Topiroxostat tablet and preparation method thereof

Abstract

The invention particularly relates to a topiroxostat tablet and a preparation method thereof. The topiroxostat tablet contains topiroxostat and pharmaceutic adjuvants, topiroxostat needs to be smashed to meet the particle size requirement, and the pharmaceutic adjuvants comprise an adhesive, a disintegrating agent and a lubricating agent. The invention also provides a preparation method of the topiroxostat tablet. The topiroxostat tablet is prepared by crushing topiroxostat through a jet mill, carrying out wet granulation and tabletting. The topiroxostat tablet provided by the invention is faster in dissolution.

Description

Technical Field

[0001] The present invention relates to a topiroxostat tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Tropiroxostat, chemical name: 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, CAS No.: 577778-58-6, molecular formula: C13H8N6, and its chemical formula is shown as follows:

[0003]

[0004] Tropiroxostat is a novel highly selective non-purine xanthine oxidase inhibitor. It has inhibitory effects on both xanthine oxidase and xanthine dehydrogenase, and has a strong uric acid-lowering effect. This drug does not undergo renal metabolism and is safer for patients with chronic kidney disease. Tropiroxostat was jointly developed by Fujisawa Pharmaceutical Co., Ltd. and Sanwa Chemical Co., Ltd. in Japan and was launched in Japan in September 2013 for the treatment of patients with gout and hyperuricemia.

[0005] Tropiroxostat is a pH-dependent compound, with a solubility of 4.3 mg / ml in 1.0 M hydrochloric acid solution, almost insoluble in buffers with pH values ranging from 3.0 to 7.0, and a solubility of only 0.007 mg / mL in water, making it a poorly soluble drug. When the maximum oral dose is 80 mg, approximately 30% of the drug is excreted as the prototype through urine or feces, resulting in poor bioavailability. Therefore, it is necessary to consider how to improve the solubility of the active ingredient, increase the dissolution rate of the active ingredient, and improve its bioavailability. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a topiroxostat tablet with fast dissolution. The third purpose of the present invention is to provide a preparation method for the topiroxostat tablet, which has simple steps and convenient operation.

[0007] To achieve the above purposes, the technical solution of the present invention is as follows:

[0008] The topiroxostat used in the topiroxostat pharmaceutical composition needs to be first air pulverized to meet the particle size requirements.

[0009] In the topiroxostat tablet of the present invention, in addition to the active ingredient topiroxostat, it may also contain any pharmaceutically acceptable excipients in the pharmaceutical field, such as fillers, binders, disintegrants, lubricants, etc.

[0010] Specifically, the present invention also provides a topiroxostat tablet, which, in addition to containing the topiroxostat composition of the present invention, further includes a filler, a binder, a disintegrant, and a lubricant.

[0011] The filler is selected from one or a combination of mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, and lactose.

[0012] The binder is selected from one or a combination of hydroxypropyl cellulose, copovidone, povidone, and starch paste; the disintegrant is selected from one or a combination of crospovidone, sodium croscarmellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and corn starch; the lubricant is selected from one or a combination of magnesium stearate, colloidal silicon dioxide, talc powder, and sodium stearyl fumarate.

[0013] In a specific embodiment of the present invention, preferably, the filler is microcrystalline cellulose and lactose, the binder is hydroxypropyl cellulose, the disintegrant is sodium croscarmellose, and the lubricant is magnesium stearate.

[0014] The present invention also provides a method for preparing toperisone tablets, comprising the following steps:

[0015] (1) Toperisone is subjected to air flow pulverization (controlling appropriate feeding pressure, grinding pressure, and feeding speed) so that the particle size distribution of the pulverized toperisone meets the requirements (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm).

[0016] (2) Then, the pulverized toperisone is mixed with the filler, binder, and disintegrant, and purified water is added for wet granulation, and dried to obtain Granule I.

[0017] (3) Granule I is sieved through a 30-mesh sieve and then mixed with the lubricant to obtain Granule II.

[0018] (4) Tableting is carried out according to the specifications and the content of Granule II.

[0019] Beneficial effects

[0020] The method for preparing toperisone tablets provided by the present invention is feasible in production. The toperisone tablets obtained by the method for preparing toperisone tablets of the present invention have the advantages of rapid dissolution and high bioavailability compared with the existing publicly disclosed tablets. Description of the drawings

[0021] Figure 1 : Comparison of dissolution curves of the original product and the self-made product of 60 mg specification in pH 3.0 buffer solution

[0022] Figure 2 : Comparison of dissolution curves of the original product and the self-made product of 60 mg specification in pH 4.5 buffer solution

[0023] Figure 3 : Comparison of dissolution curves of the original product and the self-made product of 60 mg specification in pH 6.8 buffer solution Detailed implementation manners

[0024] The technical solutions of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only illustrative of and explanatory of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope intended to be protected by the present disclosure.

