Rolling granulation production method of finasteride tablets

Abstract

The invention relates to a rolling granulation production method of finasteride tablets, which comprises the following steps of: rolling and compacting a compressible component, namely a mixture of finasteride and a mixed auxiliary material by using a roller press before lubricating and tabletting, and sieving. The finasteride tablet has the advantages that the formula and the preparation method are reasonable in design, and compared with direct tabletting, wet granulation and commercially available tablets, the prepared finasteride tablet has good frangibility, mixing uniformity, content change, disintegration and dissolution efficiency.

Description

Technical Field

[0001] The present invention relates to a granulation method of finasteride tablets, and in particular to a roller granulation production method of finasteride tablets. Background Art

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

[0003] Finasteride tablets are also used in the field of hair loss. Hair follicles contain type II 5α-reductase. In patients with male pattern baldness, the number of hair follicles in the bald area of ​​the scalp decreases, and dihydrotestosterone increases. Finasteride administration can reduce the concentration of dihydrotestosterone in the scalp and serum of these patients. Men who are congenitally deficient in type II 5α-reductase will not suffer from male pattern baldness. These data and the results of clinical studies have confirmed that finasteride can inhibit the shrinkage of scalp hair follicles and reverse the hair loss process.

[0004] In the prior art, such as CN115671062A, CN115607517A, CN111840241A, CN110623935A, CN110638777A, and CN109893512A, wet granulation is used to produce finasteride tablets, and the wet granulation method requires an additional drying step, which is time-consuming and labor-intensive. Specifically, wet granulation uses solvents such as water, organic solvents, or inorganic solvents in the granulation process of the powder mixture. Commonly used solvents include ethanol, isopropanol, purified water, or aqueous surfactant solutions. All of these solvents may be incompatible with drugs or other excipients. Even after drying, traces of the solvent will remain in the dried particles. Therefore, the finished drug has problems such as high degradation rate and poor stability.

[0005] To avoid the above, consider direct compression or dry granulation. Dry granulation and direct compression do not involve any solvents, which helps improve the stability of the finished product. In addition, using direct compression and dry granulation processes can save water resources. It also minimizes the in-process testing of moisture or solvent content required after wet granulation is dried. Compared with wet granulation, there are many advantages, and it can also improve the stability of the product, providing better and safer treatment for patients.

[0006] CN111956615A adopts direct compression method, but the tablets prepared therefrom are non-uniform and highly fragile, and the tablets are easily damaged during coating, packaging and filling processes. On the other hand, there are also problems such as low efficacy of the raw material drug and non-uniform content in the tablets.

[0007] The problem with direct compression is poor material flowability, resulting in poor tablet weight / content uniformity, poor friability, and unstable tablet tensile strength, disintegration time and dissolution properties due to the formation of rat holes and arches during the tableting process. Summary of the invention

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

[0009] The technical solution of the present invention is a roller granulation production method for finasteride tablets, which includes rolling and compacting the compressible component, i.e., the mixture of finasteride and mixed excipients, and sieving it before lubricating and tableting. Granulation using this method has good friability, mixing uniformity, content variation, disintegration and dissolution efficiency compared with wet granulation and direct tableting.

[0010] Preferably, the mixed excipients are of direct compressible grade, including lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate and polyvinyl pyrrolidone. Specifically preferably, the lactose monohydrate is 100, microcrystalline cellulose 112, pregelatinized starch is Starch Sodium starch glycolate Polyvinylpyrrolidone is Plasdone TM C-30, Sodium Lauryl Sulfate is Ultra-Pure.

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

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

[0013] 1) Mixing auxiliary materials: Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, polyvinyl pyrrolidone and sodium lauryl sulfate are sieved with a No. 30 sieve, and then mixed with a blender at a speed of 5-20 RPM for 10 minutes, and the mixed auxiliary materials are divided into 4 equal parts;

[0014] 2) Mixed API: sieve finasteride with a No. 30 sieve, then add 1 part of mixed excipients, stir the mixture at a speed of 5-20RPM for 5 minutes, add 1 part of mixed excipients again, stir the mixture at a speed of 5-20RPM for 5 minutes, repeat the above process until all the mixed excipients are used up, and then stir the mixture at a speed of 5-20RPM for 10 minutes with a blender;

[0015] 3) Roller compaction: 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 was compacted by a roller compactor, and the compacted material passed through a No. 30 screen;

[0016] 4) Lubrication: Pass magnesium stearate through a No. 60 sieve, then add it into a blender containing finasteride and other mixed excipients, and stir at a speed of 5-20 RPM for 5 minutes;

[0017] 5) Tablet pressing: using a tablet press and a mold to compress tablets;

[0018] 6) Coating: After purification 8% w / w of the coating solution was added to amb II and stirred evenly. The coating solution was sprayed on the tablets using a coating device and dried to form a film until a weight gain of 1.6±0.1% was achieved.

