Pretreatment method of raw material medicine and composition of raw material medicine

Abstract

The invention relates to the field of medicine, in particular to a nimesulide raw material medicine pretreatment method and a nimesulide raw material medicine composition. According to the nimesulide raw material medicine with the special particle size distribution, the dissolution rate of the nimesulide product can be increased by preparing the nimesulide product from the raw material medicine with the special particle size distribution, and dissolution is uniform. The invention also provides a pretreatment method of the nimesulide raw material, the indissolvable drug nimesulide is crushed by adopting an airflow crushing mode, and the micronized indissolvable drug nimesulide with a certain granularity is prepared by utilizing particle collision of the material. Loss is reduced by controlling airflow crushing parameters, the optimal feeding amount and the discharging mode; the raw material medicines subjected to airflow crushing are properly treated, so that the deterioration of excellent characteristics of the powder caused by re-agglomeration of the materials subjected to airflow crushing is reduced; monitoring the particle size of the raw material medicine obtained under jet milling parameters, preparing the nimesulide composition, and screening the optimal particle size range through a dissolution curve.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a nimesulide raw material medicine with a special particle size distribution, a pretreatment method thereof and a composition thereof. Background Art

[0002] Nimesulide is a patented product of Helsinn, Switzerland. It was first launched in Italy in 1985 and is currently used in more than 50 countries. It is a nonsteroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase II, so it has significant anti-inflammatory, analgesic and antipyretic effects. A large amount of clinical literature at home and abroad shows that compared with ibuprofen and acetaminophen, nimesulide has a faster onset of antipyretic and analgesic effects and similar adverse reactions. Nimesulide is an extremely hydrophobic drug with a water solubility of about 0.01 mg / mL at room temperature. Overcoming the poor water solubility of nimesulide will bring significant significance to the application of nimesulide preparations.

[0003] U.S. Patent No. 6,017,932 describes a pharmaceutical composition with increased therapeutic efficacy, which contains at least one NSAID selected from nimesulide, nabumetone, tepoxalin and flusulamide as an active ingredient and a bioavailability enhancer such as piperine. The above method accelerates and increases the dissolution of poorly soluble drugs and improves their bioavailability, but it is still not ideal, and piperine is not a commonly used pharmaceutical excipient, and there are great difficulties in supply. Patent CN201010526114.1 increases the solubility of nimesulide by adding a large proportion of 5-30% dispersant (low molecular weight polyethylene glycol) in the prescription, but the low molecular weight polyethylene glycol used in this technology is highly toxic and will reduce the safety of the preparation, and nimesulide belongs to the sulfonamide class of drugs and is incompatible with polyethylene glycol. Patent CN201210142624.8 aims at the low solubility of nimesulide, uses copolyvidone or povidone as the main dispersing carrier material, and adopts hot melt extrusion technology to prepare a rapid-release nimesulide solid dispersion, which greatly improves the in vitro solubility of the drug in a pH 7.4 aqueous medium. However, this technology requires the drug and the carrier material to be mixed in a molten state, involving a high operating temperature, and the resulting particles are relatively large and the structure of the drug may be destroyed. At the same time, the number and types of carrier materials that can meet the conditions of hot melt extrusion are also relatively limited, which is not conducive to diversification and screening of the best preparations.

[0004] Therefore, there is an urgent need to develop a pretreatment method and composition of nimesulide raw materials that can effectively improve the solubility of nimesulide, achieve uniform dissolution, and not affect product safety, stability and efficacy, and have a simple and easy production process. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art to at least a certain extent. On the one hand, the present invention provides a nimesulide API with a special particle size distribution. The nimesulide product is prepared by using the API with a special particle size distribution, which can improve the dissolution of the nimesulide preparation and make it dissolve evenly without affecting the safety and efficacy of the preparation product.

[0006] On the other hand, the present invention provides a pretreatment method for nimesulide raw material medicine, wherein the insoluble drug nimesulide is crushed by airflow crushing, and the material particles themselves are collided to prepare micronized insoluble drug nimesulide with a certain particle size distribution. By controlling the airflow crushing parameters, the optimal feed amount, and the discharging method, the loss is reduced; the raw material medicine after airflow crushing is properly treated to reduce the degradation of the excellent properties of the powder caused by the re-agglomeration of the material after airflow crushing; the particle size of the raw material medicine obtained under the airflow crushing parameters is monitored, and a nimesulide composition is prepared, and the optimal particle size range is screened by the dissolution curve. After being treated by the raw material pretreatment method of the present invention, the solubility of the nimesulide tablet is improved, and the dissolution is uniform, while the safety and efficacy of the preparation product are not affected.

