A highly stable tablet and its preparation method and application

Abstract

The present invention discloses a highly stable tablet and its preparation method and application. The tablet comprises the following raw materials in parts by weight: febuxostat 20 - 30 parts, spray-dried lactose 15 - 25 parts, pregelatinized starch 12 - 18 parts, disintegrant 6 - 10 parts, glidant 1 - 3 parts, lubricant 1 - 3 parts, and phenylalanine 2 - 4 parts. After mixing febuxostat, spray-dried lactose, pregelatinized starch, disintegrant, glidant, lubricant, and phenylalanine, the tablet is prepared by granulation. Due to the use of spray-dried lactose and pregelatinized starch as fillers and mixing with a certain proportion of disintegrant, glidant, and lubricant, it has a relatively fast dissolution rate. Moreover, febuxostat and phenylalanine have a synergistic effect, and the prepared tablet will not undergo crystal form transformation during long-term storage, and the stability is significantly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of tablet preparation, and particularly relates to a tablet with high stability, a preparation method thereof and an application thereof. Background Art

[0002] Hyperuricemia is caused by increased uric acid production or decreased renal uric acid secretion, and is prone to induce gout. Using drugs to reduce the blood uric acid concentration is one of the common methods to prevent the occurrence of gout. Such drugs include uricosuric drugs that can block the absorption of uric acid by the renal tubular lumen membrane and xanthine oxidase / xanthine dehydrogenase inhibitors.

[0003] Febuxostat is a novel non-purine xanthine oxidase inhibitor developed by Teijin Pharma Ltd in Japan. It was approved for marketing in France by the European Union in April 2008 and was approved by the FDA in February 2009 for the treatment of gout. Its chemical name is 2-[3-cyano-4-(2-methylpropoxyphenyl)]-4-methylthiazole-5-carboxylic acid, also known as febuxostat. Febuxostat has a highly selective inhibitory effect on xanthine oxidase and can significantly inhibit both the oxidized and reduced forms of xanthine oxidase. Due to its strong pharmacological activity and high selectivity, febuxostat is very suitable for the long-term treatment of hyperuricemia with gout symptoms.

[0004] During the long-term storage process, the performance of febuxostat tablets may be affected due to the instability of the crystal form. In addition, febuxostat is slightly soluble in methanol and acetonitrile and basically insoluble in water, which also leads to problems such as poor dissolution rate and low bioavailability of febuxostat tablets. Therefore, the present invention provides a tablet with high stability, a preparation method thereof and an application thereof. The prepared febuxostat tablets have high stability, a fast dissolution rate and good medicinal effects. Summary of the Invention

[0005] The purpose of the present invention is to solve the deficiencies of the prior art and provide a tablet with high stability, a preparation method thereof and an application thereof. The following specific technical solutions are adopted:

[0006] A tablet with high stability, comprising the following raw materials in parts by weight: 20-35 parts of febuxostat, 15-25 parts of spray-dried lactose, 12-18 parts of pregelatinized starch, 6-10 parts of disintegrant, 1-3 parts of glidant, 1-3 parts of lubricant and 2

[0007] -4 parts of phenylalanine.

[0008] Preferably, the disintegrant is selected from one, two or a combination of more of sodium croscarmellose, sodium carboxymethyl starch, crospovidone, and preferably sodium carboxymethyl starch.

[0009] Preferably, the glidant is selected from one, two or a combination of more than two of sodium stearyl fumarate, silicon dioxide, and talcum powder, and preferably silicon dioxide.

[0010] Preferably, the lubricant is selected from one, two or a combination of more than two of stearic acid, magnesium stearate, and calcium stearate, and preferably magnesium stearate.

[0011] The present invention also provides a method for preparing a highly stable tablet, comprising the following steps:

[0012] (1) Weigh 20 - 35 parts of febuxostat, 15 - 25 parts of spray-dried lactose, 12 - 18 parts of pregelatinized starch, 6 - 10 parts of disintegrant, 1 - 3 parts of glidant, 1 - 3 parts of lubricant, and 2 - 4 parts of phenylalanine by weight. After weighing, crush each raw material and pass it through a sieve;

[0013] (2) Add 20 - 35 parts of febuxostat, 15 - 25 parts of spray-dried lactose, 12 - 18 parts of pregelatinized starch, and 2 - 4 parts of phenylalanine after sieving into a wet granulator, premix, add an appropriate amount of purified water, mix and granulate to form a soft material, then pass it through a sieve to obtain wet granules;

[0014] (3) Dry the wet granules obtained in step (2) to obtain dry granules, and pass them through a sieve;

[0015] (4) Mix 6 - 10 parts of disintegrant, 1 - 3 parts of glidant, and 1 - 3 parts of lubricant after sieving with the dry granules obtained in step (3) evenly to obtain a mixture;

[0016] (5) Press the mixture obtained in step (4) into tablets and coat the tablets.

