WO2010022580A1

WO2010022580A1 - Medical composition for treating hyperuricemia and the use thereof

Info

Publication number: WO2010022580A1
Application number: PCT/CN2009/000837
Authority: WO
Inventors: 谭明胜; 张殿镇; 赵健; 朱红星
Original assignee: 天津泰普药品科技发展有限公司
Priority date: 2008-08-26
Filing date: 2009-07-27
Publication date: 2010-03-04
Also published as: CN101658519A; CN101658519B

Abstract

The present invention provides a medical composition for treating hyperuricemia or correlative diseases thereof, including febuxotat or derivatives thereof, uricosuric drug and pharmaceutically acceptable carriers, wherein the weight ratio of febuxotat or derivatives thereof, benzbromarone and pharmaceutically acceptable carriers is 1:1~4:0.5~100. 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

The present invention relates to a pharmaceutical composition for the treatment of 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 benzbromarone 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. However, there are data showing that high doses of febuxostat have a significant damaging effect on liver function.

(2) Drugs that promote uric acid excretion, such as probenecid, benzbromarone

(benzbromarone) and sulfinpyrazone, etc., but they all have varying degrees of side effects and toxicity, especially when used in larger doses, which can cause harm to the human body. Summary of the invention

The inventors of the present invention have surprisingly found through animal experiments that pharmaceutical compositions composed of febuxostat or a derivative thereof and benzomethalone in a ratio of 1-4 1-4 have an unexpected synergistic effect, which is Use a much lower dose to quickly and significantly reduce the concentration of uric acid in the serum, thus Effectively treat 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 benzbromarone and a pharmaceutically acceptable carrier; wherein febuxostat or Its derivatives: benzbromarone: The acceptable ratio of the pharmaceutically acceptable carrier is from 1: 1 to 4: 0.5 to 100. Preferably, the ratio by weight of febuxostat or its derivative to benzomethalin is from 1 : 1 to 4, particularly preferably from 1 to 2-4.

In a particularly preferred embodiment of the invention, the ratio by weight of febuxostat or its derivative to benzbromarone is 1:2.

In another particularly preferred embodiment of the invention, the ratio by weight of febuxostat or its derivative to benzbromarone is 1:1.

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.; Solvates of febuxostat and its pharmaceutically acceptable salts, such as hydrates, alcoholates, and polycrystals of febuxostat and its pharmaceutically acceptable salts, such as febuxostat, crystals of febuxostat Salt polycrystals, non-bustatin potassium salt polycrystals, etc.

The pharmaceutical compositions of the invention may be in the form of enteral and parenteral administration. The enteral administration forms include: various oral solid and liquid preparations, and parenteral administration forms including sublingual preparations, transdermal administration.

Tablets, granules, pills, pills or capsules.

The pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention is a pharmaceutically acceptable excipient, and includes: a filler such as lactose, sucrose, starch, microcrystalline cellulose, sorbitol or calcium phosphate; a binder such as syrup , gelatin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, PEG (polyethylene glycol), starch or dextrin; disintegrant, for example, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked carboxylate Methylcellulose sodium or crosslinked polyvinylpyrrolidone; a lubricant, for example, magnesium stearate; a polymeric matrix material, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, Carnauba wax, hydrogenated vegetable oil or acrylic resin; film forming materials, for example, hydroxypropyl methylcellulose, polyvinylpyrrolidone Another aspect of the invention is the use of the pharmaceutical composition for the manufacture of a medicament for the treatment of hyperuricemia and its associated various conditions. 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.

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: 20-80 mg, preferably 20-40 mg of febuxostat or a derivative thereof; and 20-120 mg, preferably 40-80 mg of benzbromarone.

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 benzbromarone 80 mg.

In another preferred embodiment, the pharmaceutical composition of the present invention is prepared into capsules, one capsule per day for adults, 20 mg per febustat or a derivative thereof, and 40 mg of benzbromarone.

In another preferred embodiment, the pharmaceutical composition of the present invention is prepared into tablets, one tablet per day for adults, each tablet containing 40 mg of febuxostat or its derivative; and benzbromarone 60 mg.

In still 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 its derivative; and benzbromarone 60 mg.

Clinical studies have confirmed that the pharmaceutical composition of the present invention is capable of rapidly lowering the high uric acid concentration in serum to a normal level or below, thereby effectively treating hyperuricemia and its related conditions, particularly 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 20 mg of febuxostat and 80 mg of benzbromarone is administered to a patient with hyperuricemia having a serum uric acid concentration of 550-680 μm ηιοΙ / L, 1 tablet per day. After 2 weeks, the serum uric acid concentration fell to a normal value or lower than the normal value, and no adverse reaction was observed in the patient who was administered.

In a clinical case of the present invention, a composition of the present invention containing febuxostat 20 mg and benzbromarone ⁴⁰ _μg is administered to a patient with chronic gout having a serum uric acid concentration of 671 mol / L, 1 tablet per day, 15 days later. The serum uric acid concentration 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.