[0007] To this end, the first aspect of the present invention provides a nimesulide bulk drug, characterized in that the particle size D of the nimesulide bulk drug is 90 Not more than 20μm and not less than 9μm, particle size D 50 Not more than 9μm and not less than 0μm.

[0008] Nimesulide belongs to BCS class II, which has low solubility and high permeability, resulting in low dissolution rate of the preparation product, and thus low bioavailability. When the inventor conducted research to improve its solubility, he found that the particle size distribution of nimesulide would significantly affect its solubility, especially the particle size D 50 Value and D 90 Furthermore, the inventors obtained the above-mentioned preferred D after in-depth research. 90 and D 50 Within this particle size distribution range, the dissolution of nimesulide is ideal, the dissolution rate is optimal, and the dissolution is uniform. 50 Value and D 90 If the particle size is too large (i.e., D 50 Value and D 90 The values ​​are all large), resulting in unsatisfactory product dissolution.

[0009] According to a preferred embodiment of the present invention, the particle size D of the nimesulide raw material is 90Not more than 15μm and not less than 10μm, particle size D 50 No more than 7 μm and no less than 5 μm. Thus, the dissolution of nimesulide is further improved to be ideal, the dissolution rate is optimized, and the dissolution is uniform.

[0010] According to an embodiment of the present invention, the particle size distribution (D 90 -D 10 ) / D 50 The ratio of is 1 to 3, preferably 1.5 to 2.0, and more preferably 1.54 to 1.81. The inventors have found that (D 90 -D 10 ) / D 50 The ratio will affect the dissolution rate and dissolution uniformity of nimesulide. Furthermore, the inventors have obtained the above-mentioned preferred ratio range through a large number of experiments, thereby further making the dissolution of nimesulide ideal, the dissolution rate optimal, and the dissolution uniform.

[0011] It should be noted that the term "D 90 "D" refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%. Its physical meaning is that the particles with a particle size smaller (or larger) than this value account for 90%. 50 " refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%. Its physical meaning is that particles with a particle size greater than this value account for 50%, and particles with a particle size less than this value also account for 50%. 50 Also called median diameter or median particle size. 50 Often used to indicate the average particle size of powder. 10 " refers to the particle size corresponding to a sample when the cumulative particle size distribution percentage reaches 10%. Its physical meaning is that particles with a size smaller (or larger) than this value account for 10%.

[0012] The second aspect of the present invention provides a pretreatment method for nimesulide API. According to an embodiment of the present invention, the method comprises: performing airflow pulverization on the nimesulide raw material to obtain the nimesulide API; wherein the airflow pulverization is performed under the following conditions: the airflow pulverization pressure is 0.2-0.8KN, and the air source pressure is 0.3-0.8KN.

[0013] According to the pretreatment method of the nimesulide API of the embodiment of the present invention, the nimesulide API itself particles are collided by airflow pulverization to achieve the purpose of pulverization, so as to obtain a nimesulide API that meets certain particle size distribution requirements. Further, the inventors found that by controlling the airflow pulverization pressure to 0.2-0.8KN and the air source pressure to 0.3-0.8KN, the particle size distribution of the nimesulide API can be better (for example, the nimesulide API with a special particle size distribution described in the first aspect of the present invention is obtained), and has better dissolution and dissolution rate.

[0014] The pretreatment method of the nimesulide bulk drug according to the embodiment of the present invention may also have at least one of the following additional technical features:

[0015] According to an embodiment of the present invention, the air flow crushing pressure is 0.3-0.5 KN, and the air source pressure is 0.3-0.6 KN. Thus, a nimesulide bulk drug with a better particle size distribution can be obtained, and the nimesulide bulk drug has better solubility and dissolution rate.

[0016] According to an embodiment of the present invention, the feeding speed of the airflow pulverization process is 20-50 g / min, and the feeding pressure is 0.2-0.8 KN, preferably 0.3-0.4 KN. Thus, a nimesulide bulk drug with a better particle size distribution can be obtained, and the nimesulide bulk drug has better solubility and dissolution rate.

