to form an oral solid preparation. Preferred oral solid preparations are various tablets, granules, pills, pills or capsules.

The pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention is a pharmaceutically commonly used excipient, and includes: a filler such as lactose, sucrose, starch, microcrystalline cellulose, sorbitol or calcium phosphate; a binder, for example, Syrup, gelatin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, PEG (polyethylene glycol), starch or dextrin; disintegrant, for example, microcrystalline cellulose, sodium carboxymethyl starch, carboxymethyl fiber Sodium or cross-linked polyvinylpyrrolidone; a lubricant such as magnesium stearate; a polymeric matrix material, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carnauba wax, hydrogenated vegetable oil Or an acrylic resin; a film-forming material, for example, hydroxypropylmethylcellulose, polyvinylpyrrolidone or C', another aspect of the invention discloses the pharmaceutical composition for the preparation of a treatment for hyperuricemia and its related The use of drugs for various conditions. The hyperuricemia includes primary and secondary hyperuricemia. The various conditions associated with hyperuricemia include acute and slow caused by hyperuricemia Sexual gout, gouty arthritis, gouty nephropathy and kidney stones.

 Another aspect of the invention provides a method of treating hyperuricemia or a variety of conditions thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention. The hyperuricemia includes primary and secondary hyperuricemia. The various conditions associated with hyperuricemia include acute and chronic gout caused by hyperuricemia, gouty arthritis, gouty nephropathy, and kidney stones.

 Preferably, the pharmaceutical composition of the present invention is prepared into a unit dose of a tablet or capsule for oral administration once a day, one tablet at a time. The daily dose for administration to an adult is 10-50 mg, preferably 20-40 mg of febuxostat or a derivative thereof, and 200-3000 mg, preferably 300-2000 mg of probenecid.

 In a preferred embodiment, the pharmaceutical composition of the present invention is prepared into tablets, one tablet per day for adults, each tablet containing 20 mg of febuxostat or a derivative thereof; and probenecid 1000 mg.

 In another preferred embodiment, the pharmaceutical composition of the present invention is prepared into capsules, one capsule per day for adults, 40 mg per febustat or a derivative thereof, and 1500 mg of probenecid.

 In another preferred embodiment, the pharmaceutical composition of the present invention is prepared into tablets, one tablet per day for adults, each tablet containing 20 mg of febuxostat or a derivative thereof; and probenecid 800 mg.

 A large number of clinical studies have confirmed that the pharmaceutical composition of the present invention can rapidly reduce the high uric acid concentration in serum to a normal level or below, thereby effectively treating hyperuricemia and its related diseases, especially acute and chronic. Gout, gouty arthritis, gouty nephropathy and kidney stones.

 In the clinical study of the present invention, the composition of the present invention containing febuxostat 40 mg and probenecid 1500 mg is administered to a patient with hyperuricemia having a serum uric acid concentration of 550-705 μηιο1 / ί, 1 tablet per day, 2 weeks later. The serum uric acid concentration dropped to normal or below normal, and no adverse reactions were observed in the patients who were administered.

 In a clinical case of the present invention, a composition of the present invention containing febuxostat 20 mg and probenecid 800 mg is administered to a patient with chronic spleen having a serum uric acid concentration of 65 (^mol / L, 1 tablet per day, 15 serum) The concentration of uric acid was reduced to normal, and the treatment was maintained for 45 days. The gout was cured and no adverse reactions were found in the patient.

 The pharmaceutical composition of the present invention rapidly and significantly reduces the level of high uric acid in the serum, and the amount of febuxostat is 1/6 to 1/4 of the amount used alone, which greatly reduces the toxicity and side effects of febuxostat. In particular, it reduces the damage of febuxostat on the liver and increases the patient's adaptability and tolerance. Can be used safely for a long time.

