Pramipexole dihydrochloride tablet and preparation method thereof

Abstract

The invention provides pramipexole dihydrochloride tablets and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The pramipexole dihydrochloride tablet is characterized by being prepared from the following components in parts by weight: 60 to 80 parts of auxiliary particles, 0.2 to 0.3 part of pramipexole dihydrochloride, 12 to 40 parts of a filling agent, 1.1 to 1.3 parts of a flow aid, 0.95 to 1.15 parts of a disintegrating agent and 0.8 to 1.2 parts of a lubricating agent, wherein the auxiliary particles are prepared from mannitol, microcrystalline cellulose and an adhesive, and the weight ratio of the mannitol to the microcrystalline cellulose is (1.5-5): 1; the weight ratio of the mannitol to the adhesive is 1: (0.01-0.03). The invention also provides a preparation method of the pramipexole dihydrochloride tablet. The pramipexole dihydrochloride tablet solves the problem that the pramipexole dihydrochloride tablet is poor in stability, the impurity content of the tablet is reduced, and the component uniformity is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a pramipexole hydrochloride tablet and a preparation method thereof. Background Art

[0002] Pramipexole hydrochloride is a drug used to treat the signs and symptoms of idiopathic Parkinson's disease in adults. The chemical formula of pramipexole hydrochloride is as follows: .

[0003] Pramipexole hydrochloride tablets are mainly used to treat the signs and symptoms of idiopathic Parkinson's disease in adults, including in the late stages of the disease, when the efficacy of levodopa gradually decreases or changes and fluctuates. In addition, pramipexole hydrochloride tablets are also used to treat the symptoms of moderate to severe idiopathic restless legs syndrome.

[0004] Chinese invention patent CN101505734A provides a method for preparing pramipexole dihydrochloride with high storage stability. The method uses a fluidized bed granulation method after dissolving the raw material, and the mannitol model is delta crystal mannitol. The process product has the problem that the content of the active ingredient gradually decreases with storage time and the accessibility of delta crystal mannitol is poor.

[0005] Chinese invention patent CN104666259A provides a pramipexole hydrochloride tablet and a preparation method thereof, which solves the problem that starch in pramipexole hydrochloride tablets interferes with the determination of related substances, thereby making it difficult to effectively control the quality of the tablets.

[0006] However, the prior art has not yet provided a process for preparing pramipexole hydrochloride tablets with better tablet stability, lower impurity content and higher component uniformity. Summary of the invention

[0007] In view of this, in view of the problems existing in the prior art, the object of the present invention is to provide a pramipexole hydrochloride tablet and a preparation method and application thereof.

[0008] To achieve the above-mentioned object of the invention, on the one hand, the present invention provides a pramipexole hydrochloride tablet prepared by the following components in parts by weight: 60-80 parts of auxiliary granules, 0.2-0.3 parts of pramipexole hydrochloride, 12-40 parts of filler, 1.1-1.3 parts of glidant, 0.95-1.15 parts of disintegrant and 0.8-1.2 parts of lubricant; Wherein, the auxiliary particles are made of mannitol, microcrystalline cellulose and a binder, the weight ratio of the mannitol to the microcrystalline cellulose is 1.5-5:1; the weight ratio of the mannitol to the binder is 1:0.01-0.03.

[0009] Preferably, the preparation method of the pramipexole hydrochloride tablets comprises the following steps: S1. Mix mannitol and microcrystalline cellulose, add a binder solution, granulate, dry, and granulate to obtain auxiliary granules; S2, mixing the auxiliary granules with pramipexole hydrochloride for the first time, then adding the filler, glidant, and disintegrant for the second time, and then adding the lubricant for the third time to obtain a total mixed powder for pramipexole hydrochloride tablets; S3, tableting the total mixed powder of pramipexole hydrochloride tablets obtained in step S2 to obtain pramipexole hydrochloride tablets.

[0010] More preferably, in step S1, the solution is an aqueous solution, and the weight fraction of the binder in the binder solution is 1%-10%, and more preferably 1%-6%.

[0011] More preferably, in step S1, the binder is selected from at least one of povidone, starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose, and is more preferably povidone. As a specific example of the present invention, the preferred binder is povidone K30.

[0012] More preferably, in step S1, the particle size of the mannitol is required to be D85=150 μm.

[0013] More preferably, in step S1, the mesh size of the auxiliary particles is 60-120 meshes.