[0017] According to an embodiment of the present invention, in the airflow pulverization process, the amount of sample pulverized in a single airflow pulverization is 10% to 30% of the volume of the equipment, preferably 10% to 20%. If the sample amount is too small, it will lead to a large loss of material and a low yield; if the material is too much, it will easily lead to insufficient airflow pulverization and poor pulverization effect.

[0018] According to an embodiment of the present invention, the method further comprises: sieving the nimesulide API after airflow pulverization using a 60-200 mesh sieve. By adopting the above sieving conditions, the phenomenon of reagglomeration of materials caused by airflow pulverization can be improved, and the electrostatic adsorption effect can be reduced.

[0019] The third aspect of the present invention provides the use of the nimesulide bulk drug described in the first aspect of the present invention in the preparation of a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition uses nimesulide as an active ingredient. As mentioned above, the nimesulide bulk drug according to the embodiment of the present invention has good solubility and dissolution rate, thereby effectively improving the therapeutic effect of the pharmaceutical composition. The fourth aspect of the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition contains the nimesulide bulk drug described in the first aspect of the present invention. As mentioned above, the nimesulide bulk drug according to the embodiment of the present invention has good solubility and dissolution rate, thereby effectively improving the therapeutic effect of the pharmaceutical composition.

[0020] The pharmaceutical composition according to the embodiment of the present invention may also have at least one of the following additional technical features:

[0021] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or excipients, so as to further improve the intake effect of the pharmaceutical composition.

[0022] The fifth aspect of the present invention provides a method for preparing a pharmaceutical composition. According to an embodiment of the present invention, the method comprises mixing the nimesulide bulk drug substance described in the first aspect of the present invention with one or more pharmaceutically acceptable carriers and / or excipients to obtain the pharmaceutical composition.

[0023] The method for preparing the pharmaceutical composition according to an embodiment of the present invention may also have at least one of the following additional technical features:

[0024] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition includes tablets, capsules, pills, and granules.

[0025] According to an embodiment of the present invention, the method comprises granulating, drying, mixing and tableting the nimesulide raw material described in the first aspect of the present invention together with a filler, a binder, a surfactant and a disintegrant to obtain nimesulide tablets.

[0026] According to an embodiment of the present invention, the filler is selected from at least one of microcrystalline cellulose, lactose and sodium starch glycolate; and / or the binder is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, preferably hydroxypropyl cellulose.

[0027] According to an embodiment of the present invention, the surfactant is at least one of sodium lauryl sulfate and docusate sodium, preferably sodium lauryl sulfate.

[0028] According to an embodiment of the present invention, the disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose, preferably sodium carboxymethyl starch.

[0029] According to an embodiment of the present invention, a lubricant is further added when preparing the pharmaceutical composition, and the lubricant is selected from at least one of magnesium stearate or silicon dioxide, preferably magnesium stearate.

[0030] According to an embodiment of the present invention, the pretreatment method of nimesulide raw material provided by the present invention specifically comprises the following steps:

[0031] 1) Turn on the airflow mill, set the airflow crushing pressure, feeding pressure and air source pressure, and after the equipment is stable, add an appropriate amount of nimesulide API at a certain rate for crushing;

[0032] 2) discharging the crushed API in 1) by appropriate means;

[0033] 3) Screening the discharged API to reduce electrostatic agglomeration;

[0034] 4) Granulating, drying, mixing and tableting the API obtained in 3) together with the filler and the binder.

[0035] Among them, the discharging adopts the method of installing a replenishing bag at the discharging port and discharging directly.

[0036] According to an embodiment of the present invention, the fabric of the supplementary bag is selected from antistatic materials such as antistatic TC fabric, antistatic TR fabric, antistatic CVC fabric, antistatic cotton fabric, etc. Thus, static electricity can be prevented from being generated and particles can be prevented from agglomerating.

[0037] There is a close connection between the dissolution rate and bioavailability of a drug. If the dissolution rate is too high or too low, the bioavailability of the drug will be affected. The present invention controls the particle size distribution of the poorly water-soluble nimesulide so that it has a good dissolution rate and further has a good bioavailability. If the particle size of the drug is large, its dissolution rate may be very low and the drug effect of use cannot be achieved. If the particle size of the drug is too small, although its dissolution rate can be improved, the dissolution rate is too fast, resulting in a low duration of drug effect and low bioavailability. Moreover, too small a particle size will also cause negative effects such as unqualified content uniformity due to electrostatic agglomeration. Therefore, for nimesulide preparations, there is no simple linear correlation between dissolution rate, dissolution rate, uniform dissolution and the duration of drug effect, but a complex relationship of mutual influence and mutual restriction exists.

