Colchicine tablet with high stability and preparation method thereof

Abstract

The invention discloses a colchicine tablet with high stability, which comprises colchicine, a filler, an adhesive, a disintegrating agent, an antioxidant, an opacifying agent, a flow aid and a lubricant, and the antioxidant is alpha-tocopherol; the invention also provides a preparation method of the colchicine tablet. The colchicine and the antioxidant alpha-tocopherol are dissolved in ethanol and then are granulated, so that the colchicine is prevented from being decomposed in water, the increase of related substances can be effectively reduced, and the stability of the colchicine tablet is improved. The compressibility and hardness of the colchicine tablet can be obviously improved by adding the microcrystalline cellulose into the prescription. In addition, a small amount of opacifying agent titanium dioxide is added into the prescription, so that the storage stability of the colchicine tablet can be obviously improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of solid pharmaceutical preparations, and particularly relates to a colchicine tablet with high stability and a preparation method thereof. BACKGROUND

[0002] Colchicine, an alkaloid, is extracted from the plant Colchicum autumnale L. of the Liliaceae family, also known as colchicine, and is a drug for treating acute attacks of gouty arthritis and preventing acute attacks of recurrent gouty arthritis. Its mechanism of action includes: it can bind to microtubular protein dimers, prevent the conversion of microtubular protein, and cause cell death by stopping cells at the metaphase of mitosis; it can reduce the activity, adhesion and chemotaxis of neutrophils by interfering with lysosome degranulation, and inhibit the migration of granulocytes to the inflammatory area, thereby exerting an anti-inflammatory effect; it can inhibit the production of interleukins and other substances by local cells, thereby achieving the control of pain, swelling and inflammatory reactions in the joint.

[0003] Colchicine is easily soluble in water, ethanol and chloroform, and unstable and easily decomposed in aqueous solution. In view of this feature, it has been reported that colchicine can be first made into a clathrate, but the process steps are complicated. In addition, colchicine can accelerate the decomposition of the raw material under light conditions, the impurities increase significantly, and it is easily oxidized, which affects the efficacy and safety of the drug. SUMMARY

[0004] The purpose of the present application is to solve the above technical problems, and provide a colchicine tablet with high stability and a preparation method thereof.

[0005] The colchicine tablet with high stability provided by the present application comprises colchicine, a filler, a binder, a disintegrant, an antioxidant, a light shielding agent, a glidant and a lubricant, and the antioxidant is alpha-tocopherol.

[0006] Further, the filler is selected from one or two of lactose monohydrate, anhydrous lactose, pregelatinized starch, corn starch or microcrystalline cellulose, preferably a mixture of anhydrous lactose and microcrystalline cellulose, and the mass ratio of the anhydrous lactose and the microcrystalline cellulose is 16:5.

[0007] Further, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or cross-linked povidone.

[0008] Further, the binder is selected from one or more of hydroxypropyl cellulose or povidone K30. Preferably, the binder is hydroxypropyl cellulose.

[0009] Further, the light shielding agent is selected from titanium dioxide.

[0010] Further, the glidant is selected from silicon dioxide, and the lubricant is selected from magnesium stearate.

[0011] The present application also provides a preparation method of colchicine tablets with high stability, characterized in that the method comprises the following steps:

[0012] 1) Colchicine and antioxidant α-tocopherol are added into anhydrous ethanol and stirred and dissolved for standby use;

[0013] 2) The filler, disintegrant, binder and glidant are mixed together in a wet mixing granulator, and then the mixed solution prepared in step 1) is poured into the wet mixing granulator for wet granulation;

[0014] 3) The wet granules obtained in step 3) are dried in a fluidized bed, and the drying temperature is 60-80°C, and the moisture content is controlled to be less than 3.0%;

[0015] 4) The dry granules are sieved by a stainless steel sieve shaker, and then lubricant is added for mixing and tabletting.

[0016] 5) The dry granules are sieved by a stainless steel sieve shaker, and then lubricant is added for mixing and tabletting.

[0017] Beneficial effects: After colchicine and antioxidant α-tocopherol are dissolved in ethanol and then granulated, the decomposition of colchicine in water is avoided, the increase of related substances is effectively reduced, and the stability of colchicine tablets is improved. The addition of microcrystalline cellulose in the prescription can significantly improve the compressibility and hardness of colchicine tablets. In addition, the addition of a small amount of light shielding agent titanium dioxide in the prescription can significantly improve the stability of colchicine tablets during storage. DETAILED DESCRIPTION

[0018] In order to deepen the understanding of the present application, the present application will be further described in combination with examples, which are only used to explain the present application and do not constitute a limitation on the protection scope of the present application.