[0014] More preferably, in step S1, the mixing is dry mixing for 4-6 min, more preferably 5 min; the granulation is shear granulation for 1-3 min, more preferably shear granulation for 2 min using a wet granulator; the drying is drying to a moisture content of ≤2%, more preferably fluidized bed drying to a moisture content of ≤2%; the granulation is granulation using a sieve with an aperture of 0.6-1 mm, more preferably granulation using a sieve with an aperture of 0.8 mm.

[0015] Preferably, in step S2, the weight ratio of the granules 1, pramipexole hydrochloride, filler, glidant, disintegrant and lubricant is 64.15-79.9: 0.2-0.3: 12.85-37.35: 1.1-1.3: 0.95-1.15: 0.8-1.2.

[0016] More preferably, in step S2, the weight ratio of the granules 1, pramipexole hydrochloride, filler, glidant, disintegrant and lubricant is 64.15-79.9:0.25:12.85-37.35:1.2:1.05:1.

[0017] Preferably, in step S2, the filler is selected from at least one of microcrystalline cellulose and lactose; the glidant is selected from at least one of silicon dioxide (including colloidal silicon dioxide and non-colloidal silicon dioxide), talc, and aluminum silicate; the disintegrant is selected from at least one of starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; the lubricant is selected from at least one of magnesium stearate, stearic acid, sodium stearyl fumarate, and hydrogenated castor oil.

[0018] More preferably, in step S2, the filler is microcrystalline cellulose, the glidant is one of silicon dioxide and colloidal silicon dioxide, the disintegrant is one of sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone, and the lubricant is one of sodium stearyl fumarate, stearic acid and magnesium stearate.

[0019] Preferably, in step S2, the first mixing time is 8-12 min, more preferably 10 min; the second mixing time is 28-32 min, more preferably 30 min; the third mixing time is 2-4 min, more preferably 3 min.

[0020] Preferably, in step S2, the first mixing comprises the following steps: mixing 40%-60% by weight of auxiliary particles with pramipexole hydrochloride, and then adding the remaining amount of auxiliary particles and mixing.

[0021] More preferably, in step S2, the first mixing comprises the following steps: mixing 50% by weight of the granules 1 with pramipexole hydrochloride, and then adding the remaining granules 1, and mixing for 10 minutes.

[0022] On the other hand, the present invention provides a method for preparing the above-mentioned pramipexole hydrochloride tablets, comprising the following steps: S1. Mixing the formulated amount of mannitol and microcrystalline cellulose, adding a binder solution, granulating, drying, and granulating to obtain auxiliary granules; S2, mixing the auxiliary particles obtained in step S1 with a formula amount of pramipexole hydrochloride for the first time, then adding a formula amount of filler, glidant, and disintegrant for a second time, and then adding a formula amount of lubricant for a third time to obtain a total mixed powder of pramipexole hydrochloride tablets; S3, tableting the total mixed powder of pramipexole hydrochloride tablets obtained in step S2 to obtain pramipexole hydrochloride tablets.

[0023] Preferably, the preparation method further comprises step S4: S4, packaging the pramipexole hydrochloride tablets obtained in step S3 in an aluminum-plastic package to obtain packaged pramipexole hydrochloride tablets.

[0024] Compared with the prior art, the present invention has the following beneficial effects: The invention provides a preparation process of pramipexole hydrochloride tablets, comprising the steps of preparing pre-prepared particles of mannitol and microcrystalline cellulose and adding pramipexole hydrochloride and auxiliary agents for mixed tableting. The pramipexole hydrochloride tablets prepared by the process solve the problem of poor tablet stability, reduce the impurity content of the tablets, and improve the uniformity of the ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a schematic diagram of the sampling method in the mixing uniformity test of the total mixed powder of Pramipexole Hydrochloride Tablets, wherein 1-11 represents 11 different sampling sites. DETAILED DESCRIPTION

[0026] Terms and Claims of the Present Invention: 1. The articles “a”, “an” and “the” include plural referents unless expressly limited to one or more referents otherwise.

[0027] 2. Numerical range: Unless otherwise expressly stated, all ranges or ratios disclosed herein will be understood to include any and all sub-ranges or sub-ratios contained therein. For example, a range or ratio of 1 to 30 stated should be considered to be included between a minimum value of 1 and a maximum value of 30, and any sub-range or sub-ratio, integer, decimal, or sub-range or sub-ratio consisting of integers or decimals including the end points.

[0028] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0029] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0030] In the following examples, some of the reagents are from the following Table 1: Table 1

[0031] In the following examples, the instruments and equipment used are shown in Table 2: Table 2

[0032] Example 1 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0033] Mannitol was crushed to a particle size of D85 = 150 μm.