[0038] The pretreatment method of nimesulide raw material provided by the invention obtains raw material medicine with the best particle size range by controlling airflow crushing parameters and sieving with a 60-200 mesh sieve after discharging.

[0039] Nimesulide belongs to BCS class II, with low solubility and high permeability. The particle size affects the key quality of the preparation. In the preparation process, in order to increase the dissolution rate, it will be optimized from two aspects:

[0040] 1) Adding a relatively large amount of surfactant or dispersant in the formulation process, generally more than 5%. This will increase the solubility of the preparation, but will greatly reduce the safety and duration of the drug's efficacy;

[0041] 2) Mechanically crushing nimesulide. The commonly used processing method is repeated mechanical crushing and passing through a sieve of 200 mesh or more. The disadvantages are low yield and heat generation of the material during the mechanical crushing process, which easily leads to decomposition of nimesulide.

[0042] The advantages of air flow milling are as follows:

[0043] 1) No temperature rise, especially suitable for ultra-fine grinding of heat-sensitive materials;

[0044] 2) Less pollution, because the principle of crushing is the collision and crushing of the material itself. Compared with other forms of crushing, such as using blades or ball mills, which will bring in other grinding media, the crusher is the crushing process with the least pollution;

[0045] 3) Easy to clean. Compared with other ultrafine grinders, the grinder has fewer internal transmission parts, especially the spiral airflow grinder, which has a simple structure, is easy to clean, and has no dead corners.

[0046] The invention provides a pretreatment method for nimesulide raw materials, which controls airflow pulverization parameters and an optimal feed amount to reduce losses; and screens the raw materials after airflow pulverization to reduce the degradation of excellent properties of the powder caused by reagglomeration of materials after airflow pulverization.

[0047] The air flow pulverization method is adopted to make the particles of the poorly soluble drug nimesulide collide with each other to achieve the purpose of pulverization, and prepare the micronized poorly soluble drug nimesulide of a certain particle size. After being treated by the raw material pretreatment method of the present invention, the dissolution rate and bioavailability of the nimesulide tablets are improved.

[0048] The technical solution of the present invention has the following technical effects:

[0049] 1) The present invention adopts nimesulide raw material with special particle size distribution, which can improve the dissolution of the preparation and has the optimal dissolution rate and uniform dissolution.

[0050] 2) In the present invention, the air flow pulverization parameters are controlled, and the material yield can reach 90.6% to 94.8%, which effectively reduces the loss and reduces the production cost;

[0051] 3) The present invention performs screening on the raw materials after airflow pulverization to reduce the degradation of the excellent properties of the powder caused by the re-agglomeration of the materials after airflow pulverization;

[0052] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0053] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0054] The air flow pulverizer in the embodiment of the present invention is a YG100 air flow pulverizer.

[0055] Example 1 Pretreatment method of nimesulide raw material

[0056] The pretreatment method steps of nimesulide raw materials are as follows:

[0057] 1) Put the nimesulide raw material into the air flow mill, and the air flow mill parameter settings are: air flow milling pressure is 0.3KN, feeding speed is 20g / min, feeding pressure is 0.3KN, air source pressure is 0.3KN, and the air flow milling sample volume is 10% of the equipment volume;

[0058] 2) After the material is discharged from step 1), the raw material is sieved with a 200-mesh sieve to obtain the nimesulide raw material after airflow crushing. The yield is calculated and its particle size distribution is detected. The results are shown in Tables 1 and 2.

[0059] Embodiment 2 Pretreatment method of nimesulide raw material

[0060] 1) Put the nimesulide raw material into the air flow mill, and the air flow mill parameter settings are: air flow milling pressure is 0.3KN, feeding speed is 30g / min, feeding pressure is 0.4KN, air source pressure is 0.4KN, and the air flow milling sample volume is 10% of the equipment volume;

[0061] 2) After the material is discharged from step 1), the raw material is sieved with a 150-mesh sieve to obtain the nimesulide raw material after airflow crushing. The yield is calculated and its particle size distribution is detected. The results are shown in Tables 1 and 2.

