Preparation method of pyridostigmine bromide tablet

Abstract

The invention provides a preparation method of pyridostigmine bromide tablets, and belongs to the technical field of pharmaceutical preparations. The preparation method of the pyridostigmine bromide tablet provided by the invention comprises the following steps: mixing a pyridostigmine bromide raw material with molten stearic acid, uniformly stirring, and preparing particles by using a spray condensing device; and mixing the obtained particles with lactose, and tabletting. According to the method provided by the invention, the problem that the product quality is influenced due to moisture absorption and deliquescence of raw material medicines in the preparation process of the pyridostigmine bromide tablet is effectively solved, the spatial humidity of a preparation environment does not need to be strictly controlled when the pyridostigmine bromide tablet is prepared by the method provided by the invention, and the operability and feasibility of production are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of pyridostigmine bromide tablets. Background Art

[0002] Pyridostigmine Bromide is a cholinesterase inhibitor drug that can reversibly bind to cholinesterase, inhibit the activity of cholinesterase, reduce the destruction of acetylcholine released by cholinergic nerve endings, accumulate acetylcholine in the synaptic cleft, and exhibit muscarinic (M) and nicotinic (N) cholinergic receptor excitatory effects. In addition, it has a direct excitatory effect on nicotinic cholinergic receptors (N2 receptors) on the motor end plate and can promote the release of acetylcholine from motor nerve endings, thereby increasing the muscle tone of the gastrointestinal tract, bronchial smooth muscle, and skeletal muscle throughout the body. The effect of pyridostigmine bromide is slightly weaker than that of neostigmine bromide, but the action duration is more persistent. Clinically, it is widely used in the treatment of myasthenia gravis (MG).

[0003] Myasthenia gravis is an autoimmune disease mediated by autoantibodies with acquired neuromuscular junction transmission disorders, mainly caused by damage to acetylcholine receptors (AChR) on the postsynaptic membrane of the neuromuscular junction. The clinical manifestations of myasthenia gravis are partial or general skeletal muscle weakness and extreme fatigue, which can lead to respiratory muscle paralysis and endanger life in severe cases. Currently, the treatment methods for this disease include cholinesterase inhibitors, glucocorticoids, immunosuppressants, intravenous immunoglobulin, plasma exchange, and thymectomy. The "Diagnosis and Treatment Guidelines for Myasthenia Gravis in China (2020 Edition)" clearly states that pyridostigmine bromide is a first-line drug for the treatment of all types of myasthenia gravis and can relieve and improve the clinical symptoms of the vast majority of myasthenia gravis patients.

[0004] The pyridostigmine bromide preparations available for clinical use were first developed by Valeant and successively launched in the United States since 1955, including dosage forms such as tablets, sustained-release tablets, injections, syrups, etc., with the trade name MESTINON. The specification of the pyridostigmine bromide tablets is 60 mg, and the prescription composition is pyridostigmine bromide, lactose, colloidal silicon dioxide, and stearic acid. The "List of Reference Preparations for Generic Drugs (Seventh Batch)" issued by the National Medical Products Administration clearly defines this preparation as the reference preparation for pyridostigmine bromide tablets.

[0005] However, during the research and development process of pyridostigmine bromide tablets, our company found that the pyridostigmine bromide raw material has strong hygroscopicity. When the environmental relative humidity is greater than 35%, the raw material medicine will quickly absorb moisture and deliquesce. The research data are shown in Table 1. To solve this problem, we tried to mix the raw material with excipients to improve its hygroscopicity. We selected low-moisture-content and low-hygroscopic excipients such as anhydrous lactose, colloidal silicon dioxide, and stearic acid according to the prescription composition of the original preparation to form a multi-component mixture with pyridostigmine bromide. However, the results showed that even if the mixture was placed in an environment with a relative humidity of 40% for only 1 hour, the percentage of weight gain due to moisture absorption could still reach 2.9%, indicating that this method could not effectively solve the hygroscopicity problem of pyridostigmine bromide. During the preparation process of pyridostigmine bromide tablets, we found that the hygroscopicity of the raw material medicine has a fatal impact on the product quality. For example, when preparing pyridostigmine bromide tablets by the conventional direct powder compression process in an environment with a relative humidity of 28% or less, when the average hardness of the tablets was 7 kg, the disintegration time limit of the tablets was about 25 minutes, which was consistent with the reference preparation. However, when preparing pyridostigmine bromide tablets by the same prescription process in an environment with a relative humidity of 35%, the disintegration time limit of the tablets was extended to 45 minutes. After exposing the intermediate granules to an environment with a relative humidity of 35% for about 1.5 hours and then performing tablet pressing, due to the influence of the hygroscopicity of the raw material medicine, the compressibility of the intermediate granules decreased significantly, and the hardness of the tablets could no longer reach 7 kg, and only tablets with a hardness of 3 kg could be pressed. The above research results show that when preparing pyridostigmine bromide tablets by conventional methods, the environmental humidity needs to be strictly controlled at an extremely low level. For this demanding requirement, even if special dehumidification equipment is installed in the production workshop and the air-conditioning system is necessary modified, there are still great difficulties, which greatly restricts the feasibility and operability of the production of pyridostigmine bromide tablets.

