Preparation method of febuxostat tablets

Abstract

The invention provides a method for preparing febuxostat tablets by dry granulation and tabletting, which not only avoids the adverse effects of moisture and high temperature on product quality in the traditional granulation and drying process, but also solves the problem of poor content uniformity caused by the adoption of a powder direct compression process due to poor powder flowability. The quality of the product is effectively ensured, the in-vitro dissolution is consistent with the reference, and the clinical bioequivalence test result is equivalent to the in-vivo bioequivalence test result.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical granulation, and in particular, relates to a method for preparing a febuxostat tablet. Background Art

[0002] Febuxostat is a xanthine oxidase inhibitor that reduces serum uric acid concentration by inhibiting uric acid synthesis. It is suitable for the long-term treatment of hyperuricemia in gout patients. Febuxostat tablets were originally developed by Teijin Pharmaceuticals of Japan and are marketed under the name It was approved for marketing in the United States in 2009 and is now widely sold in many countries and regions including China. It has been published as a reference preparation in the notice of the catalog of reference preparations for generic drugs (21st batch). Febuxostat has been included in the National Essential Medicines Catalog (2021 Edition), with medical insurance number 910.

[0003] Febuxostat is a non-hygroscopic white crystalline powder with a melting point range of 205°C to 208°C. It is easily soluble in dimethylformamide and dimethyl sulfoxide; slightly soluble in ethanol and acetonitrile, and basically insoluble in water. The solubility of Febuxostat shows weak acidity (pKa=3.3) and is pH-dependent, and the solubility increases with increasing pH. According to the biopharmaceutics classification system, Febuxostat belongs to BCS Class II. Febuxostat has multiple crystal forms, and there is a possibility of crystal transformation between individual crystal forms. For example, the several crystal forms recorded in CN1275126A may be transformed into other crystal forms under certain conditions. The transformation of crystal forms has a potential impact on the properties of drug preparations, such as the solubility or stability of drug preparations.

[0004] At present, wet granulation process is generally adopted in Febuxostat tablets. CN108714143B is prepared into adhesive solution by dissolving Febuxostat raw material and adhesive in wetting agent, granulating by spraying in the mixture of filler and disintegrant, forming particulate matter containing Febuxostat, drying, adding glidant and lubricant, tableting, coating and obtaining. CN109350603B, CN111419814B, CN102614145B etc. all adopt wet granulation process. The process of tableting coating after wet granulation of Febuxostat tablets, often adds adhesive to assist molding in production process, because Febuxostat raw material is a poorly soluble drug, needs to be micronized, and micronized raw material has the characteristics of strong hydrophobicity, easily causes the phenomenon of inconsistent particle compaction, thereby causes the failure of bioequivalence test.

[0005] There are two major disadvantages of wet granulation for Febuxostat. First, the addition of water may cause Febuxostat to undergo crystal transformation during the preparation and storage processes. Second, the difference in particle compactness will increase the risk of inequivalence with the reference preparation in vivo, affecting the efficacy of the drug.

[0006] Dry granulation poses technical difficulties for Febuxostat because its powder properties are poor and it is difficult to press it into tablets that meet quality requirements. For example, the tableting process is prone to cracking and the hardness cannot be increased. Summary of the invention

[0007] In view of the deficiencies in the prior art, the purpose of the present invention is to provide a method for preparing febuxostat tablets by dry granulation and tablet compression, which solves the problem that dry granulation is difficult to press into tablets that meet quality requirements, while avoiding the adverse effects of moisture and high temperature on product quality during the traditional granulation and drying process. In addition, the method has a simple process, is environmentally friendly and energy-saving, and is easy to scale up.

[0008] To achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] A method for preparing febuxostat tablets, using a dry granulation and tableting process, comprises the following steps:

[0010] S1: dry-mixing the febuxostat raw material with starch lactose, croscarmellose sodium, copovidone and silicon dioxide in a mixer;

[0011] S2: adding the material obtained in S1 into a dry granulator for dry granulation;

[0012] S3: Mixing the material obtained in S2 with magnesium stearate in a hopper mixer;

[0013] S4: tableting the material obtained in S3;

[0014] S5: coating the material obtained in S4 to obtain febuxostat tablets;

[0015] In step S2, the dry granulator is operated at an oil pressure of 10-30 bar, and the gap between the rollers is controlled to be between 0.5-1.5 mm during the granulation process. The granules obtained after dry granulation are sieved through a 0.6-1.5 mm sieve for granulation.

[0016] Furthermore, the febuxostat tablets contain, by weight, 7.5-32 parts of febuxostat, 60-80 parts of starch lactose, 1-10 parts of cross-linked sodium carboxymethyl cellulose, 1-8 parts of copovidone, 0.5-4 parts of silicon dioxide, and 0.5-3 parts of magnesium stearate.

[0017] Furthermore, in step S1, the mixer speed is 12 rpm and the mixing time is 10 min.