[0034] 52.5 parts by weight of mannitol and 26.25 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 3% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0035] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0036] 50% of the auxiliary particles obtained in step S1 and 0.25 weight parts of pramipexole hydrochloride are added to a mixer, and the remaining auxiliary particles are added and mixed for 10 minutes. Then 21.6 weight parts of filler microcrystalline cellulose, 1.2 weight parts of glidant silicon dioxide, and 1.05 weight parts of disintegrant sodium carboxymethyl starch are added and mixed for 30 minutes. Finally, 1 weight part of magnesium stearate is added and mixed for 3 minutes to obtain the total mixed powder of pramipexole hydrochloride tablets.

[0037] S3. Tableting.

[0038] The total mixed powder of pramipexole hydrochloride tablets is tableted, and the tableting parameters are as follows: tableting pressure 5-8 kN, tableting hardness controlled to 30-60 N, and tableting speed 10-30 rpm to obtain pramipexole hydrochloride tablets.

[0039] S4. Packaging of finished products.

[0040] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0041] Example 2 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0042] Mannitol was crushed to a particle size of D85 = 150 μm.

[0043] 52.5 parts by weight of mannitol and 35 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 1% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0044] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0045] 50% of the auxiliary particles obtained in step S1 and 0.25 weight parts of pramipexole hydrochloride are added to a mixer, and the remaining auxiliary particles are added and mixed for 10 minutes. Then 12.85 weight parts of filler microcrystalline cellulose, 1.2 weight parts of glidant silicon dioxide, and 1.05 weight parts of disintegrant sodium carboxymethyl starch are added and mixed for 30 minutes. Finally, 1 weight part of magnesium stearate is added and mixed for 3 minutes to obtain the total mixed powder of pramipexole hydrochloride tablets.

[0046] S3. Tableting.

[0047] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets. The tableting parameters are the same as those in Example 1.

[0048] S4. Packaging of finished products.

[0049] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0050] Example 3 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0051] Mannitol was crushed to a particle size of D85 = 150 μm.

[0052] 52.5 parts by weight of mannitol and 17.5 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 4% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0053] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0054] 50% of the auxiliary particles obtained in step S1 and 0.25 weight parts of pramipexole hydrochloride are added to a mixer, and the remaining auxiliary particles are added and mixed for 10 minutes. Then 30.35 weight parts of filler microcrystalline cellulose, 1.2 weight parts of glidant silicon dioxide, and 1.05 weight parts of disintegrant sodium carboxymethyl starch are added and mixed for 30 minutes. Finally, 1 weight part of magnesium stearate is added and mixed for 3 minutes to obtain the total mixed powder of pramipexole hydrochloride tablets.

[0055] S3. Tableting.

[0056] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets. The tableting parameters are the same as those in Example 1.

[0057] S4. Packaging of finished products.

[0058] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0059] Example 4 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0060] Mannitol was crushed to a particle size of D85 = 150 μm.

[0061] 52.5 parts by weight of mannitol and 13.13 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 3% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0062] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0063] 50% of the auxiliary particles obtained in step S1 and 0.25 weight parts of pramipexole hydrochloride are added to a mixer, and the remaining auxiliary particles are added and mixed for 10 minutes. Then 34.72 weight parts of filler microcrystalline cellulose, 1.2 weight parts of glidant silicon dioxide, and 1.05 weight parts of disintegrant sodium carboxymethyl starch are added and mixed for 30 minutes. Finally, 1 weight part of magnesium stearate is added and mixed for 3 minutes to obtain the total mixed powder of pramipexole hydrochloride tablets.

[0064] S3. Tableting.

[0065] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets. The tableting parameters are the same as those in Example 1.

[0066] S4. Packaging of finished products.

[0067] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0068] Example 5 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0069] Mannitol was crushed to a particle size of D85 = 150 μm.

[0070] 52.5 parts by weight of mannitol and 10.5 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 6% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0071] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0072] 50% of the auxiliary particles obtained in step S1 and 0.25 weight parts of pramipexole hydrochloride are added to a mixer, and the remaining auxiliary particles are added and mixed for 10 minutes. Then 37.35 weight parts of filler microcrystalline cellulose, 1.2 weight parts of glidant silicon dioxide, and 1.05 weight parts of disintegrant sodium carboxymethyl starch are added and mixed for 30 minutes. Finally, 1 weight part of magnesium stearate is added and mixed for 3 minutes to obtain the total mixed powder of pramipexole hydrochloride tablets.

[0073] S3. Tableting.

[0074] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets. The tableting parameters are the same as those in Example 1.