[0062] Example 3 Pretreatment method of nimesulide raw material

[0063] 1) Put the nimesulide raw material into the air flow mill, and the air flow mill parameters are set as follows: the air flow milling pressure is 0.4KN, the feeding speed is 50g / min, the feeding pressure is 0.4KN, the air source pressure is 0.5KN, and the air flow milling sample volume is 10% of the equipment volume;

[0064] 2) After the material is discharged from step 1), the raw material is sieved with a 100-mesh sieve to obtain the nimesulide raw material after airflow crushing. The yield is calculated and its particle size distribution is detected. The results are shown in Tables 1 and 2.

[0065] Example 4 Pretreatment method of nimesulide raw material

[0066] 1) Put the nimesulide raw material into the air flow mill, and the air flow mill parameters are set as follows: the air flow milling pressure is 0.4KN, the feeding speed is 20g / min, the feeding pressure is 0.4KN, the air source pressure is 0.6KN, and the air flow milling sample volume is 20% of the equipment volume;

[0067] 2) After the material is discharged from step 1), the raw material is sieved with a 200-mesh sieve to obtain the nimesulide raw material after airflow crushing. The yield is calculated and its particle size distribution is detected. The results are shown in Tables 1 and 2.

[0068] Example 5 Pretreatment method of nimesulide raw material

[0069] 1) Put the nimesulide raw material into the air flow mill, and the air flow mill parameters are set as follows: the air flow milling pressure is 0.5KN, the feeding speed is 20g / min, the feeding pressure is 0.4KN, the air source pressure is 0.5KN, and the air flow milling sample volume is 10% of the equipment volume;

[0070] 2) After the material is discharged from step 1), the raw material is sieved with a 60-mesh sieve to obtain the nimesulide raw material after airflow crushing. The yield is calculated and its particle size distribution is detected. The results are shown in Tables 1 and 2.

[0071] Example 6 Pretreatment method of nimesulide raw material

[0072] The nimesulide raw material was treated according to the method provided in Example 1, except that the air source pressure was 0.5 KN. The yield of the obtained nimesulide raw material after airflow pulverization was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0073] Example 7 Pretreatment method of nimesulide raw material

[0074] The nimesulide raw material was processed according to the method provided in Example 1, except that the airflow crushing pressure was 0.8 KN. The yield of the obtained nimesulide raw material after airflow crushing was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0075] Example 8 Pretreatment method of nimesulide raw material

[0076] The nimesulide raw material was processed according to the method provided in Example 1, except that the feeding speed was 40 g / min. The yield of the obtained nimesulide raw material after airflow pulverization was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0077] Comparative Example 1 Pretreatment method of nimesulide raw material

[0078] The nimesulide raw material was not treated and its particle size distribution is shown in Table 2.

[0079] Comparative Example 2 Pretreatment method of nimesulide raw material

[0080] The nimesulide raw material was processed according to the method provided in Example 1, except that the feeding speed was 100 g / min and the airflow milling sample volume was 50% of the equipment volume. The yield of the obtained nimesulide raw material after airflow milling was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0081] Comparative Example 3 Pretreatment method of nimesulide raw material

[0082] The nimesulide raw material was treated according to the method provided in Example 1, except that the airflow crushing pressure was 1.0 KN and the air source pressure was 1.0 KN. The yield of the obtained nimesulide raw material after airflow crushing was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0083] Comparative Example 4 Pretreatment method of nimesulide raw material

[0084] The nimesulide raw material was treated according to the method provided in Example 1, except that the airflow crushing pressure was 0.1 KN and the air source pressure was 0.3 KN. The yield of the obtained nimesulide raw material after airflow crushing was calculated and its particle size distribution was detected. The results are shown in Tables 1 and 2.

[0085] Comparative Example 5 Pretreatment method of nimesulide raw material

[0086] Mechanical pulverization was adopted, and the pulverization was repeated for 3 times, and the pulverized material was passed through a 200-mesh sieve. The yield of the obtained nimesulide raw material after mechanical pulverization was calculated and its particle size distribution was tested. The results are shown in Tables 1 and 2.