[0019] Example 1: Preparation method of colchicine tablets

[0020] The preparation is carried out according to the amounts in prescription 1-1, 1-2 and 1-3 in Table 1, and the preparation method is as follows:

[0021] Colchicine and α-tocopherol are added into anhydrous ethanol and stirred and dissolved for standby use. Then lactose, microcrystalline cellulose, titanium dioxide, hydroxypropyl cellulose and sodium carboxymethyl starch are mixed together in a wet mixing granulator, and then the ethanol solution containing colchicine and α-tocopherol is introduced into the granulator for mixing and wet granulation for 10 minutes. Then 50% (volume fraction) ethanol aqueous solution is added, and the wet granulation is continued. After the wet granulation is completed, the wet granules are sieved by a 14-mesh sieve. The wet granules are dried in a fluidized bed, and the drying temperature is 60-80°C. When the material temperature reaches 40-45°C, the heating is turned off, and the material is discharged. The moisture content is controlled to be less than 3.0%. The dry granules are sieved by a 18-mesh stainless steel sieve shaker, and then silicon dioxide and magnesium stearate are added for mixing and tabletting.

[0022] Table 1 Prescription 1-1, 1-2, 1-3 composition in Example 1

[0023] Ingredients Formulation 1-1 Formulation 1-2 Formulation 1-3 Colchicine 0.5g 1g 1g Lactose 80g 80g 80g Microcrystalline cellulose 25g 25g 25g Sodium carboxymethyl starch 5g 5g 5g Hydroxypropyl cellulose 2g 2.5g 3g Alpha-tocopherol 0.2g 0.2g 0.3g Ethanol q.s. q.s. q.s. Silica 0.5g 0.8g 1g Magnesium stearate 0.8g 0.8g 0.8g Titanium dioxide 0.5g 0.5g 0.5g

[0024] Example 2 Preparation method of colchicine tablets

[0025] Colchicine tablets were prepared according to the prescription composition of each comparative example in Table 2, and the preparation method was basically the same as that of Example 1.

[0026] Table 2 Prescription composition of each comparative example

[0027] Ingredients Formulation 2-1 Formulation 2-2 Formulation 2-3 Formulation 2-4 Formulation 2-5 Formulation 2-6 Formulation 2-7 Colchicine 0.5g 0.5g 0.5g 1g 1g 1g 1g Anhydrous lactose 80g 80g 80g 80g 80g 80g 80g Microcrystalline cellulose 25g / / 25g 25g 25g 25g Pre-gelatinized starch / 25g / / / / / Corn starch / / 25g / / / / Sodium carboxymethyl starch 5g 5g 5g 5g 5g 5g 5g Hydroxypropyl cellulose 2g 2g 2g / 2.5g 2.5g 3g Polyvidone K30 / / / 2.5g / / / Alpha-tocopherol / 0.2g 0.2g 0.2g / 0.2g 0.3g Ascorbic acid / / / / 0.2g / / Ethanol q.s. q.s. q.s. q.s. q.s. q.s. q.s. Silica 0.5g 0.5g 0.5g 0.8g 0.5g 0.8g / Talc / / / / / / 1g Magnesium stearate 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g Titanium dioxide 0.5g 0.5g 0.5g 0.5g 0.5g / 0.5g Zinc oxide / / / / / 0.5g /

[0028] Example 3 Preparation method of colchicine tablets

[0029] According to the prescription amount in Table 3, the preparation method is as follows:

[0030] Colchicine and α-tocopherol were added to purified water and stirred to dissolve for standby. Then lactose, microcrystalline cellulose, titanium dioxide, hydroxypropyl cellulose and sodium carboxymethyl starch were mixed together in a wet granulator and stirred evenly. The water solution containing colchicine and α-tocopherol was poured into the granulator for wet granulation for 10 minutes, and then purified water was added for continuous wet granulation. After wet granulation, the granules were sieved with a 14-mesh screen. The above wet whole granules were added to the fluidized bed for drying, and the drying temperature was 60-80°C. When the material temperature reached 40-45°C, the heating was turned off, and the moisture content was controlled to be less than 3.0%. The dry granules were sieved with an 18-mesh stainless steel screen, and finally silicon dioxide and magnesium stearate were added for tabletting.

[0031] Table 3 Prescription 3-1, 3-2, 3-3 composition in Example 1

[0032] Ingredients Formulation 3-1 Formulation 3-2 Formulation 3-3 Colchicine 0.5g 1g 1g Lactose 80g 80g 80g Microcrystalline cellulose 25g 25g 25g Sodium carboxymethyl starch 5g 5g 5g Hydroxypropyl cellulose 2g 2.5g 3g Alpha-tocopherol 0.2g 0.2g 0.3g Purified water q.s. q.s. q.s. Silica 0.5g 0.8g 1g Magnesium stearate 0.8g 0.8g 0.8g Titanium dioxide 0.5g 0.5g 0.5g

[0033] Example 4 Performance test of colchicine tablets

[0034] (1) Comparison of compressibility and friability

[0035] The results of the study on the tabletting process and friability of each prescription (test equipment: tablet friability tester) are as follows:

[0036] Table 4 Comparison of compressibility and friability

[0037] Example Compressibility Fragility (not more than 1%) 1-1 Good Comply with the requirements 1-2 Good Comply with the requirements 1-3 Good Comply with the requirements 2-1 Good Comply with the requirements 2-2 Slightly poor compressibility Occasionally broken pieces 2-3 Slightly poor compressibility Occasionally broken pieces 2-4 Good Comply with the requirements 2-5 Good Comply with the requirements 2-6 Good Comply with the requirements 2-7 Slightly poor compressibility, occasionally sticky phenomenon Comply with the requirements 3-1 Good Comply with the requirements 3-2 Good Comply with the requirements 3-3 Good Comply with the requirements

[0038] (2) Related substance test results of colchicine tablets

[0039] Colchicine tablets were placed under the influence of factors high temperature (60°C), high humidity (relative humidity 92.5%, temperature 25°C) and light (4500lx±500lx) for 10 days and 30 days, respectively, and the test results are shown in Table 4 below.

[0040] Table 5 Test results of related substances

[0041]

[0042]

[0043]

[0044]

[0045] As can be seen from Example 1-1, Comparative Example 2-1 and Comparative Example 2-5, the product stability is better when α-tocopherol is used as the antioxidant than when no antioxidant is added or ascorbic acid is used as the antioxidant, so the antioxidant is preferably α-tocopherol.

[0046] As can be seen from Example 1-1, Comparative Example 2-2 and Comparative Example 2-3, the compressibility is good when lactose and microcrystalline cellulose are used as the filler, and there are occasional cases of cracking when pregelatinized starch or corn starch is used to replace microcrystalline cellulose as the filler, so the filler is preferably lactose and microcrystalline cellulose.

[0047] As can be seen from Example 1-2 and Comparative Example 2-4, the compressibility is good when povidone K30 and hydroxypropyl cellulose are used as the binder, but compared with hydroxypropyl cellulose, povidone K30 is more hygroscopic, and the impurity increase is more obvious under the influence of factors, so the binder is preferably hydroxypropyl cellulose.

[0048] As can be seen from Example 1-1 and Comparative Example 2-6, the compressibility is good when titanium dioxide is used as the light shielding agent and when zinc oxide is used as the light shielding agent, and the stability of the tablets is better when titanium dioxide is used as the light shielding agent.

[0049] As can be seen from Example 1-3 and Comparative Example 2-7, the anti-sticking effect of silicon dioxide is better than that of talc, and there is no sticking phenomenon during the tabletting process, so the lubricant is preferably silicon dioxide and magnesium stearate.

[0050] As can be seen from the preparation steps of the related formulations of Example 1 and Example 3, the related substance impurity A and total impurities of the samples prepared by Example 1-1, 1-2 and 1-3 using ethanol granulation are significantly lower than those of Example 3-1, 3-2 and 3-3 using purified water granulation.

[0051] The above merely provides the preferred embodiment of the present application, and is not used to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A colchicine tablet with high stability, characterized in that, It contains colchicine, fillers, binders, disintegrants, antioxidants, opacifiers, flow aids, and lubricants, wherein the antioxidant is α-tocopherol.

2. The colchicine tablets according to claim 1, characterized in that, The filler is selected from one or two of lactose monohydrate, anhydrous lactose, pregelatinized starch, corn starch, or microcrystalline cellulose.

3. The colchicine tablets according to claim 2, characterized in that, The filler is a mixture of anhydrous lactose and microcrystalline cellulose, wherein the mass ratio of anhydrous lactose to microcrystalline cellulose is 16:

5.

4. The colchicine tablets according to claim 1, characterized in that, The disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, or croscarmellose.

5. The colchicine tablets according to claim 1, characterized in that, The adhesive is selected from one or more of hydroxypropyl cellulose or povidone K30.

6. The colchicine tablets according to claim 5, characterized in that, The adhesive is hydroxypropyl cellulose.

7. The colchicine tablets according to claim 1, characterized in that, The light-blocking agent is selected from titanium dioxide.

8. The colchicine tablets according to claim 1, characterized in that, The flow aid is selected from silicon dioxide, and the lubricant is selected from magnesium stearate.

9. The method for preparing colchicine tablets according to any one of claims 1-7, characterized in that, Includes the following steps: 1) Add colchicine and antioxidant to anhydrous ethanol, stir to dissolve, and set aside. 2) Place the filler, disintegrant, binder and flow aid together in a wet granulation machine and mix them evenly. Then pour in the mixed solution prepared in step 1) and perform wet granulation. 3) Granulation is performed using a 14-mesh sieve; 4) Add the wet-processed granules obtained in step 3) to a fluidized bed for drying, controlling the moisture content to be less than 3.0%; 5) The dry granules are sized using a stainless steel vibrating sieve, and finally lubricant is added and mixed together before tableting.

10. The method for preparing colchicine tablets according to claim 9, characterized in that, The drying temperature in step 4) is 60-80℃.

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