[0075] S4. Packaging of finished products.

[0076] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0077] Example 6 Compared with Example 1, the only difference is that the disintegrant in step S2 is replaced by an equal weight portion of cross-linked polyvinylpyrrolidone, and the rest is the same.

[0078] Example 7 Compared with Example 1, the only difference is that the lubricant in step S2 is replaced by an equal weight portion of sodium stearyl fumarate, and the rest is the same.

[0079] Example 8 Compared with Example 1, the only difference is that the lubricant in step S2 is replaced by an equal weight portion of stearic acid, and the rest is the same.

[0080] Example 9 Compared with Example 1, the only difference is that the glidant in step S2 is replaced by colloidal silicon dioxide in equal parts by weight, and the rest are the same.

[0081] Comparative Example 1 Compared with Example 1, the only difference is that in step S1, the amounts of mannitol and microcrystalline cellulose are changed to 39.375 parts by weight, and the rest are the same.

[0082] Comparative Example 2 Compared with Example 1, the only difference is that in step S1, the amount of mannitol is changed to 67.5 parts by weight and the amount of microcrystalline cellulose is changed to 11.25 parts by weight, and the rest are the same.

[0083] Comparative Example 3 Compared with Example 1, the only difference is that in step S1, the mannitol is not pulverized, and the rest is the same. The particle size distribution range of the mannitol not pulverized is 200-500 μm.

[0084] Comparative Example 4 Compared with Example 1, the only difference is that in step S1, 37.95 parts by weight of mannitol, 18.97 parts by weight of microcrystalline cellulose, and 0.83 parts by weight of povidone K30 are used (the total weight of auxiliary particles is 57.75 parts); in step S2, 43.75 parts by weight of microcrystalline cellulose as a filler are used, and the rest are the same.

[0085] Comparative Example 5 Compared with Implementation 1, the only difference is that in step S1, mannitol is changed to 58.64 parts by weight, microcrystalline cellulose is changed to 29.32 parts by weight, and povidone K30 is changed to 1.29 parts by weight (the total weight of auxiliary particles is 89.25 parts); in step S2, the filler microcrystalline cellulose is changed to 12.25 parts by weight, and the rest are the same.

[0086] Comparative Example 6 Compared with Example 1, the only difference is that pramipexole hydrochloride is wet granulated with mannitol and microcrystalline cellulose. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0087] Mannitol was crushed to a particle size of D85 = 150 μm.

[0088] 52.5 parts by weight of mannitol, 26.25 parts by weight of microcrystalline cellulose and 0.25 parts by weight of pramipexole hydrochloride were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 3% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0089] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0090] All auxiliary particles were added with 21.6 parts by weight of filler microcrystalline cellulose, 1.2 parts by weight of glidant silicon dioxide, and 1.05 parts by weight of disintegrant sodium carboxymethyl starch, and mixed for 30 minutes. Then, 1 part by weight of magnesium stearate was added and mixed for 3 minutes to obtain a total mixed powder of pramipexole hydrochloride tablets.

[0091] S3. Tableting.

[0092] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets.

[0093] S4. Packaging of finished products.

[0094] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0095] Comparative Example 7 Pramipexole hydrochloride tablets original product.

[0096] Comparative Example 8 A method for preparing pramipexole hydrochloride tablets. The specific steps are as follows: S1. Prepare mannitol and microcrystalline cellulose pre-granules.

[0097] The mannitol was crushed until the content above the 100-mesh sieve did not exceed 15%.

[0098] 52.5 parts by weight of mannitol and 26.25 parts by weight of microcrystalline cellulose were placed in a wet granulator and dry mixed for 5 minutes. 1.15 parts by weight of the binder povidone K30 was mixed with water to prepare a 3% aqueous solution by weight, added to the wet granulator, and high sheared for 2 minutes to obtain wet granules. The wet granules were dried to a moisture content of ≤2% using a fluidized bed, and then granulated using a granulator with a 0.8 mm sieve to obtain pre-prepared granules of mannitol and microcrystalline cellulose (referred to as auxiliary granules).

[0099] S2. Prepare the total mixed powder of pramipexole hydrochloride tablets.

[0100] The auxiliary granules obtained in step S1, 0.25 parts by weight of pramipexole hydrochloride, 21.6 parts by weight of microcrystalline cellulose as a filler, 1.2 parts by weight of silicon dioxide as a glidant, and 1.05 parts by weight of sodium carboxymethyl starch as a disintegrant were placed in a mixer and mixed for 40 minutes. Finally, 1 part by weight of magnesium stearate was added and mixed for 3 minutes to obtain a total mixed powder of pramipexole hydrochloride tablets.