[0087] Table 1 Parameter settings and yields of the pretreatment method of nimesulide raw materials in Examples 1-8 and Comparative Examples 1-4

[0088]

[0089] By comparing Example 1 with Comparative Example 2, it is shown that the feeding speed is too fast, the nimesulide sample cannot be completely suspended, and a large amount of nimesulide will remain in the pipeline, and the airflow crushing yield is greatly reduced; by comparing Example 7 with Comparative Example 3, it is shown that after the airflow crushing pressure and the air source pressure exceed a certain range, the airflow will take away part of the nimesulide, resulting in a significant decrease in the yield. By comparing Example 1 with Comparative Example 4, it is shown that the airflow crushing pressure is too small, the nimesulide sample cannot be completely suspended, a small amount of sample remains in the pipeline, and the airflow crushing yield is slightly reduced; by comparing Examples 1 to 8 with Comparative Example 5, it is shown that repeated mechanical crushing results in a large amount of sample loss and a low crushing yield.

[0090] Table 2 Particle size distribution of the pretreatment method of nimesulide raw materials in Examples 1-8 and Comparative Examples 1-4

[0091]

[0092]

[0093] (D 90 -D 10 ) / D 50 Indicates the width of the particle size distribution. Large values ​​indicate a wide distribution, while small values ​​indicate a narrow distribution.

[0094] Compared with Example 6, Example 1 can be concluded that the airflow crushing pressure has a greater influence on the particle size distribution of the product. The greater the airflow crushing pressure (the airflow crushing pressure in Example 6 is greater than that in Example 1), the better the raw material crushing effect and the smaller the particle size; Compared with Example 8 and Comparative Example 2 (the feeding speed is too fast), Example 1 shows that the faster the feeding speed is, the worse the airflow crushing effect of the raw material, and the larger the raw material particle size is; Compared with Comparative Example 3 (the air source pressure and airflow crushing pressure are too large), Example 1 shows that the air source pressure and airflow crushing pressure are too large, the raw material particle size is too fine, and the crushing yield is low; Compared with Comparative Example 4, Example 1 shows that the airflow crushing pressure is too small, the crushing effect is poor, and the raw material particle size is too large.

[0095] Example 9 Preparation of Nimesulide Tablets

[0096] 100g of the pre-treated sieved raw materials in Examples 1-8 and Comparative Examples 1-4 were placed in a wet granulator and stirred for 4 minutes with 1.00g of sodium lauryl sulfate, 36g of sodium carboxymethyl starch, 150.48g of lactose, and 100.32g of microcrystalline cellulose to make the mixture uniform, and 8g of hydroxypropyl cellulose aqueous solution with a mass concentration of 5% (w / w) was added for stirring and shearing granulation for 4 minutes, and the wet granules were sieved with a 24-mesh sieve, dried at 60-65°C until the moisture content was less than 4.0%, and then sieved with a 40-mesh sieve and mixed with 4g of magnesium stearate, and tableted according to the theoretical content tablet weight to obtain nimesulide tablets. The content uniformity and friability of the plain tablets were qualified.

[0097] Example 10 Detection of dissolution of nimesulide tablets

[0098] The nimesulide tablets of each group prepared in Example 9 were subjected to dissolution test in pH 6.8+1.0% Tween 80 medium. The test method was as shown in Chinese Pharmacopoeia 4th edition. The specific test results were as shown in Table 3.

[0099] Table 3 Dissolution test results

[0100]

[0101] According to Tables 1, 2, and 3, the nimesulide tablets prepared by the nimesulide bulk drug obtained by the airflow pulverization method in the above Examples 1-8 dissolve 50% in the pH 6.8+1.0% Tween 80 medium in the 5th minute, which is conducive to the rapid onset of action after the patient uses the preparation. The uniform dissolution within a certain period of time from 5 to 45 minutes can maintain the blood drug concentration in the body for a long time, and the drug effect lasts for a long time. The cumulative dissolution rate of 45min is greater than 85%, and the drug utilization rate is high. The initial solubility of the tablets prepared by the nimesulide bulk drug obtained by the method in Comparative Example 1 (untreated) and Comparative Example 2 is low, and the onset time is long after the patient takes it. The tablets prepared by the nimesulide bulk drug obtained by the method of Comparative Example 3 have a dissolution rate of more than 65% in 5min, which dissolves too quickly, and the blood drug concentration is too high after the patient takes it, resulting in adverse reactions. The solubility is low at 45min, and the drug utilization rate is low. The tablets prepared by the nimesulide API obtained by the methods of Comparative Examples 4 and 5 have low dissolution rates at 5 min and 45 min, slow onset of action, and low drug utilization. The above results show that the tablets prepared by using the nimesulide API in a specific particle size range of the present invention have high dissolution rate, optimal dissolution rate, and uniform dissolution, while good dissolution cannot be obtained if the particle size is not within the particle size range of the present invention.