[0025] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0026] Example 1

[0027] The toperisone tablets of this example have the following composition:

[0028]

[0029]

[0030] The preparation steps are as follows:

[0031] (1) Toperisone is pulverized by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0032] (2) The mixed powder of toperisone, lactose, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium is granulated with purified water. The wet granules are dried by a fluidized bed and then sieved through a 30-mesh sieve to obtain dry granules;

[0033] (3) The dry granules are mixed with magnesium stearate and then compressed into tablets, and the hardness is controlled to be 50 - 90 N to obtain toperisone tablets.

[0034] Example 2

[0035] The toperisone tablets of this example have the following composition:

[0036] Composition of 1000 tablets (g) Topiroxostat 60 Mannitol 50 Starch 42 Copovidone 8 Talc 1 Sodium carboxymethyl starch 4 Sodium stearyl fumarate 1

[0037] The preparation steps are as follows:

[0038] (1) Toperisone is pulverized by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0039] (2) The mixed powder of toperisone, mannitol, starch, copovidone, and sodium carboxymethyl starch is granulated with purified water. The wet granules are dried by a fluidized bed and then sieved through a 30-mesh sieve to obtain dry granules;

[0040] (3) Mix the dry granules with talc powder and magnesium stearate, and then press them into tablets with the hardness controlled at 50 - 90 N to obtain toperisone tablets.

[0041] Example 3

[0042] The toperisone tablets of this example have the following composition:

[0043] Composition of 1000 tablets (g) Topiroxostat 60 Sorbitol 40 Dextrin 49 Hydroxypropyl methylcellulose 5 Cross-linked polyvinylpyrrolidone 4 Sodium stearyl fumarate 1

[0044] The preparation steps are as follows:

[0045] (1) Grind toperisone by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0046] (2) Add purified water to the mixed powder of toperisone, sorbitol, dextrin, hypromellose, and crospovidone to granulate. After drying the wet granules in a fluidized bed and passing through a 30 - mesh sieve, dry granules are obtained;

[0047] (3) Mix the dry granules with sodium stearyl fumarate and then press them into tablets with the hardness controlled at 50 - 90 N to obtain toperisone tablets.

[0048] Example 4

[0049] The toperisone tablets of this example have the following composition:

[0050] Composition of 1000 tablets (g) Topiroxostat 60 Starch 30 Dextrin 60 Polyvinylpyrrolidone 4 Low-substituted hydroxypropyl cellulose 6 Colloidal silicon dioxide / Magnesium stearate 1.5

[0051] The preparation steps are as follows:

[0052] (1) Grind toperisone by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0053] (2) Add purified water to the mixed powder of toperisone, starch, dextrin, povidone, and low - substituted hydroxypropyl cellulose to granulate. After drying the wet granules in a fluidized bed and passing through a 30 - mesh sieve, dry granules are obtained;

[0054] (3) Mix the dry granules with colloidal silicon dioxide and magnesium stearate and then press them into tablets with the hardness controlled at 50 - 90 N to obtain toperisone tablets.

[0055] Example 5

[0056] The toperisone tablets of this example have the following composition:

[0057] Composition of 1000 tablets (g) Topiroxostat 60 Starch 20 Microcrystalline cellulose 30 Lactose 40 Polyvinylpyrrolidone 5 Cross-linked sodium carboxymethyl cellulose 6 Magnesium stearate 1.5

[0058] The preparation steps are as follows:

[0059] (1) Topirostat is micronized by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0060] (2) The mixed powder of topirostat, starch, microcrystalline cellulose, lactose, polyvinylpyrrolidone, and croscarmellose sodium is granulated with purified water. The wet granules are dried in a fluidized bed and then passed through a 30-mesh sieve to obtain dry granules;

[0061] (3) The dry granules are mixed with magnesium stearate and then tabletted, with the hardness controlled at 50 - 90 N, to obtain topirostat tablets.