[0017] In step (1), pass through an 80 - 100 mesh sieve;

[0018] In step (3), the drying temperature is 60 °C, and pass through a 20 - mesh sieve.

[0019] In step (5), press tablets at a tablet weight of 40 mg / tablet, and use Opadry ethanol solution for coating.

[0020] The highly stable tablet prepared by the present invention is used in the treatment of hyperuricemia with gout symptoms.

[0021] The beneficial effects of the present invention are as follows: After mixing febuxostat, spray-dried lactose, pregelatinized starch, disintegrant, glidant, lubricant, and phenylalanine and granulating them into tablets, due to the use of spray-dried lactose and pregelatinized starch as fillers and mixing with a certain proportion of disintegrant, glidant, and lubricant, the tablets have a faster dissolution rate. Moreover, febuxostat and phenylalanine have a synergistic effect, and the tablets prepared will not undergo polymorphic transformation during long-term storage, and the stability is significantly improved. Detailed implementation manners

[0022] The following will clearly and completely describe the concept of the present invention and the technical effects produced in combination with embodiments, so as to fully understand the purpose, solution and effects of the present invention. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other.

[0023] Embodiment 1

[0024] (1) Weigh 40 g of febuxostat, 30 g of spray-dried lactose, 24 g of pregelatinized starch, 12 g of sodium carboxymethyl starch, 2 g of silicon dioxide, 2 g of magnesium stearate and 4 g of phenylalanine. After weighing, crush each raw material and pass through a 100-mesh sieve;

[0025] (2) Add 40 g of febuxostat, 30 g of spray-dried lactose, 24 g of pregelatinized starch and 4 g of phenylalanine that have passed through a 100-mesh sieve into a wet granulator, premix, add an appropriate amount of purified water, mix and granulate, pass through a sieve after making the soft material, and obtain wet granules;

[0026] (3) Dry the wet granules prepared in step (2) at a drying temperature of 60 °C to obtain dry granules, and pass through a 20-mesh sieve;

[0027] (4) Mix 12 g of sodium carboxymethyl starch, 2 g of silicon dioxide and 2 g of magnesium stearate that have passed through a 100-mesh sieve with the dry granules prepared in step (3) evenly to obtain a mixture;

[0028] (5) Press the mixture prepared in step (4) into tablets with a tablet weight of 40 mg / tablet, and coat the tablets. The coating is carried out with an Opadry ethanol solution.

[0029] Embodiment 2

[0030] (1) Weigh 70 g of febuxostat, 50 g of spray-dried lactose, 36 g of pregelatinized starch, 20 g of sodium carboxymethyl starch, 6 g of silicon dioxide, 6 g of magnesium stearate and 8 g of phenylalanine. After weighing, crush each raw material and pass through a 100-mesh sieve;

[0031] (2) Add 70 g of febuxostat, 50 g of spray-dried lactose, 36 g of pregelatinized starch and 8 g of phenylalanine that have passed through a 100-mesh sieve into a wet granulator, premix, add an appropriate amount of purified water, mix and granulate, pass through a sieve after making the soft material, and obtain wet granules;

[0032] (3) Dry the wet granules prepared in step (2) at a drying temperature of 60 °C to obtain dry granules, and pass through a 20-mesh sieve;

[0033] (4) Mix 20 g of sodium carboxymethyl starch, 6 g of silicon dioxide and 6 g of magnesium stearate that have passed through a 100-mesh sieve with the dry granules prepared in step (3) evenly to obtain a mixture;

[0034] (5) Tabletting the mixture obtained in step (4) at a tablet weight of 40 mg / tablet, and coating the tablets with an Opadry ethanol solution.

[0035] Example 3

[0036] (1) Weigh 60 g of febuxostat, 40 g of spray-dried lactose, 30 g of pregelatinized starch, 16 g of sodium carboxymethyl starch, 4 g of silicon dioxide, 4 g of magnesium stearate, and 6 g of phenylalanine. After weighing, crush each raw material and pass through a 100-mesh sieve.

[0037] (2) Add 60 g of febuxostat, 40 g of spray-dried lactose, 30 g of pregelatinized starch, and 6 g of phenylalanine that have passed through a 100-mesh sieve to a wet granulator, premix, add an appropriate amount of purified water, mix and granulate. After forming a soft material, pass through a sieve to obtain wet granules.