The following study demonstrates that the combination of febuxostat and probenecid has a significant synergistic effect in reducing serum uric acid concentrations. Experimental material

 1.1 Drugs and reagents

 Febuxostat, white powder, supplied by Tianjin Taipu Pharmaceutical Technology Development Co., Ltd. Before use, 0.5% sodium carboxymethylcellulose (CMC-Na) was used to prepare a suspension of the desired concentration for oral administration to the animals.

 Probenecid, light yellow powder, supplied by Tianjin Taipu Pharmaceutical Technology Development Co., Ltd. Before use, 0.5% sodium carboxymethylcellulose (CMC-Na) was used to prepare a suspension of the desired concentration for oral administration to the animals.

 Uric acid test kit, Nanjing Institute of Bioengineering, batch number 20080516.

1.2 Animals

 Kunming mice, SPF, provided by the Experimental Animal Center of the Institute of Radiation Medicine, Chinese Academy of Medical Sciences, license number SCXK Tianjin 2005-0001.

1.3 instruments

 PK121R cryogenic refrigerated centrifuge, produced by ALC, Italy.

 722 grating spectrophotometer, produced by Shanghai Third Analytical Instrument Factory. 2. Methods and results

 2.1 Effects on uric acid in normal animals

 After the mice were fasted overnight, they were randomized by body weight. Different doses of febuxostat, probenecid, febuxostat and probenecid were administered in different ratios, and the administration volume was 20 ml/kg. Six hours after administration, 0.5 mL of blood was taken from the eyeball. After standing at room temperature for 1 h, the serum was prepared by centrifugation at 3000 rpm. Serum was taken to determine the uric acid level. The variance analysis method was used to compare the synergistic effects of the compounds with different ratios.

2.1.1 Synergistic effect of febuxostat and probenecid

In normal mice, the combination of febuxostat and probenecid has a significant anti-uric acid effect between 1:3 and 200. There is a certain additive and synergistic effect between the two drugs; 1 : 10 ~ 200 There is a synergistic effect. The inhibitory effect at 1 : 33.3 is 141.6% higher than the total dose of the same dose, the inhibition is increased by 106.1% at 1 : 100, and the inhibition is increased by 56.2% at 1:200. Learning The analysis proves that the synergy between 1:33.3-200 is very obvious. The results are shown in Table 1. Table 1 Effect of different ratios of febuxostat and probenecid on serum uric acid in normal mice (X soil s)

" ―

"

 (mg/kg, serum uric acid concentration

 Dose ratio (%) control (n=10) - 2.46 ±0.37

 Febuxostat (n=10) 4 1.71 ±0,42* 30.5 probenecid (n=10) 12 2.41 ±0.44 2.03 febuxostat + probenecid

 4+12 1: 3 1.76 ±0.24* 28.5 (n=10)

 Control (n=10) - 2.46 ±0.37

 Febuxostat (n=10) 4 1.71 ±0.42 30.5 Probenecid (n=10) 40 2.40 ±0.50 2.44 febuxostat + probenecid

 4+40 1: 10 1.63 ±0.51*** 33.7 (n=10)

 Control (n=10) - 2.46 + 0.37

 Febuxostat (n=10) 3 1.96 ±0.28 20.3 Probenecid (n=10) 100 2.38 ±0.49 3.25 febuxostat + probenecid

 3+100 1: 33.3 1.06 ±0.34 * 56.9 (n=10)

 Control (n=10) - 2.46 ±0.37

 Febuxostat (n=10) 3 1.96 + 0.28 20.3 Probenecid (n=10) 300 2.11 +0.59 14.2 febuxostat + probenecid

 3+300 1: 100 0.71 ±0.24*" 71.1 (n=10)

 Control (n=10) - 2.46 ±0.37

 Febuxostat (n=10) 3 1.96 ±0,28 20.3 probenecid (n=10) 600 1.96 ±0.24** 20.3 febuxostat + probenecid

3+600 1: 200 0.67 ± 0.3 wide* ^ώ 72.8 (n=10)

 Note: 1. Compared with the control group (analysis of variance): *Ρ<0.05, Ρ<0.01, Ρ<0.001

