A roll granulation production method of finasteride tablets

Abstract

The application is a rolling granulation production method of finasteride tablets, comprising rolling and compacting the mixture of compressible components, i.e. finasteride and mixed excipients, and sieving before lubricating and tabletting. The application has the advantages that the formula and preparation method are reasonable in design, and the prepared finasteride tablets have good friability, mixing uniformity, content variation, disintegration and dissolution efficiency compared with direct tabletting, wet granulation and commercially available tablets.

Description

TECHNICAL FIELD

[0001] The application relates to a granulation method of finasteride tablets, in particular to a roller granulation production method of finasteride tablets. BACKGROUND

[0002] Finasteride, chemical formula C 23 H 36 N2O2, is a 4-azasteroid compound. It is a specific inhibitor of intracellular enzyme type II 5a-reductase in the process of testosterone metabolism into dihydrotestosterone, which can very effectively reduce dihydrotestosterone in blood and prostate, that is, by inhibiting the conversion of testosterone into dihydrotestosterone (DHT), the prostate volume is reduced to improve symptoms, increase urine flow rate, and prevent benign prostatic hyperplasia (BPH).

[0003] Finasteride tablets are also applied to the field of hair loss. The hair follicles contain type II 5a-reductase, and the number of hair follicles in the scalp of the bald area of male baldness patients is reduced, and dihydrotestosterone is increased. Giving finasteride can reduce the concentration of dihydrotestosterone in the scalp and serum of these patients. Men who are congenitally deficient in type II 5a-reductase do not suffer from male baldness. These data and the results of clinical studies confirm that finasteride can inhibit the reduction of scalp hair follicles and reverse the hair loss process.

[0004] In the prior art, such as CN115671062A, CN115607517A, CN111840241A, CN110623935A, CN110638777A, and CN109893512A, finasteride tablets are produced by wet granulation, and the wet granulation method needs an additional drying step, which is time-consuming and labor-intensive. Specifically, the solvent, such as water, organic solvent or inorganic solvent, is used in the granulation process of the powder mixture in the wet granulation. Commonly used solvents include ethanol, isopropyl alcohol, pure water or surfactant aqueous solution. All these solvents can be incompatible with drugs or other excipients, and even after drying, traces of solvents can still remain in the dried granules, so that the finished product has problems such as high degradation rate and poor stability.

[0005] To avoid the above situation, direct compression or dry granulation is considered. Dry granulation and direct compression do not involve any solvent, which helps to improve the stability of the finished product. In addition, the use of direct compression and dry granulation process can save water resources. It can also minimize the process detection of the moisture or solvent content required after the drying of the wet granulation. Compared with wet granulation, there are many advantages, and the stability of the product can be improved to provide better and safer treatment for patients.

[0006] CN111956615A adopts direct compression method, however, the tablets prepared by it have non-uniformity and high friability, and the tablets are easy to break during coating, packaging and filling process. On the other hand, there are also problems such as low drug efficacy of the raw material, non-uniformity of the content in the tablets, etc.

[0007] The problems of direct compression are poor material flowability, leading to poor tablet weight / content uniformity, poor friability, unstable tablet tensile strength, disintegration time and dissolution performance, because mouse holes and arches are formed during the tabletting process. SUMMARY

[0008] The present application provides a roller compaction granulation production method of finasteride tablets, which aims to overcome the above-mentioned deficiencies in the prior art and improve the stability of the tablets and the uniformity of finasteride in the tablets.

[0009] The technical solution of the present application is a roller compaction granulation production method of finasteride tablets, which comprises roller compaction and sieving of the mixture of compressible components, i.e. finasteride and mixed excipients, before lubrication and tabletting. Compared with wet granulation and direct compression, this method has good friability, mixing uniformity, content variation, disintegration and dissolution efficiency.