In a clinical case of the invention, it will contain 40 mg of febuxostat and 40 mg of benzbromarone. The composition of the present invention is administered to a patient with chronic gout having a serum uric acid concentration of 690 mol / L. The serum uric acid concentration drops below the normal value (109 mol / L) after 1 day and 15 days, and the treatment is maintained for 45 days, and the gout is cured. The urate crystals precipitated from the toe joints were dissolved, 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 to 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 benzbromarone reduces serum uric acid concentration

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) is formulated into a suspension of the desired concentration for oral administration to a medicinal animal.

Benzobromarone, 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.

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, benzbromarone, febuxostat and benzbromarone, in a combination of different ratios, were administered at a volume of 20 ml/kg. 6h after administration, 0.5 mL, ^When the temperature was allowed to stand for 1 h, the serum was prepared by centrifugation at 3000 rpm, and the serum was used for the test level, and the variance analysis method was used to compare whether the compounds of different ratios had

2.1.1 Synergistic effect of febuxostat and benzbromarone

Normal mice were given a combination of febuxostat and benzbromarone to produce a significant anti-uric acid effect between 2:1 and 1:8. There was a certain additive and synergistic effect between the two drugs; There is a synergy between 1 and 1:4. The inhibition at 1:1 is 23.7% higher than the sum of the same doses used alone, and the inhibition is increased by 60.0% at 1:2, and the inhibition is improved at 1:4. 322.0%; Statistical analysis proved that the synergy between 1:2~1 is very obvious. The results are shown in Table 1. Effect of serum uric acid in rats (X± s) dose compound inhibition rate group serum uric acid concentration

(mg/kg) dose ratio (%) control (n=lC 0 -2.33 + 0.30 0 febuxostat (n= :10) 4 1.71 ±0.42 26.2 benzbromarone (n= :10) 2 2.29 ± 0.48 1.0 febuxostat + benzene ^

4+2 2: 1 1.59 ±0.14 19.2 (ii=10)

Control (η=10) - 2.33 ±0.30 0 febuxostat (η=10) 4 1.71 +0.42 26.2 benzbromarone (η=10) 4 2.29 ±0.48 1.2 febuxostat + benzbromarone

4+4 1: 1 1.59 ±0.14* 33.9 (η=10)

Control (η=10) - 2.33 ±0.30 0 febuxostat (η=10) 4 1.71 ±0.42 26.2 benzbromarone (η=10) 8 2.30 + 0.63 0.8 febuxostat + benzbromarone

4+8 1: 2 1.32 ±0.47*** * 43.2 (η-5)

Control (η=10) 2.33 ±0.30 0 febuxostat (η=10) 1.96 ±0.28* 15.5 benzbromarone (η=10) 2.30 ±0.45 0.9 Febuxostat + benzbromarone

3+12 1: 4 0.73 ± 0.20*** * 69.3

(n=10)

Control (n=10) - 2.33 ±0.30 0 febuxostat (n=10) 3 1.96 + 0.28 15.5 benzbromarone (n=10) 24 0.87 ±0.20 62.3 febuxostat + benzbromarone

3+24 1: 8 0.68 ±0.31*** 70.8 (n=10)

Note: 1. Compared with the control group (analysis of variance): *P<0.05, **P<0.01 PO.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, benzbromarone, febuxostat and benzomethalin in different ratios were administered at a dose of 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 benzbromarone

In the hyperuricemia mice, the combination of febuxostat and benzbromarone was administered with a significant anti-uric acid increase between 2:1 and 1:8. There was a certain additive between the two drugs. Synergistic effect; compound with ratio between 1:1 and 1:4, statistically proved to have obvious synergistic effect, the anti-uric acid increase at 1:1 was 23.6% higher than the total dose of the same dose alone. , I: ² when increased ^23.6% 1: 4 increased 43.3%. The results are shown in Table 2. Effects of different ratios of febuxostat and benzbromarone on serum uric acid in hyperuricemia mice

(X soil S)

Group ¹ J Qi amount of complex inhibition of serum uric acid concentration ^

(mg/kg) \ (%) Normal control (n=10) 2.27 ±0.35

Model Control (n=10) - 10.69 + 2.17

Febuxostat (n=10) 4 8.31 ±2.82* 28.3 benzbromarone (n=10) 2 10.08 ±2.17 7.3 febuxostat + benzbromarone

4+2 2: 1 7.47 ±2.87 38.2 (n=10)

Model control (n= 10) ― 10.69 ±2.17

Febuxostat (n=10) 4 8.31 ±2.82* 28.3 benzbromarone (n=l ⁽⁾ ) 4 9.68 ±2.36 12.0 febuxostat + benzbromarone

4+4 1: 1 6.49 ± 1.58* ^Λ 49.8 (n=10)

Model Control (η=10) - 10.69 + 2.17

Febuxostat (η=10) 3 8.31 +2.82* 15.8 benzbromarone (η=10) 6 8.72 ± 1.70 23.5 febuxostat + benzbromarone

4+8 1: 2 5.39 ±0.78"* * 62.9 (η=10)