[0006] Table 1 Hygroscopicity test results of pyridostigmine bromide raw material under different humidity conditions (25 °C)

[0007] Table 2 Hygroscopicity investigation results of pyridostigmine bromide, excipients and the mixture of raw materials and excipients in an environment with RH40% (25 °C)

[0008] Table 3 Investigation results of the influence of environmental humidity on the quality of pyridostigmine bromide tablets

[0009] *Note: Tablets were pressed immediately after preparing the total mixed intermediate granules in an environment with RH35%; **Note: After preparing the total mixed intermediate granules in an environment with RH35%, the total mixed intermediate granules were exposed to the above environment for about 1.5 hours and then tablet preparation was carried out. Summary of the Invention

[0010] In view of the problems existing in the above-mentioned prior art, the present invention provides a method for preparing pyridostigmine bromide tablets. This method effectively solves the problem that the quality of pyridostigmine bromide tablets is affected by the hygroscopic deliquescence of the raw drug during the preparation process. When preparing pyridostigmine bromide tablets by the method provided by the present invention, there is no need to strictly control the space humidity of the preparation environment, and the preparation of pyridostigmine bromide tablets can be carried out under the conventional environmental humidity (RH45% - RH60%) in the GMP preparation workshop, which improves the operability and feasibility of production.

[0011] The object of the present invention is achieved by the following technical solutions A method for preparing pyridostigmine bromide tablets, comprising the following steps: Step ①: Granulation Melt stearic acid by an appropriate method, place the pyridostigmine raw material with an appropriate particle size into the molten stearic acid, stir evenly by an appropriate method, and spray and condense the above suspension with an appropriate atomizing device to prepare granules; Step ②: Mixing Mix the pyridostigmine-stearic acid granules obtained in step ① with lactose by an appropriate method; Step ③: Tabletting Press the intermediate granules obtained after mixing in step ② into tablets by an appropriate method.

[0012] As an embodiment of the present invention, the weight ratio of pyridostigmine to stearic acid in step ① is 1 part: 0.1 part - 1.5 parts. Further, the weight ratio of pyridostigmine to stearic acid is 1 part: 0.5 part - 1.5 parts.

[0013] As an embodiment of the present invention, the particle size range of the pyridostigmine raw material in step ① is 20 mesh - 200 mesh. Further, the particle size range of the pyridostigmine raw material is 80 mesh - 200 mesh.

[0014] As an embodiment of the present invention, the appropriate method for melting stearic acid in step ① is heating. Further, the target temperature reached by heating is any temperature value within the range of 50°C - 85°C.

[0015] As an embodiment of the present invention, the appropriate method in step ① is stirring. Further, the stirring methods include manual stirring and mechanical stirring.

[0016] As an embodiment of the present invention, the atomizing device in step ① includes a device that can disperse a liquid into droplets based on the principles of compressed atomization, air jet atomization, ultrasonic atomization, high-speed centrifugal / vortex disk atomization, mechanical oscillation atomization, two-fluid impinging atomization, etc. Further, the atomizing device is a centrifugal atomizing device.

[0017] As an embodiment of the present invention, the particle size range of the pyridostigmine bromide-stearic acid particles prepared in step ① is 20 mesh to 100 mesh. Further, the particle size range of the obtained pyridostigmine bromide-stearic acid particles is 20 mesh to 60 mesh.

