A dry granulation method for methotrexate tablets

Abstract

The present application is a dry granulation method of methotrexate tablets, comprising: mixing methotrexate and excipients by geometric dilution method, and adopting roll pressing method and directly pressing to obtain methotrexate tablets. The excipients include anhydrous lactose, microcrystalline cellulose, pre-gelatinized starch and sodium carbonate. The content of methotrexate in each methotrexate tablet is 2-3%. The present application has the advantages that the components and method design are reasonable, the cost and energy can be effectively saved, the solvent contact in the granulation process is reduced, the time is saved, the stability of the pharmaceutical preparation components can be effectively improved, and the production efficiency is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to a production method of methotrexate tablets, and particularly relates to a dry granulation method of methotrexate tablets. BACKGROUND

[0002] Methotrexate, also known as aminopterin, amethopterin, etc., is an anti-folate antitumor drug, which mainly inhibits the synthesis of tumor cells by inhibiting dihydrofolate reductase, so as to inhibit the growth and reproduction of tumor cells.

[0003] The production of tablets generally includes dry granulation and wet granulation. The defect of wet granulation is that the solvent used is water, an organic solvent or an inorganic solvent, which may cause drug degradation or poor stability. Dry granulation does not have these problems, and compared with wet granulation, it can save the production time and energy of tablets. Direct compression method is generally used in dry granulation, which has problems of brittleness, hardness and poor uniformity.

[0004] The concentration of methotrexate in the methotrexate tablet is generally very low, and there is also a problem of uniformity.

[0005] The dry granulation method is considered to be used, which consumes less time and can improve the brittleness and hardness of the tablet. The granulation process can avoid the waste of water or other solvents, save energy consumption, and the product is similar to that of wet granulation. SUMMARY

[0006] The present application provides a dry granulation method of methotrexate tablets, which aims to overcome the above-mentioned deficiencies in the prior art, improve production efficiency, reduce energy consumption and cost, and improve the stability of the active ingredient.

[0007] The technical solution of the present application is a dry granulation method of methotrexate tablets, which comprises: mixing methotrexate and excipients by geometric dilution method, and using roll pressing method and direct compression to prepare methotrexate tablets.

[0008] Preferably, the excipients include anhydrous lactose, microcrystalline cellulose, pregelatinized starch and sodium carbonate.

[0009] Preferably, the content of methotrexate in each methotrexate tablet is 1-50%.

[0010] Preferably, the content of methotrexate in each methotrexate tablet is 2-15%.

[0011] Preferably, the content of methotrexate in each methotrexate tablet is 2-3%.

[0012] Preferably, it specifically comprises the following steps:

[0013] 1) Powder mixing: Pass the formula amount of anhydrous lactose, microcrystalline cellulose, pregelatinized starch and sodium carbonate through a 30-mesh sieve to form a uniform excipient powder, and stir in a mixer at 10±5 rpm for 10±5 minutes.

[0014] 2) Geometric dilution: Add the prescribed amount of methotrexate to the excipient powder at a ratio of 1:1 and stir in a mixer at 10±5 rpm for 5 minutes. Then mix the drug powder and excipient powder at a ratio of 1:1 and stir at 10±5 rpm for 5 minutes. Repeat the above process until the excipient is used up.

[0015] 3) Roller pressing: The material is passed through the roller press pelletizer at a roller pressing speed of 5-20 rpm and a roller pressing gap of 1-3 mm, and then passed through a 30-mesh sieve to form uniform powder particles.

[0016] 4) Pre-lubrication: Pass talc powder through a 60-mesh sieve and mix it evenly with the powder obtained in step 3). Stir in a mixer at 10±5 rpm for 5 minutes.

[0017] 5) Lubrication: Magnesium stearate group is passed through a 60-mesh sieve and mixed evenly with the powder obtained in step 4). Stir at 5±2 rpm for 5 minutes in a stirrer.

[0018] 6) Tableting: The mixed granules obtained in step 5) are compressed into tablets;

[0019] 7) Coating: The coating agent is reconstructed in pure water with 15% by weight of solids and homogenized until uniform dispersion is achieved. The tablets are then coated using a coating machine until the tablet weight gain reaches 2.5-3.5%.

