Composition containing dotenorad and xanthinase inhibitor as well as preparation method and application of composition

Abstract

The invention provides a composition containing dotenorad and a xanthinase inhibitor as well as a preparation method and application of the composition, and belongs to the technical field of pharmacy. The composition provided by the invention comprises dotenorad, a xanthinase inhibitor and at least one pharmaceutically acceptable additive. The composition prepared by the invention has good stability and can be used for clinically treating gout and hyperuricemia.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a composition containing dotinorex and a xanthine enzyme inhibitor, and a preparation method and application thereof. Background Art

[0002] Hyperuricemia (HUA) refers to the condition in which the fasting blood uric acid level on two different days is higher than 420mmol / L for men and higher than 360mmol / L for women under a normal purine diet.

[0003] Uric acid is a product of purine metabolism. Long-term elevated uric acid levels in the blood are considered to be an important factor in causing gout, cardiovascular disease, type II diabetes and chronic kidney disease (CKD). Under normal circumstances, the body's uric acid is in a dynamic balance, but long-term high-purine diet or renal damage will break this balance, eventually leading to elevated uric acid levels.

[0004] Xanthine oxidase is the rate-limiting enzyme in purine metabolism, which catalyzes the oxidation of hypoxanthine to xanthine, and further oxidizes xanthine to uric acid. Its inhibition can reduce the production of uric acid in the body. Therefore, xanthine oxidase is considered a reliable target for lowering uric acid.

[0005] The xanthine oxidase inhibitors currently on the market are mainly allopurinol and febuxostat. Allopurinol, as the most classic xanthine oxidase inhibitor, has been the first choice for lowering uric acid for decades. Febuxostat is a potent xanthine oxidase inhibitor suitable for the long-term treatment of hyperuricemia with gout symptoms. Topiramate is another non-purine xanthine oxidase inhibitor after febuxostat. It reaches the peak blood concentration faster than febuxostat, so it takes effect faster; there is no accumulation in the body; it is not affected by diet, and it is safe for the cardiovascular system and has low side effects, which improves the safety and compliance of patients.

[0006] However, up to now, no one has studied the combined use of polytinol and xanthine enzyme inhibitors. Therefore, it is very important to provide a composition containing polytinol and xanthine enzyme inhibitors with good stability. Summary of the invention

[0007] The object of the present invention is to provide a composition containing polytinorethinol and a xanthine enzyme inhibitor, and a preparation method and application thereof, so as to solve the technical problem of the lack of research on the combined use of polytinorethinol and a xanthine enzyme inhibitor in the prior art.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a composition containing polytinorel and a xanthine enzyme inhibitor, comprising the following raw materials in parts by weight:

[0010] 0.25 parts of dotinorel,

[0011] 20-40 parts of xanthine enzyme inhibitor,

[0012] 79-210 parts of at least one pharmaceutically acceptable additive;

[0013] The xanthine enzyme inhibitors include one or more of topiramate, febuxostat and allopurinol.

[0014] Furthermore, the additives include one or more of an excipient, a binder, a disintegrant, a lubricant and a coating agent.

[0015] Further, the excipient includes one or more of mannitol, lactose, microcrystalline cellulose, sorbitol, glucose, starch and pregelatinized starch;

[0016] The binder includes one or more of hydroxypropyl cellulose, hypromellose and povidone;

[0017] The disintegrant comprises one or more of substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose;

[0018] The lubricant includes one or more of magnesium stearate, talc, calcium stearate, sodium stearyl fumarate, polyethylene glycol 4000 and polyethylene glycol 6000.

[0019] The present invention provides a method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor, comprising the following steps:

[0020] 1) grinding polytinorel and a xanthine enzyme inhibitor to obtain a powder;

[0021] 2) mixing the powder and excipients, and then adding water for granulation;

[0022] 3) passing the prepared granules through a 20-mesh sieve for granulation;

[0023] 4) adding a disintegrant and a lubricant to the granules obtained in step 3) in sequence and mixing them to obtain a total mixed material;

[0024] 5) The total mixed material is tableted and coated in sequence.

[0025] Furthermore, in the step 2), the mixing time is 3 to 7 minutes;

[0026] The granulation is carried out in a fluidized bed, the inlet air temperature of the fluidized bed is 50-60°C, the inlet air volume is 15-30m 3 / h, the granulation speed is 2-6rpm;

[0027] The dosage ratio of dotinorep to water is 0.25 g:70-80 mL.