[0019] The advantages of the present invention are as follows: the formula and the preparation method are reasonably designed; the prepared finasteride tablets have good friability, mixing uniformity, content variation, disintegration and dissolution efficiency compared with direct tableting, wet granulation and commercially available tablets. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0021] A roller granulation production method for finasteride tablets includes rolling and compacting a compressible component, i.e., a mixture of finasteride and mixed excipients, and sieving the mixture before lubrication and tableting. Granulation using this method has good friability, mixing uniformity, content variation, disintegration and dissolution efficiency compared to wet granulation and direct tableting.

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

[0023] Example 1: Direct tableting and coating

[0024] formula:

[0025]

[0026]

[0027] Preparation method:

[0028] 1) Weighing: Place all ingredients into a polyethylene bag.

[0029] 2) Mixing of auxiliary materials: Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, polyvinyl pyrrolidone and sodium lauryl sulfate were sieved with a No. 30 sieve, and then mixed with a blender at a speed of 5-20 RPM for 10 minutes. The mixed auxiliary materials were divided into 4 equal parts.

[0030] 3) Mixed API: sieve finasteride with a No. 30 sieve, then add 1 part of mixed excipients, and stir the mixture at a speed of 5-20RPM for 5 minutes. Add 1 part of mixed excipients again, and stir the mixture at a speed of 5-20RPM for 5 minutes. Repeat the above process until all the mixed excipients are used up, and then stir the mixture at a speed of 5-20RPM for 10 minutes with a blender.

[0031] 4) Lubrication: Pass magnesium stearate through a No. 60 sieve, then add it into a blender containing finasteride and other mixed excipients, and blend at a speed of 5-20 RPM for 5 minutes.

[0032] 5) Tablet compression: Tablets are compressed using a tablet press and a mold of appropriate size.

[0033] 6) Coating: After purification 8% w / w coating solution was added to amb II and stirred evenly. The coating solution was sprayed on the tablets using a prior art coating device and dried to form a film until a weight gain of 1.6±0.1% was achieved.

[0034] Example 2: Roller compression and coating

[0035] The recipe is the same as in Example 1.

[0036] The difference from Example 1 is that a roller pressing step is further included between steps 3) and 4) in the preparation method: the mixture is compacted by a roller press 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 compacted material is passed through a No. 30 sieve.

[0037] Example 3: Wet granulation and coating

[0038] The formula is different from that of Example 1 in that sodium lauryl sulfate is replaced with docusate sodium.

[0039] Preparation method:

[0040] 1) Weighing: Place all ingredients into a polyethylene bag.

[0041] 2) Mixing auxiliary materials: sieve lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and polyvinyl pyrrolidone through a No. 30 sieve, and then stir with a mixer at a speed of 5-20 RPM for 10 minutes.

[0042] 3) Mixed API: Sieve finasteride with a No. 30 sieve, then add an equal amount of mixed excipients. Stir the mixture at a speed of 5-20 RPM for 5 minutes. Add the remaining mixed excipients and stir at a speed of 5-20 RPM for 5 minutes.

[0043] 4) Wet granulation: dissolve docusate sodium in water under stirring. Add the solution to the mixture in a rapid mixing granulator and prepare granules using appropriate process parameters.

[0044] 5) Drying: Dry the wet granules using a dryer at 60°C until the moisture content is uniform and cannot be further reduced.

[0045] 6) Screening: Pass the hard, dry large particles through a No. 30 sieve to make them uniform in size.

[0046] 7) Lubrication: Sieve magnesium stearate through a No. 60 sieve, then add it into a blender containing finasteride and other mixed excipients, and blend at a speed of 5-20 RPM for 5 minutes.

[0047] 8) Tablet compression: Tablets are compressed using a tablet press and a mold of appropriate size.

[0048] 9) Coating: After purification 8% w / w coating solution was added to amb II and stirred evenly. The coating solution was sprayed on the tablets using a prior art coating device and dried to form a film until a weight gain of 1.6±0.1% was achieved.