[0020] Preferably, the tablets obtained in step 6) weigh about 100 (100±5) mg and have a diameter of 6-7 mm.

[0021] Preferably, the coating agent in step 7) is Opadry II Yellow 30B120016.

[0022] The advantages of this invention are: the components and methods are rationally designed, which can effectively save costs and energy, reduce solvent contact during granulation, and save time. It can effectively improve the stability of pharmaceutical formulation components and production efficiency. Detailed Implementation

[0023] The present invention will be further described in detail below with reference to embodiments and specific implementation methods.

[0024] A methotrexate tablet wherein methotrexate is present in a dispersed form within a solid matrix of excipients.

[0025] As one example, each tablet contains 1-50 mg of methotrexate.

[0026] As a further preferred embodiment, the methotrexate content of each tablet is 2-15 mg.

[0027] As a most preferred embodiment, the methotrexate content of each tablet is 2-3 mg.

[0028] As another embodiment, the methotrexate content of each tablet is 2.5, 5, 7.5, 10, 12.5 or 15 mg, dispersed in a solid matrix consisting of fillers, binders and lubricants, etc.

[0029] The fillers can be modified lactose monohydrate, lactose (monohydrate a-lactose, anhydrous b-lactose, spray-dried lactose), microcrystalline cellulose (Avi c el PH 101, Avi c el PH 200, Emco c el), starch (corn starch, partially hydrolyzed starch), D-starch (D-starch, D-starch disalt calcium phosphate (Emcompress, D i-Tab), mannitol (Parteck, De l ta M), sorbitol (Neosorb 60), calcium sulfate (De l af l o), compressible sucrose (D i-Pac, Des-tab, Nu-Tab), but not limited thereto.

[0030] The binders can be polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, but not limited thereto.

[0031] The lubricants can be magnesium stearate, stearic acid and talc, but not limited thereto.

[0032] As an embodiment, 2.5 mg of methotrexate per tablet is dispersed in a solid matrix consisting of anhydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium carbonate, talc and magnesium stearate.

[0033] The geometric dilution described below is a pharmaceutical technology for ensuring uniform distribution of potent or concentrated substances in a mixture. The mixing method of low-concentration drug substances in tablets is geometric dilution, which helps to achieve uniform distribution of drug substances in the tablet matrix. This technology includes gradually adding ingredients in equal proportions, starting from the smallest amount, and mixing well until uniform mixing is achieved.

[0034] A dry granulation method of methotrexate tablets includes mixing methotrexate with the above-mentioned excipient powder by the geometric dilution method to achieve volume uniformity and uniformity of drug substances in tablets.

[0035] As an embodiment, geometric dilution is performed by a suitable stirrer.

[0036] As a preferred embodiment, roller compaction is used.

[0037] As a further preferred embodiment, the roller compaction method is used and direct compression is employed.

[0038] As a further preferred embodiment, the ready-to-use coating agent mixture is used for coating.

[0039] As a preferred embodiment, the coating agent is I I Yellow 30B 1200 16.

[0040] The tablets produced by the formulations and methods of the present application have good processability, for example, a large hardness range. That is, the tablets can be compressed over a large range of compression forces to form tablets having acceptable tabletting properties, such as tablet breaking force as assessed using USP No. 1217 test and / or friability as assessed using USP No. 1217 test.

[0041] As an embodiment, the tablets have a hardness range greater than 10 N, for example, greater than 15 N, such as greater than 20 N or greater than 30 N.

[0042] As a preferred embodiment, the tablets have a hardness range greater than 10 N. The hardness range can also be less than 30 N, for example, less than 20 N.

[0043] As a further preferred embodiment, the hardness range is less than 18 N, for example, less than 16 N, less than 15 N or 10 N.

[0044] The tablets produced by the formulations and methods of the present application have good friability. Friability refers to the ability of the tablet to withstand abrasion during packaging, handling and shipping. Friability can be measured by any suitable measurement technique, for example, according to USP Standard No. 1216.