[0028] Furthermore, in the step 4), the mixing time for adding the disintegrant is 8 to 12 minutes, and the mixing time for adding the lubricant is 1 to 5 minutes.

[0029] The present invention provides a method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor, comprising the following steps:

[0030] 1) dissolving a binder in water to obtain a binder solution;

[0031] 2) wet granulating the excipients and part of the disintegrant for 0.5 to 2 minutes, then adding polytinoride and the xanthine enzyme inhibitor to mix to obtain a premix;

[0032] 3) adding the binder solution to the premixed material for granulation, then adding water for secondary granulation, and then drying and granulating to obtain granules;

[0033] 4) mixing the granules obtained in step 3) and the remaining disintegrant for 12 to 17 minutes, and then adding a lubricant and mixing for 1 to 5 minutes to obtain a total mixed material;

[0034] 5) The total mixed material is tableted and coated in sequence.

[0035] Furthermore, in the step 2), the rotation speed of the wet granulation is 60-70 rpm, and the cutting speed is 1200-1700 rpm;

[0036] The mass ratio of the partial disintegrant to the remaining disintegrant is 1:0.5-2.

[0037] Furthermore, in the step 3), the time for granulation and secondary granulation is independently 50 to 70 seconds;

[0038] The particle size of the granulation is 10 to 25 meshes;

[0039] The particle size of the granules is 30 to 50 meshes.

[0040] The present invention also provides an application of the composition containing dotinorex and a xanthine enzyme inhibitor in the preparation of a drug for treating hyperuricemia and gout.

[0041] Beneficial effects of the present invention:

[0042] The composition containing dotinorex and a xanthine enzyme inhibitor prepared by the present invention has good stability and can be used for clinical treatment of gout and hyperuricemia;

[0043] The preparation method of the present invention selects appropriate particle sizes of polytinorel and xanthine enzyme inhibitors. When the particle size is less than 250 mesh (65 μm), the dissolution limit can be greater than 75%, thereby avoiding the problem that the solubility of the drug will affect the bioavailability of the drug because the drug has poor water solubility and its absorption in the body is mainly related to its solubility. DETAILED DESCRIPTION

[0044] The present invention provides a composition containing polytinorel and a xanthine enzyme inhibitor, comprising the following raw materials in parts by weight:

[0045] 0.25 parts of dotinorel,

[0046] 20-40 parts of xanthine enzyme inhibitor,

[0047] 79-210 parts of at least one pharmaceutically acceptable additive.

[0048] In the present invention, the amount of the xanthine enzyme inhibitor is preferably 22 to 38 parts by weight, and more preferably 25 to 35 parts by weight.

[0049] In the present invention, the xanthine enzyme inhibitor includes one or more of topirastat, febuxostat and allopurinol, preferably topirastat and / or allopurinol, and more preferably topirastat.

[0050] In the present invention, the amount of the additive is preferably 80 to 205 parts by weight, and more preferably 85 to 200 parts by weight.

[0051] In the present invention, the additives include one or more of excipients, binders, disintegrants, lubricants and coating agents.

[0052] In the present invention, the excipient includes one or more of mannitol, lactose, microcrystalline cellulose, sorbitol, glucose, starch and pregelatinized starch, preferably one or more of mannitol, lactose, microcrystalline cellulose, sorbitol, starch and pregelatinized starch, and further preferably one or more of mannitol, lactose, microcrystalline cellulose, starch and pregelatinized starch.

[0053] In the present invention, the binder includes one or more of hydroxypropyl cellulose, hypromellose and povidone, preferably hydroxypropyl cellulose and / or hypromellose, and more preferably hypromellose.

[0054] In the present invention, the disintegrant includes one or more of substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose, preferably one or more of substituted hydroxypropyl cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose, and further preferably one or more of substituted hydroxypropyl cellulose, carboxymethyl cellulose and cross-linked sodium carboxymethyl cellulose.

[0055] In the present invention, the lubricant includes one or more of magnesium stearate, talc, calcium stearate, sodium stearyl fumarate, polyethylene glycol 4000 and polyethylene glycol 6000, preferably one or more of magnesium stearate, talc, calcium stearate, sodium stearyl fumarate and polyethylene glycol 6000, further preferably one or more of magnesium stearate, talc, calcium stearate and polyethylene glycol 6000.