[0018] As an embodiment of the present invention, the weight part ratio of the pyridostigmine bromide-stearic acid particles to lactose in step ② is 1 part: 1 part to 4 parts.

[0019] As an embodiment of the present invention, the appropriate mixing method in step ② is manual mixing and mechanical mixing. Further, the appropriate mixing method can be achieved by means of a three-dimensional or two-dimensional motion mixer.

[0020] As an embodiment of the present invention, the appropriate tableting method in step ③ can be to press tablets through a tablet press.

[0021] The present invention provides a preparation method of pyridostigmine bromide tablets. Compared with the prior art, ① the present invention effectively solves the problem of easy hygroscopic deliquescence of pyridostigmine bromide, improves the wet stability of pyridostigmine bromide, and solves the problems of harsh environmental humidity requirements and high production costs during the preparation of pyridostigmine bromide tablets; ② by reasonably controlling the particle size of the raw material drug and the particle size of the pyridostigmine bromide-stearic acid particles, the dissolution curve of the obtained product is consistent with that of the reference preparation; ③ in order to make the intermediate have good fluidity, the glidant colloidal silica is used in the original research preparation. For the intermediate particles prepared by the method provided by the present invention, even without using colloidal silica or other similar glidants, extremely excellent fluidity can still be obtained, and the excellent fluidity of the intermediate particles is very important for ensuring the dose uniformity of the target product. Specific Embodiments

[0022] To further understand the present invention, the present invention will be described in detail below in conjunction with embodiments, but the present invention is not limited thereto Table 4 Prescription Composition of Examples

[0023] Example 1 The prescription composition of the pyridostigmine bromide tablets provided in this example is shown in Table 1: Its preparation method includes the following steps: (1) Take the prescribed amount of stearic acid, heat it until melted, and maintain the temperature at 70 °C. Place the prescribed amount of pyridostigmine bromide raw material (the particle size range of the raw material is 100 mesh to 140 mesh) into the molten stearic acid, and stir for 10 min to disperse evenly. Add the above suspension into a centrifugal atomization device to form droplets. The rotational speed of the centrifugal disk of the centrifugal atomization device is 13,200 rpm. The droplets are cooled and condensed to obtain pyridostigmine bromide-stearic acid granules. Screen and collect the part with a particle size in the range of 40 mesh to 60 mesh for standby; (2) Take the pyridostigmine bromide-stearic acid granules obtained by screening in step (1) and place them in a three-dimensional motion mixer together with the prescribed amount of anhydrous lactose, and mix at a rotational speed of 10 rpm for 15 min to obtain the total mixing intermediate granules; (3) Press the total mixing intermediate granules obtained in step (2) into tablets through a rotary tablet press.

[0024] Example 2 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1, except that "pyridostigmine bromide raw material (the particle size range of the raw material is 100 mesh to 140 mesh)" is replaced with "pyridostigmine bromide raw material (the particle size range of the raw material is 20 mesh to 40 mesh)", and "screen and collect the part with a particle size in the range of 40 mesh to 60 mesh" is replaced with "screen and collect the part with a particle size in the range of 20 mesh to 40 mesh".

[0025] Example 3 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1, except that "pyridostigmine bromide raw material (the particle size range of the raw material is 100 mesh to 140 mesh)" is replaced with "pyridostigmine bromide raw material (the particle size range of the raw material is 40 mesh to 80 mesh)".

[0026] Example 4 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1, except that "pyridostigmine bromide raw material (the particle size range of the raw material is 100 mesh to 140 mesh)" is replaced with "pyridostigmine bromide raw material (the particle size range of the raw material is 80 mesh to 100 mesh)".

[0027] Example 5 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: Basically the same as the preparation method in Example 1, except that "pyridostigmine bromide raw material (raw material particle size range 100 mesh - 140 mesh)" is replaced with "pyridostigmine bromide raw material (raw material particle size range 140 mesh - 180 mesh)".

[0028] Example 6 The prescription composition of the pyridostigmine bromide - stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: Basically the same as the preparation method in Example 1, except that "pyridostigmine bromide raw material (raw material particle size range 100 mesh - 140 mesh)" is replaced with "pyridostigmine bromide raw material (raw material particle size range 180 mesh - 200 mesh)".