[0045] In particular, a dry granulation method for a methotrexate tablet comprises:

[0046] Powder mixing: The formulation amount of lactose anhydrous, microcrystalline cellulose, pre-gelatinized starch, sodium carbonate, talc and magnesium stearate are passed through a 30 mesh screen to form a uniform powder of excipients. The powder is mixed in a suitable size blender for 10 ± 5 minutes at 10 ± 5 rpm.

[0047] The solid matrix is composed of lactose anhydrous, microcrystalline cellulose, pre-gelatinized starch, sodium carbonate, talc and magnesium stearate

[0048] Geometric dilution: The formulation amount of methotrexate is added to the powder of excipients in a ratio of 1 : 1 and mixed in a suitable size blender for 5 minutes at 10 ± 5 rpm. The powder containing the drug and the powder of excipients are then mixed in a ratio of 1 : 1 and mixed in a suitable size blender for 5 minutes at 10 ± 5 rpm. The process is repeated until the excipients are used up.

[0049] Rolling: The material is passed through a roller compactor at a rolling speed of 5-20 rpm and a rolling gap of 1-3 mm. The uniform powder particles are formed by passing through a 30 mesh screen.

[0050] Pre-lubrication: The talc is passed through a 60 mesh screen and mixed thoroughly. It is stirred in a blender at 10 ± 5 rpm for 5 minutes.

[0051] Lubrication: The magnesium stearate lot is passed through a 60 mesh screen and mixed thoroughly. It is stirred in a blender at 5 rpm for 5 ± 2 minutes.

[0052] Tabletting: The blended granules are compressed into tablets using appropriate tooling, with a final weight of approximately 100 (100 ± 5) mg and a diameter of approximately 6-7 mm.

[0053] Coating: The tablet is reconstituted in purified water at a weight percent of 15% solids II Yellow 30B 1200 16, and homogenized until uniform dispersion is achieved. The tablets are coated using a coating machine until the tablets have gained 2.5-3.5% in weight.

[0054] Example 1: Uncoated tablets

[0055] Formulation:

[0056]

[0057] Manufacturing process:

[0058] Powder mixing: The formulation quantities 24 AN, Avicel PH 200, StarCap 1500, and DC grade sodium carbonate are passed through a 30 mesh screen to form uniform excipient powder. The excipient powder is stirred in a blender at 10 rpm for 10 minutes.

[0059] Geometric dilution: The formulation quantity methotrexate is added to the excipient powder in a ratio of 1:1 and stirred in a blender at 10 rpm for 5 minutes. The drug-containing powder is then mixed with the excipient powder in a ratio of 1:1 and stirred at 10 rpm for 5 minutes. The above process is repeated until the excipient is used up.

[0060] Rolling: The material is passed through a roller compactor at a rolling speed of 5-20 rpm and a rolling gap of 1-3 mm. The uniform powder particles are formed by passing through a 30 mesh screen.

[0061] Pre-lubrication: LUB MST is passed through a 60 mesh screen and mixed thoroughly. It is stirred in a blender at 10 rpm for 5 minutes.

[0062] Lubrication: LIGAMED MF-3-V-MB was sieved through a 60 mesh screen and mixed well. The mixture was stirred in a blender at 5 rpm for 5 minutes.

[0063] Tabletting: The blended granules were compressed into tablets using appropriate size tooling to a final weight of approximately 100 mg and a diameter of approximately 6-7 mm.

[0064] Example 2: Coated tablets

[0065] Formulation: Same as Example 1 with the addition of 3 mg of coating agent I I Yellow 30B 120 016.

[0066] Manufacturing process: Same as Example 1 with the addition of a coating step: the coating agent was reconstituted in purified water at 15% w / w solids and homogenized until a uniform dispersion was achieved. The tablets were coated using a coating machine until the tablets gained 2.5-3.5% in weight. I I Yellow 30B 120 016.

[0067] Example 3: Uncoated tablets

[0068] Formulation: Same as Example 1.