[0010] Preferably, the mixed excipients are directly compressible grade, including lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, sodium dodecyl sulfate and polyvinylpyrrolidone. Specifically, the lactose monohydrate is 100, the microcrystalline cellulose is 112, the pre-gelatinized starch is Starch The sodium starch glycolate is The polyvinylpyrrolidone is Plasdone TM C-30, and the sodium dodecyl sulfate is Ultra-Pure.

[0011] Preferably, the lubricant used in the lubrication step is magnesium stearate.

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

[0013] 1) Excipient mixing: screen the lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, polyvinylpyrrolidone and sodium dodecyl sulfate with a 30 mesh screen, then mix them with a blender at a speed of 5-20 RPM for 10 minutes, and divide the mixed excipients into 4 equal parts;

[0014] 2) Mixing of API: Finely sieve Finasteride using 30 mesh sieve, then add 1 part of mixing excipients, mix the mixture for 5 minutes at 5-20 RPM, again add 1 part of mixing excipients, mix the mixture for 5 minutes at 5-20 RPM, repeat the above process until all mixing excipients are used, then mix the mixture for 10 minutes at 5-20 RPM using a blender;

[0015] 3) Roller compaction: compact the mixture using a roller compactor at a hydraulic pressure of 30-50 bar, screw speed of 30-50 RPM and roller speed of 5-10 RPM, sieve the compacted mass through 30 mesh sieve;

[0016] 4) Lubrication: sieve magnesium stearate through 60 mesh sieve, then add to the blender containing Finasteride and other mixing excipients, mix for 5 minutes at 5-20 RPM;

[0017] 5) Compression: compress the tablets using a tablet compression machine and die;

[0018] 6) Coating: add 8% w / w of coating solution in purified amb II, mix well, use a coating apparatus to spray the coating solution on the tablets and dry to form a film until a weight gain of 1.6 ± 0.1% is achieved.

[0019] Advantages of the present application: The formulation and the method of preparation are rationally designed. The Finasteride tablets prepared have good friability, blend uniformity, content variation, disintegration and dissolution efficiency as compared to direct compression, wet granulation and commercially available tablets. DETAILED DESCRIPTION

[0020] The present application is further described in detail by the following examples and specific embodiments.

[0021] A roller compaction granulation method for preparing Finasteride tablets, comprising compacting and sieving the mixture of compressible ingredients, i.e. Finasteride and mixing excipients, before lubrication and tablet compression. This method of granulation has good friability, blend uniformity, content variation, disintegration and dissolution efficiency as compared to wet granulation and direct compression.

[0022] The mixing excipients are directly compressible grades, including lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, sodium lauryl sulfate and polyvinyl pyrrolidone. The lubricant used in the lubrication step is magnesium stearate.

[0023] Example 1: Direct compression and coating

[0024] Formulation:

[0025]

[0026]

[0027] Preparation method:

[0028] 1) Weighing: All ingredients were loaded into a polyethylene bag.

[0029] 2) Blend the excipients: Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, polyvinyl pyrrolidone and sodium lauryl sulfate were sieved through a No. 30 mesh screen and then mixed in a blender for 10 minutes at a speed of 5-20 RPM. The blended excipients were divided into 4 equal portions.

[0030] 3) Blend the drug substance: Finely sieved finasteride through a No. 30 mesh screen and then added to 1 portion of the blended excipients and the mixture was blended for 5 minutes at a speed of 5-20 RPM. Another portion of the blended excipients was added and the mixture was blended for 5 minutes at a speed of 5-20 RPM. The above process was repeated until all the blended excipients were used and then the mixture was blended for 10 minutes at a speed of 5-20 RPM in a blender.

[0031] 4) Lubrication: Magnesium stearate was sieved through a No. 60 mesh screen and then added to the blender containing the finasteride and other blended excipients and blended for 5 minutes at a speed of 5-20 RPM.

[0032] 5) Compression: The tablets were compressed using a tablet press and appropriate size die.