[0029] Example 7 The prescription composition of the pyridostigmine bromide - stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: Basically the same as the preparation method in Example 1, except that "the centrifugal disk speed of the centrifugal atomization device is 13200 rpm" is replaced with "the centrifugal disk speed of the centrifugal atomization device is 8000 rpm", and "sieving the part with a particle size in the range of 40 mesh - 60 mesh" is replaced with "sieving the part with a particle size in the range of 20 mesh - 40 mesh".

[0030] Example 8 The prescription composition of the pyridostigmine bromide - stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: Basically the same as the preparation method in Example 1, except that "the centrifugal disk speed of the centrifugal atomization device is 13200 rpm" is replaced with "the centrifugal disk speed of the centrifugal atomization device is 18400 rpm", and "sieving the part with a particle size in the range of 40 mesh - 60 mesh" is replaced with "sieving the part with a particle size in the range of 60 mesh - 80 mesh".

[0031] Example 9 The prescription composition of the pyridostigmine bromide - stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: Basically the same as the preparation method in Example 1, except that "the centrifugal disk speed of the centrifugal atomization device is 13200 rpm" is replaced with "the centrifugal disk speed of the centrifugal atomization device is 23600 rpm", and "sieving the part with a particle size in the range of 40 mesh - 60 mesh" is replaced with "sieving the part with a particle size in the range of 80 mesh - 100 mesh".

[0032] Example 10 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0033] Example 11 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0034] Example 12 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0035] Example 13 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0036] Example 14 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0037] Example 15 The prescription composition of the pyridostigmine bromide-stearic acid granules provided in this example is shown in Table 1: Its preparation method includes the following steps: It is basically the same as the preparation method in Example 1.

[0038] Comparative Example 1 The prescription composition of the pyridostigmine bromide tablets provided in this comparative example is shown in Table 1: Its preparation method includes the following steps: (1) Weigh the prescribed amounts of pyridostigmine bromide, stearic acid, anhydrous lactose, and colloidal silicon dioxide and place them in a three-dimensional motion mixer. Mix at a speed of 10 rpm for 15 minutes to obtain the total mixed intermediate granules; (2) Press the total mixed intermediate granules obtained in step (1) into tablets by a rotary tablet press.

[0039] Comparative Example 2 The prescription composition of the pyridostigmine bromide tablets provided in this comparative example is shown in Table 1: The preparation method comprises the following steps: Weigh the prescribed amounts of pyridostigmine bromide, stearic acid, and anhydrous lactose, and place them in a three-dimensional motion mixer. Mix at a rotation speed of 10 rpm for 15 minutes to obtain intermediate granules; Granulate the intermediate granules obtained in step (1) through a dry granulator, with a roller pressure of 40 - 60 kg / cm 2 , a granulation sieve mesh of 0.8 mm, sieve the obtained granules, and take the granules with a particle size in the range of 40 - 60 mesh; Mix the granules obtained by sieving in step (2) with colloidal silica in a corresponding proportion to obtain total mixed intermediate granules; Press the total mixed intermediate granules obtained in step (3) into tablets through a rotary tablet press.

[0040] Experimental Example 1 Hygroscopicity Test of the Drug Conduct the hygroscopicity test of the drug according to General Rule 9103 of the Chinese Pharmacopoeia (2020 Edition). Take a dry stoppered glass weighing bottle, place it in an environment of 25°C ± 1°C and a relative humidity of 60% ± 5% for 24 hours, and then accurately weigh its weight (m1). Weigh approximately 1 g of pyridostigmine bromide raw material, approximately 6 g each of Comparative Example 1 - Comparative Example 2, approximately 2 g each of the pyridostigmine bromide - stearic acid granules prepared in Examples 1 - 9, approximately 1.1 g of the pyridostigmine bromide - stearic acid granules prepared in Example 10, approximately 1.5 g of the pyridostigmine bromide - stearic acid granules prepared in Example 11, and approximately 2.5 g of the pyridostigmine bromide - stearic acid granules prepared in Example 12, and spread them evenly in the above-mentioned weighing bottle so that the thickness of the test samples is basically the same and about 1 mm, and then accurately weigh the weight (m2). Open the above-mentioned weighing samples, and place them together with the bottle caps in the above-mentioned environment of 25°C ± 1°C and a relative humidity of 60% ± 5% for 24 hours. Cover the weighing bottle caps, and accurately weigh the weight (m3). Calculate the weight gain percentage according to the following formula:

[0041] The measurement results are shown in the following table: Table 5 Measurement Results of the Hygroscopic Weight Gain Percentage

[0042] In Table 2, the hygroscopicity of the pyridostigmine bromide - stearic acid granules prepared in Examples 1 - 12 is much less than that of the pyridostigmine bromide raw material and the pyridostigmine bromide granules prepared in Comparative Examples 1 - 2, indicating that the method provided by the present invention can effectively improve the moisture stability of pyridostigmine bromide.