[0069] Manufacturing process: Same as Example 1 with the geometric dilution step and the roller compaction step replaced by a mixing step: the methotrexate was added to the excipient powder and stirred in a suitable size blender at 10 rpm for 10 minutes.

[0070] Example 4: Coated tablets

[0071] Formulation: Same as Example 2.

[0072] Manufacturing process: Same as Example 3 with the addition of a coating step: the coating agent was reconstituted in purified water at 15% w / w solids and homogenized until a uniform dispersion was achieved. The tablets were coated using a coating machine until the tablets gained 2.5-3.5% in weight. I I Yellow 30B 120 016.

[0073] Example 5: Uncoated tablets

[0074] Formulation: Same as Example 1.

[0075] Manufacturing process: Same as Example 1 with the roller compaction step replaced by an extrusion step: the blended powder was compressed into small pieces of approximately 4-5 grams using appropriate size tablet tooling. The pieces were passed through a vibrating granulator with a 30 mesh screen to make uniform powder granules.

[0076] Example 6: Coated tablets

[0077] Formulation: Same as Example 1.

[0078] Manufacturing Process: The difference between Example 5 is that it further includes a coating step: reconstitute I I Yellow 30B 120 016, and homogenize until uniform dispersion is achieved. Coat the tablets using a coating machine until the tablets have gained 2.5-3.5% weight.

[0079] Example 7: Coated Tablets

[0080] Formulation: Same as Example 1.

[0081] Manufacturing Process: The difference between Example 3 is that it further includes a wet granulation step and a drying step between the mixing step and the pre-lubrication step.

[0082] Wet Granulation: The mixed powder is granulated using a rapid mixer granulator at impeller speed (i.e. mixing speed) of 80 rpm and chopper speed (i.e. kneading speed) of 120 rpm using purified water.

[0083] Drying: The wet granules are dried in a Restch dryer at a temperature of 65 ± 5 °C with a loss on drying of less than 0.5%. The bulk material is passed through a shaking granulator with a 30 mesh screen to form uniform powder granules.

[0084] Example 8: Coated Tablets

[0085] Formulation: Same as Example 2.

[0086] Manufacturing Process: The difference between Example 7 is that it further includes a coating step: reconstitute I I Yellow 30B 120 016, and homogenize until uniform dispersion is achieved. Coat the tablets using a coating machine until the tablets have gained 2.5-3.5% weight.

[0087] Example 9: Batch Uniformity Analysis

[0088] Samples of the mixed powder from each example are collected in duplicate prior to pre-lubrication. The samples are analyzed using validated analytical methods and the results are recorded in the table below.

[0089] Embodiments Top 1 Top 2 Top 3 Bottom 1 Bottom 2 Bottom 3 1 99.9 99.8 100.1 99.9 99.7 100.3 2 99.9 99.8 100.5 99.9 99.7 100.3 3 98.2 101.1 102.5 103.5 96.8 95.6 4 103.4 102.4 98.1 97.2 99.6 104.1 5 100.3 100.1 99.8 99.9 100.3 99.8 6 100.1 99.6 100.3 99.7 99.9 100.2 7 99.7 98.1 99.4 96.9 99.6 96.3 8 98.6 99.2 99.4 96.7 98.3 97.3

[0090] Example 10: Friability Test

[0091] The formulated tablets are evaluated for friability using a USP apparatus.

[0092] Ten tablets of methotrexate were accurately weighed and then placed in the drum of the instrument. The tablets were rotated at 24-26 rpm for 100 rotations. The tablets were again accurately weighed and the loss in weight was calculated. In addition, the tablets were examined for appearance of the edges and shape. The results are shown in the table below.

[0093]

[0094]

[0095] Example 11: Hardness Test

[0096] The tablets were tested for hardness using a digital hardness tester. Ten tablets were used for the test and the average value is reported in the table below.

[0097]

[0098] Example 12: Weight Variation Analysis

[0099] The tablets were evaluated for tablet weight variation.

[0100] Ten tablets were accurately weighed separately. Based on the weight of each tablet and the assay result, the content of each tablet was calculated and expressed as a percentage of the label claim.