[0056] The present invention provides a method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor, comprising the following steps:

[0057] 1) grinding polytinorel and a xanthine enzyme inhibitor to obtain a powder;

[0058] 2) mixing the powder and excipients, and then adding water for granulation;

[0059] 3) passing the prepared granules through a 20-mesh sieve for granulation;

[0060] 4) adding a disintegrant and a lubricant to the granules obtained in step 3) in sequence and mixing them to obtain a total mixed material;

[0061] 5) The total mixed material is tableted and coated in sequence.

[0062] In the present invention, in step 2), the mixing time is 3 to 7 minutes, preferably 4 to 6 minutes, and more preferably 5 minutes;

[0063] The granulation is carried out in a fluidized bed, the air inlet temperature of the fluidized bed is 50-60°C, preferably 52-58°C, more preferably 55°C; the air volume of the air inlet is 15-30m 3 / h, preferably 17 to 28 m 3 / h, more preferably 20 to 25 m 3 / h; the granulation speed is 2 to 6 rpm, preferably 3 to 5 rpm, and more preferably 4 rpm;

[0064] The dosage ratio of dotinorep to water is 0.25 g:70-80 mL, preferably 0.25 g:72-78 mL, and more preferably 0.25 g:75 mL.

[0065] In the present invention, in step 4), the mixing time for adding the disintegrant is 8 to 12 minutes, preferably 9 to 11 minutes, and more preferably 10 minutes; the mixing time for adding the lubricant is 1 to 5 minutes, preferably 2 to 4 minutes, and more preferably 3 minutes.

[0066] The present invention provides a method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor, comprising the following steps:

[0067] 1) dissolving a binder in water to obtain a binder solution;

[0068] 2) wet granulating the excipient and the first part of the disintegrant for 0.5 to 2 minutes, then adding polytinoride and the xanthine enzyme inhibitor to mix to obtain a premix;

[0069] 3) adding the binder solution to the premixed material for granulation, then adding water for secondary granulation, and then drying and granulating to obtain granules;

[0070] 4) mixing the granules obtained in step 3) and the remaining disintegrant for 12 to 17 minutes, and then adding a lubricant and mixing for 1 to 5 minutes to obtain a total mixed material;

[0071] 5) The total mixed material is tableted and coated in sequence.

[0072] In the present invention, in the step 2), the rotation speed of the wet granulation is 60-70 rpm, preferably 62-68 rpm, and more preferably 64-66 rpm; the cutting speed is 1200-1700 rpm, preferably 1300-1600 rpm, and more preferably 1400-1500 rpm, and the mixing time is.

[0073] In the present invention, in step 3), the time for granulation and secondary granulation is independently 50 to 70 seconds, preferably 55 to 65 seconds, and more preferably 60 seconds;

[0074] The particle size of the granulation is 10 to 25 meshes, preferably 15 to 22 meshes, and more preferably 20 meshes;

[0075] The particle size of the sized particles is 30 to 50 meshes, preferably 35 to 45 meshes, and more preferably 40 meshes.

[0076] In the present invention, the mass ratio of the partial disintegrant to the remaining disintegrant is 1:0.5-2, preferably 1:0.8-1.5, and more preferably 1:1.

[0077] The present invention also provides an application of the composition containing dotinorex and a xanthine enzyme inhibitor in the preparation of a drug for treating hyperuricemia and gout.

[0078] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0079] Example 1

[0080] The raw materials for preparing 1000 tablets of the composition containing polytinorex and a xanthine enzyme inhibitor are shown in Table 1.

[0081] Table 1 Raw material ratio of Example 1

[0082] Components Dosage Dotinor 0.25g Topiramate 20g Lactose 200 160g Pregelatinized starch PC-10 37.5g Hydroxypropylcellulose HPC-SL 6.00g Cross-linked carboxymethyl cellulose sodium (external) 5.00g Magnesium stearate (external) 1.25g Total weight 230g

[0083] The preparation method of the composition containing polytinore and a xanthine enzyme inhibitor is as follows:

[0084] The raw materials of dotinorep and topiramate are crushed to obtain powder;

[0085] The raw materials and auxiliary materials were weighed according to the prescription amount. The powder, pregelatinized starch PC-10, lactose 200 and hydroxypropyl cellulose HPC-SL were added into the multifunctional fluidized bed and mixed for 5 minutes. Then 75 mL of purified water was added for granulation. The granulation was carried out in the fluidized bed. The inlet air temperature of the fluidized bed was 55 ° C and the air volume was 20 m 3 / h, the granulation speed is 4rpm, and granules are obtained;

[0086] The prepared granules are sieved through a 20-mesh screen for granulation;

[0087] The amount of the additional auxiliary materials is calculated according to the particle yield, and cross-linked sodium carboxymethyl cellulose is first added and mixed for 10 minutes, and then magnesium stearate is added and mixed for 3 minutes to obtain a total mixed material;

[0088] The total mixed material is Tableting is done with a 9mm round shallow concave upper punch die;

[0089] The coating powder is dissolved in water to obtain a coating solution, and the obtained compressed tablets are coated with 10% coating solution, and the coating weight is increased by 3-5%.