[0043] Examples 1 to 6 are pyridostigmine bromide-stearic acid granules prepared by using pyridostigmine bromide with different particle sizes according to the method provided by the present invention. The hygroscopic weight gain percentages of the pyridostigmine bromide-stearic acid granules prepared from pyridostigmine bromide raw materials with particle sizes of 20 mesh - 40 mesh, 40 mesh - 80 mesh, 80 mesh - 100 mesh, 100 mesh - 140 mesh, 140 mesh - 180 mesh, and 180 mesh - 200 mesh are 1.2%, 0.5%, 0.1%, 0.1%, 0.04%, and 0.03% respectively, indicating a positive correlation between the hygroscopic weight gain percentage of the prepared granules and the particle size of the raw materials. The reason for this phenomenon may be that as the particle size of the pyridostigmine bromide raw material increases, the coating thickness of stearic acid on its surface relatively decreases so that it cannot be effectively coated, and the pyridostigmine bromide raw materials that cannot be effectively coated or are exposed outside the stearic acid layer are prone to hygroscopicity. According to the above test results, the preferred particle size range of the pyridostigmine bromide raw material should be 80 mesh to 200 mesh.

[0044] Examples 1, 7 to 9 are pyridostigmine bromide-stearic acid granules with different particle size ranges prepared by using pyridostigmine bromide raw materials with the same particle size (100 mesh - 140 mesh) according to the method provided by the present invention. The hygroscopic weight gain percentages of the pyridostigmine bromide-stearic acid granules with particle sizes of 20 mesh - 40 mesh, 40 mesh - 60 mesh, 60 mesh - 80 mesh, and 80 mesh - 100 mesh are 0.08%, 0.1%, 0.1%, and 0.2% respectively, indicating an inverse correlation between the hygroscopic weight gain percentage of the prepared granules and the particle size of the granules, that is, the smaller the particle size of the prepared pyridostigmine bromide-stearic acid granules, the greater the hygroscopic weight gain percentage. For pyridostigmine bromide raw materials with the same particle size range, a smaller particle size of the pyridostigmine bromide-stearic acid granules means a decrease in the coating degree of stearic acid on the raw materials and an increase in the hygroscopic probability. According to the above test results, the preferred particle size range of the pyridostigmine bromide-stearic acid granules should be 20 mesh to 80 mesh.

[0045] Examples 1, 10 to 12 are granules with different API-stearic acid ratios prepared by using pyridostigmine bromide raw materials with the same particle size (100 mesh - 140 mesh) according to the method provided by the present invention. The hygroscopic weight gain percentages of the pyridostigmine bromide-stearic acid granules with API-stearic acid ratios of 1:0.1, 1:0.5, 1:1, and 1:1.5 are 1.9%, 0.6%, 0.1%, and 0.05% respectively, indicating an inverse correlation between the hygroscopic weight gain percentage of the prepared granules and the proportion of stearic acid in the granules. The reason for this phenomenon may be that as the proportion of stearic acid in the pyridostigmine bromide-stearic acid granules increases, stearic acid can be more fully coated on the raw materials, and the probability that the pyridostigmine bromide raw materials cannot be effectively coated or are exposed outside the stearic acid layer decreases. According to the above test results, the preferred parts ratio of the pyridostigmine bromide raw material to stearic acid should be 1 part: 0.5 part to 1.5 parts.