[0033] 6) Coating: The tablets were coated in a purified amb II with 8% w / w of the coating solution and mixed well. The coating solution was sprayed on the tablets using the existing coating equipment and dried to form a film until a weight gain of 1.6 ± 0.1% was achieved.

[0034] Example 2: Roller compaction and coating

[0035] The formulation was the same as in Example 1.

[0036] The difference from Example 1 was that the preparation method included a roller compaction step between steps 3) and 4): The mixture was compacted using a hydraulic roller compaction pressure of 30-50 bar, a screw speed of 30-50 RPM and a roller speed of 5-10 RPM. The compacted mass was sieved through a No. 30 mesh screen.

[0037] Example 3: Wet granulation and coating

[0038] The difference from Example 1 was that sodium lauryl sulfate was replaced by sodium docusate.

[0039] Preparation method:

[0040] 1) Weighing: All ingredients were loaded into a polyethylene bag.

[0041] 2) Mixing of excipients: Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and polyvinyl pyrrolidone are sieved through 30 mesh sieve and then stirred in a blender at 5-20 RPM for 10 minutes.

[0042] 3) Mixing of API: Finely sieved Finasteride through 30 mesh sieve and then added equal quantity of mixed excipients. The mixture is stirred at 5-20 RPM for 5 minutes. Remaining mixed excipients are added and stirred at 5-20 RPM for 5 minutes.

[0043] 4) Wet granulation: Sodium docusate is dissolved in water under stirring. This solution is added to the mixture in a rapid mixer granulator and granules are prepared using suitable process parameters.

[0044] 5) Drying: The wet granules are dried in a drier at 60°C until the moisture content is uniform and cannot be reduced further.

[0045] 6) Sifting: The hard dried granules are sieved through 30 mesh sieve to make them uniform in size.

[0046] 7) Lubrication: Magnesium stearate is sieved through 60 mesh sieve and then added to the blender containing Finasteride and other mixed excipients and stirred at 5-20 RPM for 5 minutes.

[0047] 8) Compression: The tablets are compressed using a tablet compression machine and suitable size die.

[0048] 9) Coating: The tablets are coated in a purified amb II with 8% w / w coating solution and stirred well. The coating solution is sprayed on the tablets using the existing art coating equipment and dried to form a film until the weight gain of 1.6 ± 0.1% is achieved.

[0049] Example 4: Evaluation of content uniformity, friability, disintegration and weight variation

[0050] The formulated Finasteride tablets are evaluated for tablet content uniformity, friability, disintegration and weight variation and the results are tabulated below.

[0051]

[0052] From the above results, the direct compression method of Example 1 shows faster disintegration, higher friability and greater variation in weight and tablet content. The roller compaction method of Example 2 is more successful in achieving the target parameters of the marketed tablet. The tablets prepared by the roller compaction method of Example 2 show shorter disintegration time, less friability, less variation in weight and better results as compared to the direct compression method of Example 1 and the wet granulation method of Example 3.

[0053] Example 5: Dissolution study

[0054] Dissolution studies were performed using 0.1 N hydrochloric acid solution using USP Apparatus-I I (paddle), 50 RPM, 500 ml medium, temperature maintained at 37.0 ± 0.5 °C. Tablets were placed in the respective dissolution vessels and samples were collected at different time points of 5, 10, 15, 20, 30, 45 and 60 minutes. The aliquot withdrawn was diluted and injected into the HPLC for analysis and the results are tabulated below.

[0055]

[0056]

[0057] Based on the above results, the dissolution profiles of Example 1 direct compression, Example 2 roller compaction and Example 3 wet granulation were significantly different from the marketed tablet. The dissolution profiles of Example 2 roller compaction and Example 3 wet granulation were similar to the marketed tablet. The significant feature of Example 2 roller compaction was complete release with a difference of less than 2.2% between the 6 results, which is negligible compared to the maximum 9.8% results of other examples. This indicates that the addition of the blend of excipients in 4 portions in the preparation method of Example 2 allows for uniformity of the product, while the roller compaction method helps in complete release of the drug from the formulation.