[0038] (3) Dry the wet granules obtained in step (2) at a drying temperature of 60 °C to obtain dry granules, and pass through a 20-mesh sieve.

[0039] (4) Mix 16 g of sodium carboxymethyl starch, 4 g of silicon dioxide, and 4 g of magnesium stearate that have passed through a 100-mesh sieve with the dry granules obtained in step (3) evenly to obtain a mixture.

[0040] (5) Tabletting the mixture obtained in step (4) at a tablet weight of 40 mg / tablet, and coating the tablets with an Opadry ethanol solution.

[0041] Comparative Example 1:

[0042] (1) Weigh 40 g of febuxostat, 24 g of pregelatinized starch, 12 g of sodium carboxymethyl starch, 2 g of silicon dioxide, 2 g of magnesium stearate, and 4 g of phenylalanine. After weighing, crush each raw material and pass through a 100-mesh sieve.

[0043] (2) Add 40 g of febuxostat, 24 g of pregelatinized starch, and 4 g of phenylalanine that have passed through a 100-mesh sieve to a wet granulator, premix, add an appropriate amount of purified water, mix and granulate. After forming a soft material, pass through a sieve to obtain wet granules.

[0044] (3) Dry the wet granules obtained in step (2) at a drying temperature of 60 °C to obtain dry granules, and pass through a 20-mesh sieve.

[0045] (4) Mix 12 g of sodium carboxymethyl starch, 2 g of silicon dioxide, and 2 g of magnesium stearate that have passed through a 100-mesh sieve with the dry granules obtained in step (3) evenly to obtain a mixture.

[0046] (5) Tabletting the mixture obtained in step (4) at a tablet weight of 40 mg / tablet, and coating the tablets with an Opadry ethanol solution.

[0047] Comparative Example 2:

[0048] (1) Weigh 60 g of febuxostat, 40 g of spray-dried lactose, 30 g of pregelatinized starch, 16 g of sodium carboxymethyl starch, 4 g of silicon dioxide, and 4 g of magnesium stearate. After weighing, crush each raw material and pass through a 100-mesh sieve;

[0049] (2) Add 60 g of febuxostat, 40 g of spray-dried lactose, and 30 g of pregelatinized starch that have passed through a 100-mesh sieve into a wet granulator, premix, add an appropriate amount of purified water, mix and granulate, and pass through a sieve after making into soft materials to obtain wet granules;

[0050] (3) Dry the wet granules prepared in step (2) at a drying temperature of 60 °C to obtain dry granules, and pass through a 20-mesh sieve;

[0051] (4) Mix 16 g of sodium carboxymethyl starch, 4 g of silicon dioxide, and 4 g of magnesium stearate that have passed through a 100-mesh sieve with the dry granules prepared in step (3) evenly to obtain a mixture;

[0052] (5) Press the mixture prepared in step (4) into tablets with a tablet weight of 40 mg / tablet, and coat the tablets with an Opadry ethanol solution.

[0053] Dissolution test:

[0054] Using 1000 mL of phosphate buffer solution with pH 6.8 as the dissolution medium, at a rotation speed of 50 revolutions per minute, and using ultra-high performance liquid chromatography, test the dissolution of the febuxostat tablets prepared in Examples 1-3 and Comparative Examples 1-2 at 5 min, 10 min, 20 min, 30 min, 45 min, and 60 min respectively. The dissolution results are shown in Table 1.

[0055] Table 1 Dissolution results

[0056] Mark cumulative release percentage 5 min 10 min 20 min 30 min 45 min 60 min Example 1 85.24 96.36 97.83 99.04 99.98 100.05 Example 2 84.98 96.05 98.22 99.53 100.23 100.90 Example 3 83.60 94.74 98.06 98.17 99.65 100.28 Comparative Example 1 69.49 81.63 90.45 95.72 98.14 98.56 Comparative Example 2 77.54 86.24 93.33 98.06 99.12 99.89

[0057] Stability test:

[0058] Take the febuxostat tablets prepared in Examples 1-3 and Comparative Examples 1-2 as samples for stability investigation.

[0059] Seal and package the above febuxostat tablets separately with aluminum foil bags, place them in an incubator at 45 °C for 5 months, and determine the content of the active ingredient and the content of related substances (expressed as the maximum single impurity and total impurities) of each febuxostat tablet at 0 month and 5 months.