[0046] Experimental Example 2 Determination of Fluidity According to "GB / T31057.3-2018 Physical Property Testing of Granular Materials - Part 3: Measurement of Fluidity Index", the angle of repose of the total mixing intermediate granules of Comparative Examples 1 and 2 and the pyridostigmine bromide-stearic acid granules of Examples 1, 7, 8, and 9 was determined. The device for measuring the angle of repose consists of a horizontally placed circular tray and a funnel suspended above the tray. Before measurement, the tray is placed horizontally, the funnel is vertically suspended above the tray, and the center line of the funnel and the center of the tray are on the same line. The sample to be measured is added to the hopper, and the powder is kept flowing evenly and continuously into the horizontal tray. When the accumulated cone of the sample to be measured exceeds the horizontal tray, the addition of the material is stopped. After the slope of the cone is stable, the angle value formed by the slope and the horizontal plane is read with a protractor, which is the angle of repose.

[0047] The measurement results are shown in the following table Table 6 Investigation and Measurement Results of the Angle of Repose

[0048] Examples 1, 7 to 9 are pyridostigmine bromide-stearic acid granules with different particle size ranges prepared by using pyridostigmine bromide raw materials (100 mesh - 140 mesh) of the same particle size according to the method provided by the present invention. The angles of repose of the pyridostigmine bromide-stearic acid granules of 20 mesh - 40 mesh, 40 mesh - 60 mesh, 60 mesh - 80 mesh, and 80 mesh - 100 mesh are 28°, 30°, 35°, and 37° respectively, indicating that the fluidity of the prepared granules has a positive correlation with the particle size of the granules, that is, the larger the particle size of the prepared pyridostigmine bromide-stearic acid granules, the better the fluidity. According to the above test results, the preferred particle size range of the pyridostigmine bromide-stearic acid granules should be 20 mesh to 60 mesh.

[0049] The angle of repose of the granules prepared by the method provided by the present invention is smaller than that of the granules prepared by Comparative Examples 1 and 2. Comparative Examples 1 and 2 are intermediate granules prepared by conventional powder direct compression process or dry granulation process. In order to meet the requirements of the fluidity of the intermediate granules, when applying the above conventional process to prepare samples, it is still necessary to add glidants such as colloidal silica, while the granules prepared by the method provided by the present invention itself have excellent fluidity and can meet the requirements of the tabletting process without adding auxiliary materials such as glidants.

[0050] Experimental Example 3 Process Robustness Study In order to investigate the robustness of the method for preparing pyridostigmine tablets provided by the present invention and its sensitivity to environmental humidity, pyridostigmine tablets were prepared according to the methods provided by Example 1 and Comparative Examples 1 and 2 at different environmental humidities, and the storage time limit of the total mixing intermediate granules in a high humidity environment was also investigated.

[0051] The test results are shown in the following table: Table 7 Investigation Results of the Sensitivity of the Preparation Process of Comparative Example 1 to Environmental Humidity and Process Robustness

[0052] *Note: The total mixed intermediate granules were prepared in an environment of RH35% and then immediately tabletted; **Note: After the total mixed intermediate granules were prepared in an environment of RH35%, the total mixed intermediate granules were exposed and placed in the above environment for about 1.5 h and then tablet preparation was carried out.

[0053] Table 7 shows that pyridostigmine bromide tablets were prepared according to the powder direct compression process provided in Comparative Example 1. The results showed that in an environment with a relative humidity of 28% or less, when the average hardness of the tablets was 7 kg, the disintegration time limit of the tablets was about 25 minutes, which was consistent with the reference preparation; however, when pyridostigmine bromide tablets were prepared with the same prescription process in an environment of relative humidity 35%, the disintegration time limit of the tablets was extended to 45 minutes; after the intermediate granules were placed open in an environment of relative humidity 35% for about 1.5 h and then tablet pressing was carried out, due to the hygroscopicity of the active pharmaceutical ingredient, the compressibility of the intermediate granules decreased significantly, and the hardness of the tablets could no longer reach 7 kg.

[0054] Table 8 Investigation Results of the Sensitivity of the Preparation Process of Comparative Example 2 to Environmental Humidity and Process Robustness

[0055] Table 8 shows that pyridostigmine bromide tablets were prepared according to the conventional dry granulation process provided in Comparative Example 2. The results showed that in an environment with a relative humidity of 26% or less, when the average hardness of the tablets was 7 kg, the disintegration time limit of the tablets was about 25 minutes, which was consistent with the reference preparation; however, when pyridostigmine bromide tablets were prepared with the same prescription process in an environment of relative humidity 37%, the compressibility of the total mixed intermediate granules decreased and the disintegration time limit of the tablets was extended. The reason for the above phenomenon may be that the dry granulation process takes longer than the powder direct compression process, and the extended exposure time in the preparation environment means an increase in the moisture absorption degree of the intermediate granules.