Model control (η= 10) - 10.69 + 2.17

Febuxostat (η=10) 3 8.31 ±2.82* 15.8 benzbromarone (η=10) 12 7,49 ± 1.96 38.0 febuxostat + benzbromarone

3+12 1: 4 4.20 soil 0.84 77.1

(η=10)

Model control (η=10) - 10.69 ±2.17

Febuxostat

3 8.31 ±2.82* 15.8 benzbromarone (η=1 ⁽⁾ ) 24 5.54 ± 1.56 61.2 febuxostat + benzbromarone

3+24 1: 8 3.76 ±0.93 82.3 ( 10)

: force, Ρ<0·05, Ρ<0.01, Ρ<0.001: 3. Experimental conclusion

The uric acid production inhibitory drug, febuxostat and the uric acid excretion promoting drug, benzbromarone, can reduce serum uric acid levels in normal mice and hyperuricemia mice. The test shows that the combination of febuxostat and benzbromarone There is a very significant synergy in the ratio of 1:1 to 1:4. The best way to implement the invention

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 salt, potassium salt can be prepared by a conventional method. Benzolamonone is commercially available from the market. Example 1

Preparation of tablets: 50 g of benzbromarone, 20 g of febuxostat, 43 g of lactose, 16 g of microcrystalline cellulose, uniformly mixed, granulated by adding appropriate amount of 10% PEG6000 solution, dried, and then added sodium carboxymethyl starch 5.3g, 1.5g magnesium stearate, mixed, compressed, coated film. Example 2

Preparation of tablets: 80 g of benzbromarone, 20 g of febuxostat, 397 g of lactose, 93 g of pregelatinized starch, 15 g of hydroxypropylcellulose, 29.8 g of croscarmellose sodium, stearic acid Magnesium 7.5g, mixed evenly, pure water granulation, drying, tableting, film coating. Example 3

Preparation of tablets: 40 g of benzbromarone, 20 g of febuxostat, 28.5 g of lactose, 10.5 g of microcrystalline cellulose, uniformly mixed, granulated with an appropriate amount of 10% PEG4000 solution, dried, and then added with carboxymethyl starch. Sodium 4.7g, magnesium stearate 1.2g, mixed, compressed, coated film. Example 4

Febuxostat potassium salt (equivalent to buprostat 40 g), benzbromarone 6 () g, dextrin 100 g, lactose 270 g, granulated with pure water, dried, and encapsulated to obtain 1000 capsules. Example 5

20 g of febuxostat, 60 g of benzbromarone, 45 g of lactose, 18 g of microcrystalline cellulose, mixed evenly, Add appropriate amount of 10% PEG6000 granules, dry, add 58g of sodium carboxymethyl starch, 1.8g of magnesium stearate, mix, compress, and coat the film. Example 6

20g of febuxostat; 20g of benzbromarone, (1: 1) is added to 100g of molten polyethylene glycol 4000, stirred in molten polyethylene glycol 4000, all dissolved and mixed evenly, maintaining a constant temperature of 60 ° C Under the conditions, drip into liquid paraffin (5 ~ 10 ° C), condense into drops, absorb liquid paraffin, select the particles, that is. Example 7 Preparation of Injection

Febuxostat potassium salt (equivalent to buprostatil 2g), benzbromarone 8g, ethanol 200ml, propylene glycol 150ml, polysorbate 35g. The febuxostat potassium salt is taken. The benzbromarone is added to the water for injection which has dissolved sorbitol and propylene glycol. After dissolution, the water for injection is supplemented to 1000 ml, filtered, potted and sterilized.

Claims

Rights request

A pharmaceutical composition for treating hyperuricemia, characterized in that the composition comprises febuxostat or a derivative thereof and benzbromarone and a pharmaceutically acceptable pharmaceutically acceptable carrier; Sitamin or its derivative: benzbromarone: The acceptable ratio of the pharmaceutically acceptable carrier is from 1: 1 to 4: 0.5 to 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 by weight of febuxostat or a derivative thereof to benzbromarone is from 1:2 to 4.

The pharmaceutical composition according to claim 3, wherein the ratio by weight of febuxostat or a derivative thereof to benzomethalin is 1:4.

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 hyperacemia.

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.

The use according to any one of claims 7 to 9, wherein the daily oral dose of the drug adult is: 20-80 mg of febuxostat or a derivative thereof, and 20-120 mg of benzbromarone.

11. The use of claim 10, wherein the daily oral dose of the drug adult is: 20-40 mg of febuxostat or its derivative, 40-80 mg of benzbromarone.

12. 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.

13. The method of claim 12 wherein said hyperuricemia is selected from the group consisting of primary and secondary hyperuricemia.

14. The method of claim 12 wherein said condition is selected from the group consisting of acute and chronic gout, gouty arthritis, gouty nephropathy and kidney stones.

15. The method of any of claims 12-14, wherein the medicament is a daily oral dose for adults: febuxostat or derivatives 2 () - 80mg, benzbromarone 20-l ² 0mg.

16. The method of claim 15, wherein the medicament is a daily oral dose for adults: febuxostat or its derivative 20- 40mg, benzbromarone 40- ⁸ 0mg.