2. ^ώ indicates ^synergy with unilateral comparison (ANOVA). 2.2 Effect on uric acid in mice with hyperuricemia

 After the mice were fasted overnight, they were randomized by body weight. Different doses of febuxostat, probenecid, febuxostat and probenecid were combined in different ratios, and the dosage volume was 20 ml/kg. Three hours after the administration, hypoxanthine 1000 mg/kg was administered by intragastric administration, and the hyperuricemia model was induced by subcutaneous injection of potassium oxonate 300 mg/kg. After 3 hours, 0.5 ml of blood was taken from the eyeball and allowed to stand at room temperature. After lh, the serum was prepared by centrifugation at 3000 rpm, and the uric acid level was determined by using the kit. The variance analysis method was used to compare the synergistic effects of the compounds of different ratios.

2.2.1 Synergistic effect of febuxostat and probenecid

 The mice were intragastrically administered with a combination of febuxostat and probenecid. The ratio of 1:10 to 1:150 could significantly antagonize the increase of serum uric acid caused by the complex styling agent, and had obvious anti-uric acid effect. In this ratio, the combination of the two drugs has a certain additive and synergistic effect, and statistical analysis shows that there is a significant synergy between 1:10 and 1:100. The results are shown in Table 2. Table 2 Effect of different ratios of febuxostat and probenecid on serum uric acid in hyperuricemia mice

 (X soil s)

 Dose compound inhibition rate group serum uric acid concentration

 (mg/kg) dose ratio (%) normal control (n=10) - 2.20 + 0.32

 10.52 ± 2.95

 8.30 ±2.78* 26.7

10.26 ±2.61 3.1

1:10 8.63 ±2.21* 22.8

10.52 ± 2,95

4+80 1:20 7.25 soil 1.86 39.4

10.52 ± 2.95

8.30 ±2.78* Probenecid (n=10) 150 8.07 ± 1.92* 29.4 febuxostat + probenecid

4+150 1:37.5 4.37 ±2.08* ^ώ 74.0 (n=10)

 Model control (n=10) - 10.52 ±2.95

 Febuxostat (n=10) 4 8.30 ±2.78* 26.7

 *

 Probenecid (n=10) 300 7.03 ±2.53 42.0 febuxostat + probenecid

4+300 1:75 3.17± 1.60*** ^Α 88.4 (n=10)

 Model control (n=10) - 10.52 ±2.95

 Febuxostat (n=10) 4 8.30 ±2.78* 26.7 Probenecid (n=10) 400 5.89 ±2.00 55.7 Febuxostat + probenecid

4+400 1:100 2·64± 1,02*** ^Λ 94.8 (n=10)

 Model control (n=10) - 10.52 ±2.95

 Febuxostat (n=10) 4 8.30 ±2.78* 26.7 Probenecid (n=10) 600 4.22 + 2.11 75.7 febuxostat + probenecid

 4+600 1:150 2.50 + 0.80 96.4 (n=10)

 Comparison with control group (analysis of variance): *P<0.05, **P<0.01, ***P<0.001; indicates synergy with unilateral comparison (ANOVA).

3. Experimental conclusion

 The uric acid production inhibitory drug, febuxostat and the uric acid excretion-promoting drug, probenecid, can inhibit serum uric acid in normal mice and hyperuricemia mice. The combination of febuxostat and probenecid has a synergistic effect in the ratio of 1:10 to 1:200, and has a significant synergistic effect in the ratio of 1:10 to 1:100. The best way to implement the invention

实施例 1 The following examples are intended to further illustrate the invention and not to limit the scope of the invention. Febuxostat can be prepared by reference to U.S. Patent No. 5,614,529. The corresponding sodium can be prepared by a conventional method.