[0056] Table 9 Investigation Results of the Sensitivity of the Preparation Process of Example 1 to Environmental Humidity and Process Robustness

[0057] *Note: The total mixed intermediate granules were prepared in an environment of RH50% and then immediately tabletted; **Note: After the total mixed intermediate granules were prepared in an environment of RH50%, the total mixed intermediate granules were exposed and placed in the above environment for about 6 h and then tablet preparation was carried out.

[0058] Table 9 shows pyridostigmine bromide tablets prepared according to the prescription process provided in Example 1. The results show that in an environment with a relative humidity of 25% to 50%, the preparation process of pyridostigmine bromide tablets has good robustness, and the disintegration times of the obtained tablets are basically the same; after the obtained total mixing intermediate granules are exposed in an environment with a relative humidity of 50% for 6 hours and then tableted, the compressibility of the granules and the disintegration times of the obtained tablets have not changed significantly.

[0059] Experimental Example 4 In vitro dissolution test Respectively take the pyridostigmine bromide tablets prepared in Example 1, Example 13, Example 14, Example 15 and the reference preparation (trade name: MESTINON, specification: 60 mg). According to the dissolution test method (Method 2 in General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition), using water as the dissolution medium and a rotation speed of 50 rpm, operate according to the law. Take 10 mL of the dissolution solution at 5, 10, 15, 20, 30, and 45 minutes respectively, and immediately supplement the dissolution medium with the same temperature and the same volume. Filter the sampled sample solution through a 0.45 μm filter membrane, discard the initial filtrate, and take the subsequent filtrate to determine the content of the main component by ultraviolet spectrophotometry and calculate the cumulative dissolution amount.

[0060] The measurement results are shown in Table 10: Table 10 Measurement results of dissolution test

[0061] Examples 1, 13, 14, and 15 are tablets prepared from pyridostigmine bromide-stearic acid granules and anhydrous lactose in different proportions. The results of dissolution curve determination show that when the weight ratio of pyridostigmine bromide-stearic acid granules to anhydrous lactose is 1 part: 1 part to 4 parts, the fitting similarity of the dissolution curves of the prepared tablets to the reference preparation is far greater than 50.

[0062] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing pyridostigmine bromide tablets, characterized in that: The method comprises the following steps: Step ①: Granulation: melt stearic acid by an appropriate method, place pyridostigmine bromide raw material of appropriate particle size in the melted stearic acid, stir evenly by an appropriate method, spray and condense the above suspension by an appropriate atomizing device to prepare particles; Step ②: Mixing: Mix the pyridostigmine bromide-stearic acid granules obtained in step ① with lactose by an appropriate method; Step ③: Tableting: The mixed intermediate granules obtained in step ② are compressed into tablets by an appropriate method.

2. A method for preparing pyridostigmine bromide tablets according to claim 1, characterized in that: In the step ①, the weight ratio of pyridostigmine bromide to stearic acid is 1 part: 0.5 parts to 1.5 parts; the appropriate method in step ① is heating, and further, the target temperature reached by heating is any temperature value in the range of 50°C to 85°C; the appropriate stirring method in step ① is manual stirring and mechanical stirring; the atomization device in step ① is a centrifugal atomization device.

3. A method for preparing a pyridostigmine bromide tablet according to claim 1 or 2, characterized in that: The particle size range of the pyridostigmine bromide raw material in the step ① is 80 mesh to 200 mesh.

4. A method for preparing a pyridostigmine bromide tablet according to claim 1 to 3, characterized in that: The particle size range of the pyridostigmine bromide-stearic acid particles prepared in step ① is 20 mesh to 60 mesh.

5. A method for preparing pyridostigmine bromide tablets according to claim 1, characterized in that: In the step ②, the weight ratio of pyridostigmine bromide-stearic acid particles to lactose is 1 part: 1 part to 4 parts; and the appropriate mixing method in the step ② is manual mixing and mechanical mixing.

6. The method for preparing pyridostigmine bromide tablets according to claim 1, characterized in that: The appropriate tableting method in step ③ is to compress the tablets by a tablet press.

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