[0049] Example 4: Content Uniformity, Friability, Disintegration and Weight Change Evaluation

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

[0051]

[0052] According to the above results, the direct compression method of Example 1 showed fast disintegration speed, high friability, and large variation in weight and tablet content. The dry granulation method of roller compaction in Example 2 was more effective in achieving the target parameters of commercial tablets. Compared with the direct compression method of Example 1 and the wet granulation method of Example 3, the tablets prepared by the roller compaction method of Example 2 had a shorter disintegration time, less friability, less weight variation, and better effect.

[0053] Example 5: Dissolution studies

[0054] Dissolution studies were performed using 0.1N hydrochloric acid solution using USP Apparatus-II (paddle type) at 50 RPM, 500 ml of medium, and 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 aliquots were diluted and injected into HPLC for analysis, and the results are tabulated below.

[0055]

[0056]

[0057] According to the above results, the dissolution curves of direct compression in Example 1, roller compaction granulation in Example 2, and wet granulation in Example 3 are very different from the dissolution curves of commercially available tablets. The dissolution curves of roller compaction granulation in Example 2 and wet granulation in Example 3 are similar to those of commercially available tablets. The notable feature of roller compaction granulation in Example 2 is complete release, and the difference between the 6 results is less than 2.2%, which is negligible compared to the maximum 9.8% results of other examples. This shows that adding the mixed excipients in 4 portions in the preparation method of Example 2 can make the product uniform, and the roller compaction method helps to completely release the drug from the preparation.

[0058] Example 6: Multi-media dissolution test

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

[0060]

[0061]

[0062] According to the above results, compared with commercially available tablets, the dry-process tablets prepared by the method of Example 2 have better dissolution in all identification test media than commercially available tablets, and are completely released with less change in RSD%, which indicates that roller compaction can reduce the change in drug release. The use of the formulation and production method of Example 2 helps to reduce production costs, save energy and water, and help achieve carbon footprint.

[0063] Example 7: Stability Study

[0064] The stability study was conducted on the products manufactured by wet granulation in Example 3 and dry granulation by roller compaction in Example 2, and the results are tabulated below.

[0065]

[0066]

[0067] According to the above results, from the perspective of test results and impurity content, the tablets prepared by roller compaction in Example 2 are more stable than the tablets prepared by wet granulation in Example 3.

[0068] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A roller compaction granulation production method for finasteride tablets, characterized in that: The method comprises the following steps: firstly subjecting the compressible component, i.e., the mixture of finasteride and the mixed auxiliary materials, to roller compaction and sieving before lubrication tableting.

2. The roller compaction granulation production method of finasteride tablets according to claim 1, characterized in that: The mixed auxiliary materials are of directly compressible grade and include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate and polyvinyl pyrrolidone.

3. The roller compaction granulation production method of finasteride tablets according to claim 2, characterized in that: The lactose monohydrate is 100, microcrystalline cellulose 112, pregelatinized starch is Starch Sodium starch glycolate Polyvinylpyrrolidone is Plasdone TM C-30, Sodium Lauryl Sulfate is Ultra-Pure.

4. The roller granulation production method of finasteride tablets according to claim 2 or 3, characterized in that: The lubricant used in the lubrication step is magnesium stearate.

5. The roller compaction granulation production method of finasteride tablets according to claim 4, characterized in that: The magnesium stearate is LIGAMED MF-3-V-MB.

6. The roller compaction granulation production method of finasteride tablets according to claim 5, characterized in that: The specific steps include: 1) Mixing auxiliary materials: Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, polyvinyl pyrrolidone and sodium lauryl sulfate are sieved with a No. 30 sieve, and then mixed with a blender at a speed of 5-20 RPM for 10 minutes, and the mixed auxiliary materials are divided into 4 equal parts; 2) Mixed API: sieve finasteride with a No. 30 sieve, then add 1 part of mixed excipients, stir the mixture at a speed of 5-20RPM for 5 minutes, add 1 part of mixed excipients again, stir the mixture at a speed of 5-20RPM for 5 minutes, repeat the above process until all the mixed excipients are used up, and then stir the mixture at a speed of 5-20RPM for 10 minutes with a blender; 3) Roller compaction: 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 was compacted by a roller compactor, and the compacted material passed through a No. 30 screen; 4) Lubrication: Pass magnesium stearate through a No. 60 sieve, then add it into a blender containing finasteride and other mixed excipients, and stir at a speed of 5-20 RPM for 5 minutes; 5) Tablet pressing: using a tablet press and a mold to compress tablets; 6) Coating: After purification 8% w / w of the coating solution was added to amb II, stirred evenly, and the coating solution was sprayed on the tablets using a coating device and dried to form a film until a weight gain of 1.6±0.1% was achieved.

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