[0102] Example 11 Stability Determination

[0103] Each group of nimesulide tablets prepared in Example 9 was placed at a temperature of 40±2° C. and a relative humidity of RH75±5% for 30 days, and then their dissolution was tested. The test results are shown in Table 4.

[0104] Table 4 Dissolution in pH 6.8 + 1.0% Tween 80 after 30 days

[0105]

[0106] According to Table 4, the nimesulide tablets in the above examples, i.e., the tablets prepared using the nimesulide API prepared by the pretreatment method in Examples 1-8 as raw materials, still maintain a high dissolution rate after 30 days of stability, and the product quality is stable. However, the tablets prepared using the nimesulide API prepared by the pretreatment method in Comparative Examples 1-5 as raw materials have a large difference in initial solubility compared with the tablets in the examples, with too low or too high solubility and low final dissolution.

[0107] In summary, the present invention prepares nimesulide tablets by controlling the airflow crushing parameters to crush and screen the nimesulide raw materials, obtains nimesulide raw materials that meet the specific particle size distribution, and the prepared nimesulide tablets have good dissolution, optimal dissolution rate and uniform dissolution. In addition, the processing method has a high raw material yield, prevents the electrostatic aggregation of the treated nimesulide raw materials, and ensures the uniformity of the preparation content and the therapeutic effect. The preparation process is simple and suitable for large-scale industrial production.

[0108] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0109] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A nimesulide bulk drug, characterized in that: The particle size D of the nimesulide raw material 90 Not more than 20μm and not less than 9μm, particle size D 50 Not more than 9μm and not less than 0μm.

2. The nimesulide bulk drug according to claim 1, characterized in that The particle size D of the nimesulide raw material 90 Not more than 15μm and not less than 10μm, particle size D 50 Not more than 7μm and not less than 5μm.

3. The nimesulide bulk drug according to claim 1 or 2, characterized in that: The particle size distribution (D 90 -D 10 ) / D 50 The ratio is 1 to 3, preferably 1.5 to 2.0, and more preferably 1.54 to 1.

81.

4. A pretreatment method for nimesulide bulk drug, characterized in that: include: Performing air flow pulverization on the nimesulide raw material to obtain the nimesulide raw material; Wherein, the air flow crushing process is carried out under the following conditions: The air flow crushing pressure is 0.2~0.8KN, and the air source pressure is 0.3~0.8KN.

5. The method according to claim 4, characterized in that The air flow crushing pressure is 0.3-0.5 KN; optionally, the air source pressure is 0.3-0.6 KN.

6. The method according to claim 4 or 5, characterized in that: The feeding speed of the air flow pulverization process is 20 to 50 g / min; Optionally, the feeding pressure is 0.2 to 0.8 KN, preferably 0.3 to 0.4 KN.

7. The method according to claim 4, characterized in that In the airflow pulverization process, the sample volume of a single airflow pulverization is 10% to 30% of the volume of the equipment, preferably 10% to 20%.

8. The method according to claim 4, characterized in that Further including: The nimesulide raw material drug which has been subjected to air flow milling treatment is screened using a 60-200 mesh sieve.

9. Use of the nimesulide bulk drug according to any one of claims 1 to 3 in the preparation of a pharmaceutical composition, wherein the pharmaceutical composition contains nimesulide as an active ingredient.

10. A pharmaceutical composition, characterized in that A nimesulide raw material drug comprising the nimesulide raw material drug according to any one of claims 1 to 3.

11. The pharmaceutical composition according to claim 10, characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or excipients.

12. A method for preparing a pharmaceutical composition, characterized in that: The method comprises mixing the nimesulide raw material drug according to any one of claims 1 to 3 with one or more pharmaceutically acceptable carriers and / or excipients to obtain the pharmaceutical composition.

13. The method according to claim 12, characterized in that The dosage forms of the pharmaceutical composition include tablets, capsules, pills and granules.

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