[0090] Example 2

[0091] The raw materials for preparing 1000 tablets of the composition containing polytinorel and a xanthine enzyme inhibitor are shown in Table 2.

[0092] Table 2 Raw material ratio of Example 2

[0093] Components Dosage Dotinor 0.25g Topiramate 40g Lactose 200 160g Pregelatinized starch PC-10 37.5g Hydroxypropylcellulose HPC-SL 6.00g Cross-linked carboxymethyl cellulose sodium (external) 5.00g Magnesium stearate (external) 1.25g Total weight 250g

[0094] The preparation method of the composition containing polytinorex and a xanthine enzyme inhibitor is the same as that in Example 1.

[0095] Example 3

[0096] The raw materials for preparing 1000 tablets of the composition containing polytinorel and a xanthine enzyme inhibitor are shown in Table 3.

[0097] Table 3 Raw material ratio of Example 3

[0098]

[0099]

[0100] The preparation method of the composition containing polytinorex and a xanthine enzyme inhibitor is the same as that in Example 1.

[0101] Example 4

[0102] The raw materials for preparing 1000 tablets of the composition containing polytinorel and a xanthine enzyme inhibitor are shown in Table 4.

[0103] Table 4 Raw material ratio of Example 4

[0104] Components Dosage Dotinor 0.25g Febuxostat 40g Lactose 200 160g Pregelatinized starch PC-10 37.5g Hydroxypropylcellulose HPC-SL 6.00g Cross-linked carboxymethyl cellulose sodium (external) 5.00g Magnesium stearate (external) 1.25g Total weight 250g

[0105] The preparation method of the composition containing polytinorex and a xanthine enzyme inhibitor is the same as that in Example 1.

[0106] Example 5

[0107] The raw materials for preparing 1000 tablets of the composition containing polytinorex and a xanthine enzyme inhibitor are shown in Table 5.

[0108] Table 5 Raw material ratio of Example 5

[0109]

[0110]

[0111] The preparation method of the composition containing polytinore and a xanthine enzyme inhibitor is as follows:

[0112] Dissolving hypromellose in water to obtain a hypromellose solution;

[0113] Lactose monohydrate, mannitol, 7.5 g of microcrystalline cellulose (internal addition part), and 2.5 g of carboxymethyl cellulose (internal addition part) were wet granulated in a wet granulator, the rotation speed of the wet granulator was 66 rpm, the cutting speed was low speed 1500 rpm, and after mixing for 1 min, polytinorethamine and xanthine enzyme inhibitor were added and mixed to obtain a premixed material;

[0114] 3) adding the hydroxypropyl methylcellulose solution to the premixed material and granulating for 60 seconds, then adding water for secondary granulation for 60 seconds, then passing through a 20-mesh sieve, and then drying in a fluidized bed granulation dryer, and granulating the dried material in a swing granulator to obtain granules with a particle size of 40 mesh;

[0115] 4) mixing the granules obtained in step 3), 7.5 g of microcrystalline cellulose (added portion) and 2.5 g of carboxymethyl cellulose (added portion) for 15 min, and then adding magnesium stearate and mixing for 3 min to obtain a total mixed material;

[0116] 5) tabletting the total mixed material, dissolving the coating powder in water to obtain a coating solution, and coating the tablets with the coating solution.

[0117] Example 6

[0118] The raw materials for preparing 1000 tablets of the composition containing polytinorel and a xanthine enzyme inhibitor are shown in Table 6.

[0119] Table 6 Raw material ratio of Example 6

[0120]

[0121]

[0122] The preparation method of the composition containing polytinoride and a xanthine enzyme inhibitor is the same as that in Example 5.

[0123] The long-term stability test of the compositions containing polytinore and xanthine enzyme inhibitor prepared in Examples 1 to 6 was carried out:

[0124] The test method is: refer to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 9001, Guidelines for Drug Stability Testing;

[0125] The test conditions are:

[0126] Long-term test temperature: 25℃±2℃;

[0127] Long-term test humidity: relative humidity 60% ± 5%;

[0128] Long-term test observation period: 0, 3, 6, 9, 12, 24 months.