[0060] For each sample, take the percentage value obtained by dividing the active ingredient content at 5 months by the active ingredient content at 0 month as the relative content (%) of the active ingredient after 5 months of high-temperature treatment. The calculation formula is as follows:

[0061] Relative content of active ingredient (%) = (content in May ÷ content in Month 0) × 100%

[0062] In addition, for each sample, the percentage value obtained by dividing the maximum single impurity content in May by the maximum single impurity content at Month 0 is used as the relative content (%) of the maximum single impurity after 5 months of high-temperature treatment. The calculation formula is as follows:

[0063] Relative content of maximum single impurity (%) = (maximum single impurity content in May ÷ maximum single impurity content in Month 0) × 100%

[0064] In addition, for each sample, the percentage value obtained by dividing the total impurity content in May by the total impurity content at Month 0

[0065] is used as the relative content (%) of the total impurities after 5 months of high-temperature treatment. The calculation formula is as follows:

[0066] Relative content of total impurities (%) = (total impurity content in May ÷ total impurity content in Month 0) × 100%

[0067] The results of the changes in the stability of the active ingredient and impurities after 5 months of high-temperature treatment are shown in Table 2.

[0068] Table 2 Changes in the stability of the active ingredient and impurities

[0069] Relative content of active ingredient Relative content of maximum single impurity Relative content of total impurities Example 1 99.2％ 133.8％ 161.3％ Example 2 99.5％ 124.5％ 156.0％ Example 3 99.0％ 127.6％ 152.7％ Comparative Example 1 97.4％ 180.2％ 250.6％ Comparative Example 2 93.6％ 240.3％ 300.5％

[0070] It can be seen that in the present invention, febuxostat raw material is mixed with spray-dried lactose and pregelatinized starch as fillers, significantly accelerating the dissolution rate of the prepared febuxostat tablets. In addition, after mixing febuxostat raw material with phenylalanine in the present invention, they have a synergistic effect, preventing the prepared febuxostat tablets from undergoing polymorphic transformation during long-term storage, with small changes in the content of the active ingredient and impurities, and significantly improved stability.

[0071] As mentioned above, it is only a preferred embodiment of the present invention. The present invention is not limited to the above-mentioned implementation manner. As long as it achieves the technical effects of the present invention by the same means, it should fall within the protection scope of the present invention. Within the protection scope of the present invention, various modifications and changes can be made to its technical solutions and / or implementation manners.

Claims

1. A tablet with high stability, characterized in that, It comprises the following raw materials in parts by weight: febuxostat 20 - 35 parts, spray-dried lactose 15 - 25 parts, pregelatinized starch 12 - 18 parts, disintegrant 6 - 10 parts, glidant 1 - 3 parts, lubricant 1 - 3 parts, and phenylalanine 2 - 4 parts.

2. The tablet according to claim 1, characterized in that, The disintegrant is selected from one, two or a combination of more than two of sodium croscarmellose, sodium carboxymethyl starch, and crospovidone.

3. The tablet according to claim 1, characterized in that, The glidant is selected from one, two or a combination of more than two of sodium stearyl fumarate, silicon dioxide, and talc powder.

4. The tablet according to claim 1, wherein The lubricant is selected from one, two or a combination of more than two of stearic acid, magnesium stearate, and calcium stearate.

5. A preparation method of a tablet with high stability, characterized in that, The preparation method of the tablet comprises the following steps: (1) Weigh febuxostat 20 - 35 parts, spray-dried lactose 15 - 25 parts, pregelatinized starch 12 - 18 parts, disintegrant 6 - 10 parts, glidant 1 - 3 parts, lubricant 1 - 3 parts, and phenylalanine 2 - 4 parts in parts by weight. After weighing, crush each raw material and sieve it. (2) Add 20 - 35 parts of the sieved febuxostat, 15 - 25 parts of spray-dried lactose, 12 - 18 parts of pregelatinized starch, and 2 - 4 parts of phenylalanine to a wet granulator, premix, add an appropriate amount of purified water, mix and granulate, and sieve after making into a soft material to obtain wet granules. (3) Dry the wet granules obtained in step (2) to obtain dry granules, and sieve them. (4) Mix 6 - 10 parts of the sieved disintegrant, 1 - 3 parts of glidant, and 1 - 3 parts of lubricant evenly with the dry granules obtained in step (3) to obtain a mixture. (5) Press the mixture obtained in step (4) into tablets and coat the tablets.

6. The preparation method according to claim 5, characterized in that, In step (1), sieve through an 80 - 100 mesh sieve.

7. The preparation method according to claim 5, characterized in that, In step (3), the drying temperature is 60 °C, and sieve through a 20 mesh sieve.

8. The preparation method according to claim 5, characterized in that, In step (5), press the tablets at a tablet weight of 40 mg / tablet, and use Opadry ethanol solution for coating.

9. Use of the tablet according to any one of claims 1 - 4 in the preparation of a drug for treating hyperuricemia with gout symptoms.