[0058] Example 6: Multiple media dissolution test

[0059] The multiple media dissolution test was performed using acetate buffer of pH 4.5, phosphate buffer of pH 6.8, fasted state simulated intestinal fluid and fed state simulated intestinal fluid using USP Apparatus-I I (paddle), 50 RPM, 900 ml medium, temperature maintained at 37.0 °C. Tablets were placed in the respective dissolution vessels and samples were collected at different time points of 5, 10, 15, 20, 30, 45 and 60 minutes. The aliquot withdrawn was diluted and injected into the HPLC for analysis and the results are tabulated below.

[0060]

[0061]

[0062] Based on the above results, the dry tablet prepared using the method of Example 2 was superior to the marketed tablet in terms of dissolution in all the test media and complete release with less variation in RSD% compared to the marketed tablet, which indicates that the roller compaction method reduces variation in drug release. The use of the formulation and production method of Example 2 helps in reducing production costs, saving energy and water, and helps in achieving carbon footprint.

[0063] Example 7: Stability study

[0064] A stability study was performed on the product manufactured by the wet granulation method of Example 3 and the roller compaction dry granulation method of Example 2, and the results are listed below.

[0065]

[0066]

[0067] Based on the above results, from the assay results and impurity levels, the tablets prepared by the roller compaction method of Example 2 were more stable than the tablets prepared by the wet granulation method of Example 3.

[0068] The preferred embodiments described above are only a part of the present application, and it should be pointed out that for ordinary skilled in the art, without departing from the inventive concept, a number of variations and improvements can be made, which are within the scope of the present application.

Claims

1. A method for producing finasteride tablets by roller compression granulation, characterized in that, The process involves compacting and sieving a mixture of the compressible component, finasteride, and mixed excipients using a roller press before lubrication and tableting; the mixed excipients are of a directly compressible grade and include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate, and polyvinylpyrrolidone. Specifically, the following steps are included: 1) Mixing of excipients: Sift lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, polyvinylpyrrolidone and sodium dodecyl sulfate through a No. 30 sieve, and then mix them with a mixer at a speed of 5-20 RPM for 10 minutes. Divide the mixed excipients into 4 equal parts. 2) Mixing raw materials: Sieve finasteride through a No. 30 sieve, then add 1 part of mixed excipients. Stir the mixture at 5-20 RPM for 5 minutes. Add another 1 part of mixed excipients and stir the mixture at 5-20 RPM for 5 minutes. Repeat the above process until all the mixed excipients are used up. Then stir the mixture with a mixer at 5-20 RPM for 10 minutes. 3) Roller pressing: Using a hydraulic roller pressure of 30-50 bar, a screw speed of 30-50 RPM and a roller speed of 5-10 RPM, the mixture is compacted through a roller press, and the compacted material is passed through a No. 30 sieve. 4) Lubrication: Pass magnesium stearate through a No. 60 sieve, then add it to a mixer containing finasteride and other mixed excipients, and stir at a speed of 5-20 RPM for 5 minutes. 5) Tableting: Using a tablet press and molds to compress tablets; 6) Coating: Add 8% w / w coating solution to purified Opadry® amb II, stir well, spray the coating solution onto the tablets using a coating device and dry it into a film until a weight gain of 1.6 ± 0.1% is achieved.

2. The method for producing finasteride tablets by roller compression granulation as described in claim 1, characterized in that, The lactose monohydrate is FlowLac® 100, the microcrystalline cellulose is Pharmacel® 112, the pregelatinized starch is Starch 1500®, the sodium starch glycolate is EXPLOTAB®, the polyvinylpyrrolidone is Plasdone™ C-30, and the sodium dodecyl sulfate is Ultra-Pure.

3. The method for producing finasteride tablets by roller compression granulation as described in claim 1 or 2, characterized in that, The magnesium stearate mentioned is LIGAMED MF-3-V-MB.

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