[0101]

[0102]

[0103] Example 13: Disintegration Time Test

[0104] The tablets were tested for disintegration using the USP disintegration test apparatus and the results are shown in the table below.

[0105]

[0106] Example 14: Dissolution Test

[0107] The tablets were evaluated for dissolution using the USP dissolution test apparatus 2 at 5 rpm using 900 mL of 0.1 N hydrochloric acid over 45 minutes.

[0108] Example 2 Geometric Dilution - Roll-pressed - Coated Tablets have a dissolution profile similar to the reference formulation.

[0109] Example 4 Tablets made using direct compression have a too fast release rate.

[0110] Example 6 The granules disintegrate poorly and the extrusion process increases the dissolution time.

[0111] The dissolution is considered equivalent if the similarity factor (f2) is greater than 50 (50-100) and the difference factor (f1) is not more than 15 (0-15).

[0112] Example 2 Geometric dilution - roller compaction - coated tablets showed excellent results in both f2 and f1 values.

[0113] The detailed results are shown in the table below.

[0114]

[0115] Example 15: Stability study

[0116] The examples using wet granulation and roller compaction dry granulation were subjected to stability study.

[0117] In terms of impurity content, the tablets prepared by roller compaction were more stable than the tablets prepared by wet granulation and the reference formulation.

[0118] Example 2 using geometric dilution and roller compaction had better control of impurities compared to the wet granulation process and the reference formulation.

[0119] The details are shown in the table below.

[0120]

[0121]

[0122] From the results of Examples 9-15, it can be concluded that the geometric dilution method helps to effectively mix the drug and excipient powders, thereby improving uniformity, while the use of roller compaction for dry granulation minimizes the degradation of the drug caused by moisture content in the formulation, thereby improving stability. In addition, the formulation and process of Example 2 also improve product quality, save energy, cost and time.

[0123] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the inventive concept, several modifications and improvements can be made, which are all within the scope of the present application.

Claims

1. A dry granulation method for methotrexate tablets, characterized in that, Includes the following steps: 1) Powder mixing: Pass the formula amount of anhydrous lactose, microcrystalline cellulose, pregelatinized starch and sodium carbonate through a 30-mesh sieve to form a uniform excipient powder, and stir in a mixer at 10±5 rpm for 10±5 minutes. 2) Geometric dilution: Add the prescribed amount of methotrexate to the excipient powder at a ratio of 1:1, stir in a mixer at 10±5 rpm for 5 minutes, then mix the drug powder and excipient powder at a ratio of 1:1 and stir at 10±5 rpm for 5 minutes. Repeat the above process until the excipient is used up. 3) Roller pressing: The material is passed through the roller press pelletizer at a roller pressing speed of 5-20 rpm and a roller pressing gap of 1-3 mm, and then passed through a 30-mesh sieve to form uniform powder particles. 4) Pre-lubrication: Pass talc powder through a 60-mesh sieve and mix it evenly with the powder obtained in step 3). Stir in a mixer at 10±5 rpm for 5 minutes. 5) Lubrication: Magnesium stearate group is passed through a 60-mesh sieve and mixed evenly with the powder obtained in step 4). Stir at 5±2 rpm for 5 minutes in a stirrer. 6) Tableting: The mixed granules obtained in step 5) are compressed into tablets; 7) Coating: The coating agent is reconstructed in pure water with 15% by weight of solids and homogenized until uniform dispersion is achieved. The tablets are then coated using a coating machine until the tablet weight gain reaches 2.5-3.5%. Each of the aforementioned methotrexate tablets contains 2-15% methotrexate.

2. The dry granulation method for methotrexate tablets as described in claim 1, characterized in that, Each of the aforementioned methotrexate tablets contains 2-3% methotrexate.

3. The dry granulation method for methotrexate tablets as described in claim 1 or 2, characterized in that, The tablets obtained in step 6) weigh 100±5 mg and have a diameter of 6-7 mm.

4. A dry granulation method for methotrexate tablets as described in claim 1 or 2, characterized in that, The coating agent in step 7) is Opadry II Yellow 30B120016.

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