[0062] Example 6

[0063] The topirostat tablets of this example have the following composition:

[0064] Composition of 1000 tablets (g) Topiroxostat 60 Microcrystalline cellulose 90 Polyvinylpyrrolidone 5 Cross-linked polyvinylpyrrolidone 6 Sodium stearyl fumarate 1.5

[0065] The preparation steps are as follows:

[0066] (1) Topirostat is micronized by air flow to (d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm);

[0067] (2) The mixed powder of topirostat, microcrystalline cellulose, polyvinylpyrrolidone, and crospovidone is granulated with purified water. The wet granules are dried in a fluidized bed and then passed through a 30-mesh sieve to obtain dry granules;

[0068] (3) The dry granules are mixed with sodium stearyl fumarate and then tabletted, with the hardness controlled at 50 - 90 N, to obtain topirostat tablets.

[0069] Dissolution comparison experiment

[0070] The topirostat tablets obtained above are subjected to a dissolution comparison experiment with the original research reference preparation in a hydrochloric acid medium at pH 3.0.

[0071] (％) 5 min 10 min 15 min 30 min 45 min Original research reference preparation 47 67 75 90 95 Example 1 55 77 88 95 97 Example 2 61 80 90 95 96 Example 3 52 78 88 96 99 Example 4 59 75 85 93 95 Example 5 57 80 92 97 97 Example 6 64 85 92 100 100

[0072] The topirostat tablets obtained above are subjected to a dissolution comparison experiment with the original research reference preparation in a hydrochloric acid medium at pH 4.5

[0073] (％) 5 min 10 min 15 min 30 min 45 min Original research reference preparation 17 23 27 30 31 Example 1 22 32 35 35 35 Example 2 24 30 37 35 35 Example 3 20 30 41 39 39 Example 4 21 28 37 39 39 Example 5 25 31 40 39 40 Example 6 20 32 34 40 40

[0074] The topirostat tablets obtained above are subjected to a dissolution comparison experiment with the original research reference preparation in a hydrochloric acid medium at pH 6.8

[0075] (％) 5 min 10 min 15 min 30 min 45 min Original research reference preparation 31 44 51 59 63 Example 1 45 58 69 70 70 Example 2 49 58 66 72 71 Example 3 40 55 67 69 69 Example 4 45 55 63 67 70 Example 5 47 56 67 71 71 Example 6 49 61 73 74 73

[0076] The topirostat tablets obtained above are subjected to a related substances and content comparison experiment with the original research reference preparation

[0077]

[0078] Conclusion: The related substances and content of the samples in the examples are comparable to those of the original research reference preparation, and the dissolution rate of the samples in the examples is significantly faster than that of the original research reference preparation in the media of pH 3.0, pH 4.5 and pH 6.8.

[0079] The above has given an exemplary description of the implementation manners of the technical solutions of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manners. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A tozasertib tablet, characterized in that The active ingredient is crushed to prepare tozasertib meeting the particle size requirements, and tablets are prepared after wet granulation and tabletting; the active ingredient in the tablets is tozasertib, and the weight percentages of each material in the tablets are as follows: tozasertib (specification 20 - 60 mg) 15 - 40%, filler 20 - 50%, binder 2% - 4%, disintegrant 2% - 20%, lubricant 0.5% - 4%.

2. The active ingredient according to claim 1 is subjected to a comminution treatment, characterized in that, The tozasertib after crushing treatment refers to being air - crushed to a tozasertib particle size distribution of d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm.

3. The tozasertib tablets according to claims 1 to 3, characterized in that, The filler is selected from one or a combination of mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, lactose; preferably microcrystalline cellulose and lactose.

4. The tozasertib tablets according to claims 1 to 3, characterized in that, The binder is selected from one or a combination of hydroxypropyl cellulose, copovidone, povidone, starch paste; preferably hydroxypropyl cellulose.

5. The tozasertib tablets according to any one of claims 1 to 4, characterized in that, The disintegrant is selected from one or a combination of crospovidone, croscarmellose sodium, low - substituted hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch; preferably croscarmellose sodium.

6. The tozasertib tablets according to any one of claims 1 to 5, characterized in that, The lubricant is selected from one or a combination of magnesium stearate, colloidal silicon dioxide, talc, sodium stearyl fumarate; preferably magnesium stearate.

7. The preparation method of the tozasertib tablets described in claims 1 to 6, characterized in that, It includes the following steps: (1) tozasertib is air - crushed to d(0.9) ≤ 5 μm, d(0.5) ≤ 30 μm, d(0.1) ≤ 70 μm; (2) tozasertib, lactose, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium are mixed evenly, purified water is added for granulation, drying and sizing; (4) magnesium stearate is added and mixed evenly; (5) tabletting.

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