[0129] The results of the long-term stability test are shown in Table 7.

[0130] Table 7 Long-term stability test results of the compositions prepared in Examples 1 to 6

[0131]

[0132]

[0133]

[0134]

[0135] As can be seen from the above examples, the present invention provides a composition containing polytinore and a xanthine enzyme inhibitor, and a preparation method and application thereof, wherein the composition of the present invention comprises polytinore, a xanthine enzyme inhibitor and at least one pharmaceutically acceptable additive. As can be seen from Table 7, the properties, identification, related substances, dissolution and content of the compositions prepared in Examples 1 to 6 did not change significantly under the condition of long-term stability for 24 months, and the degradation impurities of the related substances had almost no growth rate, indicating that the composition prepared by the preparation method of the present invention has good stability.

[0136] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A composition containing polytinoride and a xanthine enzyme inhibitor, characterized in that: It includes the following raw materials in parts by weight: 0.25 parts of dotinorel, 20-40 parts of xanthine enzyme inhibitor, 79-210 parts of at least one pharmaceutically acceptable additive; The xanthine enzyme inhibitors include one or more of topiramate, febuxostat and allopurinol.

2. The composition containing polytinoride and a xanthine enzyme inhibitor according to claim 1, characterized in that: The additives include one or more of excipients, binders, disintegrants, lubricants and coating agents.

3. The composition containing polytinorex and a xanthine enzyme inhibitor according to claim 2, characterized in that: The excipients include one or more of mannitol, lactose, microcrystalline cellulose, sorbitol, glucose, starch and pregelatinized starch; The binder includes one or more of hydroxypropyl cellulose, hypromellose and povidone; The disintegrant comprises one or more of substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose; The lubricant includes one or more of magnesium stearate, talc, calcium stearate, sodium stearyl fumarate, polyethylene glycol 4000 and polyethylene glycol 6000.

4. A method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) grinding polytinorel and a xanthine enzyme inhibitor to obtain a powder; 2) mixing the powder and excipients, and then adding water for granulation; 3) passing the prepared granules through a 20-mesh sieve for granulation; 4) adding a disintegrant and a lubricant to the granules obtained in step 3) in sequence and mixing them to obtain a total mixed material; 5) The total mixed material is tableted and coated in sequence.

5. The method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor according to claim 4, characterized in that: In the step 2), the mixing time is 3 to 7 minutes; The granulation is carried out in a fluidized bed, the inlet air temperature of the fluidized bed is 50-60°C, the inlet air volume is 15-30m 3 / h, the granulation speed is 2-6rpm; The dosage ratio of dotinorep to water is 0.25 g:70-80 mL.

6. The method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor according to claim 5, characterized in that: In the step 4), the mixing time for adding the disintegrant is 8 to 12 minutes, and the mixing time for adding the lubricant is 1 to 5 minutes.

7. A method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) dissolving a binder in water to obtain a binder solution; 2) wet granulating the excipients and part of the disintegrant for 0.5 to 2 minutes, then adding polytinoride and the xanthine enzyme inhibitor to mix to obtain a premix; 3) adding the binder solution to the premixed material for granulation, then adding water for secondary granulation, and then drying and granulating to obtain granules; 4) mixing the granules obtained in step 3) and the remaining disintegrant for 12 to 17 minutes, and then adding a lubricant and mixing for 1 to 5 minutes to obtain a total mixed material; 5) The total mixed material is tableted and coated in sequence.

8. The method for preparing the composition containing polytinorex and a xanthine enzyme inhibitor according to claim 7, characterized in that: In the step 2), the rotation speed of the wet granulation is 60-70 rpm, and the cutting speed is 1200-1700 rpm; The mass ratio of the partial disintegrant to the remaining disintegrant is 1:0.5-2.

9. The method for preparing the composition containing polytinoride and a xanthine enzyme inhibitor according to claim 8, characterized in that: In the step 3), the time for granulation and secondary granulation is independently 50 to 70 seconds; The particle size of the granulation is 10 to 25 meshes; The particle size of the granules is 30 to 50 meshes.

10. Use of the composition containing dotinorex and a xanthine enzyme inhibitor according to any one of claims 1 to 3 in the preparation of a drug for treating hyperuricemia and gout.

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