[0018] Furthermore, in step S3, the rotation speed of the hopper mixer is 12 rpm, and the mixing time is 5 min.

[0019] Furthermore, in the step S5, the material obtained in S4 is coated with a gastric soluble coating solution, and the coating weight gain is 2%-4%.

[0020] The inventors carried out dry granulation according to the prescription in the instructions of Fiberline, and the prescription and powder properties are as follows:

[0021]

[0022] Febuxostat tablets require micronized raw materials for preparation, resulting in a strong hydrophobicity of the powder. The dry granulated particles have poor powder properties and are difficult to be pressed into tablets that meet quality requirements. No matter how the parameters are adjusted, the powder has poor fluidity, capping occurs during tableting, and the hardness cannot be increased. For this reason, the prescription is optimized, and the fillers pregelatinized starch and lactose are optimized to a single auxiliary material starch lactose, breaking through the shortcomings of the prescription, and copolyvidone is selected instead of sodium hydroxypropyl cellulose. The stronger affinity for the surface of hydrophobic materials is used to enhance the plasticity of the material, which can significantly improve the fluidity of the powder after dry granulation and improve the compressibility. The fillers pregelatinized starch and lactose are optimized to a single auxiliary material starch lactose to optimize the pretreatment efficiency. Colloidal silicon dioxide was added to aid flow, and the final formula for dry granulation was determined as follows: by weight, 7.5-32 parts of febuxostat, 60-80 parts of starch lactose, 1-10 parts of cross-linked sodium carboxymethyl cellulose, 1-8 parts of copovidone, 0.5-4 parts of silicon dioxide, and 0.5-3 parts of magnesium stearate.

[0023] The preparation method of a febuxostat tablet provided by the present invention not only avoids the adverse effects of moisture and high temperature on product quality during the traditional granulation and drying process, but also solves the problem of poor content uniformity caused by the direct compression process of powder due to poor powder fluidity. The method can effectively ensure the quality of the product, the in vitro dissolution is consistent with the reference, and the clinical bioequivalence test results are also equivalent to those in vivo. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with the embodiments.

[0025] Example 1

[0026] The formula of Febuxostat tablets is shown in the following table:

[0027]

[0028] Preparation method: The prescribed amount of febuxostat, starch lactose, cross-linked sodium carboxymethyl cellulose and copovidone are put into a mixing granulator for dry mixing, the stirring speed is adjusted to 12 rpm, and the material is discharged after the mixing time is 10 minutes.

[0029] The above materials were added into a dry granulator for dry granulation. The dry granulator was operated at an oil pressure of 10 bar. During the granulation process, the gap between the rollers was controlled to be between 1.0 mm. The granules obtained after dry granulation were sieved through a 1.0 mm sieve for granulation.

[0030] Magnesium stearate was added, and the hopper mixer was adjusted to mix at a speed of 12 rpm. The material was discharged after a total mixing time of 5 minutes.

[0031] Use a tablet press to compress into tablets according to dosage requirements.

[0032] The tablet cores were coated with a gastric soluble coating solution, and the coating weight gain was 3%.

[0033] Example 2

[0034]

[0035] Preparation method: The prescribed amount of febuxostat, starch lactose, cross-linked sodium carboxymethyl cellulose and copovidone are put into a mixing granulator for dry mixing, the stirring speed is adjusted to 12 rpm, and the material is discharged after the mixing time is 10 minutes.

[0036] The above materials were added into a dry granulator for dry granulation. The dry granulator was operated at an oil pressure of 10 bar. During the granulation process, the gap between the rollers was controlled to be between 1.5 mm. The granules obtained after dry granulation were sieved through a 1.5 mm sieve for granulation.

[0037] Magnesium stearate was added, and the hopper mixer was adjusted to mix at a speed of 12 rpm. The material was discharged after a total mixing time of 5 minutes.

[0038] Use a tablet press to compress into tablets according to dosage requirements.

[0039] The tablet cores were coated with a gastric soluble coating solution, and the coating weight gain was 2%.

[0040] Example 3

[0041]

[0042]

[0043] Preparation method: The prescribed amount of febuxostat, starch lactose, cross-linked sodium carboxymethyl cellulose and copovidone are put into a mixing granulator for dry mixing, the stirring speed is adjusted to 12 rpm, and the material is discharged after the mixing time is 10 minutes.

[0044] The above materials were added into a dry granulator for dry granulation. The dry granulator was operated at an oil pressure of 30 bar. During the granulation process, the gap between the rollers was controlled to be between 0.5 mm. The granules obtained after dry granulation were sieved through a 0.6 mm sieve for granulation.

[0045] Magnesium stearate was added, and the hopper mixer was adjusted to mix at a speed of 12 rpm. The material was discharged after a total mixing time of 5 minutes.

[0046] Use a tablet press to compress into tablets according to dosage requirements.

[0047] The tablet cores were coated with a gastric soluble coating solution, and the coating weight gain was 4%.