Example 1

1000 g of probenecid, 10 g of febuxostat, 675 g of lactose, 250 g of microcrystalline cellulose, uniformly mixed, granulated with an appropriate amount of 10% PEG ⁶ 000 solution, dried, and then added with sodium carboxymethyl starch 83 g, stearic acid Magnesium 23.5g, mix, tablet, film coat. Example 2

 Preparation of tablets: 400 g of probenecid, 20 g of febuxostat, 1667 g of lactose, 390 g of pregelatinized starch, 15 g of hydroxypropylcellulose, 63 g of croscarmellose sodium, stearic acid Magnesium oxide 3 1.5g, evenly mixed, pure water granulation, drying, tableting, film coating. Example 3

 Preparation of tablets: Mix 400g of probenecid, 20g of febuxostat, add 300g of lactose, 10g of microcrystalline cellulose, mix well, add appropriate amount of 10% PEG4000 solution, granulate, dry, then add sodium carboxymethyl starch 52g, magnesium stearate 13.5g, mixed, compressed, coated film. Example 4

 Debastatin sodium salt (equivalent to 10 g of buprostatin), 600 g of probenecid, 610 g of dextrin, 1830 g of lactose, granulated with pure water, dried, and encapsulated to obtain 1000 capsules. Example 5

 Mix 750g of probenecid and 10g of febuxostat, add 800g of molten polyethylene glycol 4000, stir to dissolve and mix well, keep the liquid paraffin (5 ~ 10 °C) under the constant temperature of 60 °C In the case, it is condensed into drops, and the liquid paraffin is exhausted. Example 6 Preparation of Injection

 Fabbutostat potassium salt (equivalent to buprostatil 2g), probenecid 100g, propylene glycol 150ml, and polysorbate 35g. Take febuxostat potassium salt, probenecid into the water for injection of dissolved sorbitol and propylene glycol, add medicinal base to adjust the pH value to 8-9, dissolve it, make up the injection water to 2000ml, filter, potting , sterilized.

Claims

Patent claim A pharmaceutical composition for treating hyperuricemia, characterized in that the composition comprises febuxostat or a derivative thereof and probenecid and a pharmaceutically acceptable pharmaceutically acceptable carrier; He or a derivative thereof: probenecid: The acceptable ratio of the pharmaceutically acceptable carrier is 1:10 - 200: 0.5 ~ 100.  2. The pharmaceutical composition of claim 1 wherein said febuxostat derivative is selected from the group consisting of: a salt of febuxostat, a solvate of febuxostat and febuxostat, and febuxostat and Polycrystals of febuxostat salt.  The pharmaceutical composition according to claim 1, wherein the ratio of the weight fraction of febuxostat or its derivative to probenecid is 1: 20 to 100.  The pharmaceutical composition according to claim 3, wherein the ratio of the weight fraction of febuxostat or its derivative to probenecid is 1: 1 to 30 to 75.  5. A pharmaceutical composition according to any one of claims 1 to 4 which is in the form of enteral or parenteral administration. 6. A pharmaceutical composition according to claim 5, wherein said enteral administration form is in the form of various tablets, granules, pills, pills or capsules.  7. Use of a pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of hyperuricemia or a variety of conditions thereof.  8. The use of claim 7, wherein said hyperuricemia is selected from the group consisting of primary and secondary hyperuricemia.  9. The use of claim 7, wherein the condition is selected from the group consisting of acute and chronic gout, gouty arthritis, gouty nephropathy and kidney stones.  10. The application of any of claims 7-9, wherein the daily oral dose of the drug adult is: febuxostat or a derivative thereof 10-50 mg, probenecid 300-2000 mg.  11. A method of treating hyperuricemia or a variety of conditions thereof, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any of claims 1-6.  12. The method of claim 11 wherein said hyperuricemia is selected from the group consisting of primary and secondary hyperuricemia.  13. The method of claim 11 wherein said condition is selected from the group consisting of acute and chronic gout, gouty arthritis, gouty nephropathy and kidney stones.  The method according to any one of claims 11 to 13, wherein the daily oral dose of the drug adult is: febuxostat or a derivative thereof 10-50 mg, probenecid 300-2000 mg.