[0048] Performance Testing

[0049] Samples and reference preparations prepared in Examples 1 to 3 As test samples, the dissolution of each sample in 0.01 mol / L hydrochloric acid, water, pH 4.5 acetate buffer, and pH 6.8 acetate buffer was tested at different times, and the results are shown in Tables 1 to 4. The results show that the dissolution of the homemade sample is equivalent to that of the reference tablet.

[0050] Table 1 Dissolution data of each sample in pH 1.2 + 1% SDS hydrochloric acid dissolution medium

[0051] Time (min) Commercially available products (%) Example 1 (%) Example 2 (%) Example 3 (%) 5 16 28 30 15 10 50 56 54 42 15 69 70 67 60 20 79 78 75 71 30 89 86 83 82 45 96 91 90 91 60 99 93 93 96 90 102 95 95 99 f2 72 68 54

[0052] Table 2 Dissolution data of each sample in pH 5.5 dissolution medium

[0053]

[0054]

[0055] Table 3 Dissolution data of each sample in pH 6.0 dissolution medium

[0056] Time (min) Commercially available products (%) Example 1 (%) Example 2 (%) Example 3 (%) 5 54 61 44 44 10 86 87 80 78 15 95 94 92 93 20 99 97 96 98 30 101 99 98 101 45 102 99 98 102 60 102 99 98 102

[0057] Table 4 Dissolution data of each sample in pH 6.8 dissolution medium

[0058] Time (min) Commercially available products (%) Example 1 (%) Example 2 (%) Example 3 (%) 5 67 74 56 51 10 95 98 88 89 15 99 101 95 99 20 101 101 97 100 30 101 101 98 101 45 102 101 98 101 60 102 101 98 101

[0059] Furthermore, the samples prepared in Example 3 were used as test samples, and the quality was compared with the commercial products according to the requirements of the Chinese Pharmacopoeia Drug Preparation Stability Test Guidelines, and accelerated tests and long-term sample retention were conducted. At the same time, a portion of the samples were taken to conduct influencing factor tests using naked packaging. The tests were conducted according to the relevant items of the quality standards and compared with the results of day 0; the results are shown in Tables 5 to 10.

[0060] Table 5 Related substances and dissolution results

[0061]

[0062]

[0063] Table 6 Experimental results of influencing factors in Example 3

[0064]

[0065] Table 7 Example 3 Accelerated test

[0066]

[0067]

[0068] Table 8 Example 3 Long-term test

[0069]

[0070] The quality of self-developed products meets the standard requirements and has good stability.

[0071] Furthermore, healthy subjects orally took the test preparation Febuxostat Tablets of Example 3 and the reference preparation Febuxostat Tablets (trade name: ) to evaluate whether the test preparation and the reference preparation are bioequivalent. The C max , AUC 0-t and AUC 0-∞ The geometric mean ratio (T / R) and its 90% confidence interval were both within the range of 80.00% to 125.00%, meeting the bioequivalence criteria.

[0072] Table 9 Bioequivalence data

[0073]

[0074]

[0075] The above test results show that the Febuxostat tablets prepared by the prescription and process of the present invention have a simple prescription, energy-saving and environmentally friendly process, and are easy to operate. The prepared product has the same pharmaceutical quality as the reference preparation and is bioequivalent, and can be used as a substitute for Febuxostat in clinical practice.

Claims

1. A method for preparing febuxostat tablets, characterized in that: The dry granulation and tableting process includes the following steps: S1: dry-mixing the febuxostat raw material with starch lactose, croscarmellose sodium, copovidone and silicon dioxide in a mixer; S2: adding the material obtained in S1 into a dry granulator for dry granulation; S3: Mixing the material obtained in S2 with magnesium stearate in a hopper mixer; S4: tableting the material obtained in S3; S5: coating the material obtained in S4 to obtain febuxostat tablets; In step S2, the dry granulator is operated at an oil pressure of 10-30 bar, and the gap between the rollers is controlled to be between 0.5-1.5 mm during the granulation process. The granules obtained after dry granulation are sieved through a 0.6-1.5 mm sieve for granulation.

2. The method for preparing Febuxostat according to claim 1, characterized in that: By weight, the composition comprises 7.5-32 parts of febuxostat, 60-80 parts of starch lactose, 1-10 parts of cross-linked sodium carboxymethyl cellulose, 1-8 parts of copovidone, 0.5-4 parts of silicon dioxide and 0.5-3 parts of magnesium stearate.

3. The method for preparing Febuxostat according to claim 1, characterized in that In step S1, the mixer speed is 12 rpm and the mixing time is 10 min.

4. The method for preparing Febuxostat according to claim 1, characterized in that In step S3, the hopper mixer mixes at a rotation speed of 12 rpm for a total mixing time of 5 minutes.

5. The method for preparing Febuxostat according to claim 1, characterized in that: Step S5 is: coating the material obtained in S4 with a gastric soluble coating solution, and the coating weight gain is 2%-4%.

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