[0101] S3. Tableting.

[0102] The total mixed powder of pramipexole hydrochloride tablets is tableted to obtain pramipexole hydrochloride tablets.

[0103] S4. Packaging of finished products.

[0104] The pramipexole hydrochloride tablets are packaged in aluminum-plastic packaging and then packaged externally to obtain the pramipexole hydrochloride tablets product.

[0105] Comparative Example 9 Pramipexole hydrochloride tablets were prepared by the method for preparing pramipexole hydrochloride tablets provided in Example 1 of Chinese invention patent CN104666259A.

[0106] Effect evaluation The pramipexole hydrochloride tablets total mixed powder and pramipexole hydrochloride tablets prepared in Examples 1-9 and Comparative Examples 1-9 were taken to test the mixing uniformity of the pramipexole hydrochloride tablets total mixed powder, the content uniformity of the pramipexole hydrochloride tablets, and the conditions of related substances.

[0107] 1. Mixing uniformity of the total mixed powder of Pramipexole Hydrochloride Tablets.

[0108] The evaluation method is as follows: After the total mixing is completed, samples are taken as shown in the figure, with 105-315 mg sampled at each point, for a total of 11 points. The content of each point is measured by the method under the content determination item, and the RSD results of all values ​​are calculated.

[0109] Sampling Figure 1 A square cone mixer was used to take samples from 11 locations, including the top of the mixer (positions marked 1, 2, 3, 4, and 5), the corner edges (positions marked 6, 7, 8, 9, and 10), and the discharge port (position marked 11).

[0110] The results are shown in Table 3: Table 3

[0111] 2. Content uniformity of Pramipexole Hydrochloride Tablets The evaluation method is as follows: Randomly take 10 finished tablets and calculate the content of each tablet measured under the content determination item. The calculation method shall be implemented in accordance with General Rules 0941 of Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0112] The results are shown in Table 4: Table 4

[0113] 3. The content of related substances in pramipexole hydrochloride tablets.

[0114] The evaluation method is determined in accordance with high performance liquid chromatography (Chinese Pharmacopoeia 2020 Part IV General Rules 0512).

[0115] The relevant substance information is as follows: Compound 1: SND1117BS. The chemical structure is as follows: .

[0116] Compound 2: BI-II546CL. The chemical structure is as follows: .

[0117] Compound 3: BI-IO460BS. The chemical structure is as follows: .

[0118] Compound 4: BI-II828BS. The chemical structure is as follows: .

[0119] Compound 5: BI-II751XX. The chemical structure is as follows: .

[0120] Compound 6: 2-aminobenzothiazole. The chemical structure is as follows: .

[0121] Compound 7: BI-II820BS. The chemical structure is as follows: .

[0122] Compound 8: BI-II786BS. The chemical structure is as follows: .

[0123] The results are shown in Table 5 and Table 6: Table 5

[0124] Table 6

[0125] 4. Determination of the content of active ingredients in pramipexole hydrochloride tablets.

[0126] The content of active ingredient in freshly prepared (0 day) pramipexole hydrochloride tablets and accelerated storage pramipexole hydrochloride tablets for 6 months was determined.

[0127] The evaluation method is as follows: Content determination: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Part IV General Rules 0512).

[0128] The results are shown in Table 7: Table 7

[0129] 5. Determination of the dissolution rate of pramipexole hydrochloride tablets.

[0130] The evaluation method is as follows: According to the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Method 2).

[0131] The results are shown in Table 8: Table 8

[0132] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A pramipexole hydrochloride tablet, characterized in that: Made from the following ingredients by weight: 60-80 parts of auxiliary granules, 0.2-0.3 parts of pramipexole hydrochloride, 12-40 parts of filler, 1.1-1.3 parts of glidant, 0.95-1.15 parts of disintegrant and 0.8-1.2 parts of lubricant; Wherein, the auxiliary particles are made of mannitol, microcrystalline cellulose and a binder, the weight ratio of the mannitol to the microcrystalline cellulose is 1.5-5:1; the weight ratio of the mannitol to the binder is 1:0.01-0.

03.

2. The pramipexole hydrochloride tablets according to claim 1, characterized in that The preparation method of the pramipexole hydrochloride tablets comprises the following steps: S1. Mix mannitol and microcrystalline cellulose, add a binder solution, granulate, dry, and granulate to obtain auxiliary granules; S2, mixing the auxiliary particles obtained in step S1 with pramipexole hydrochloride for the first time, then adding a filler, a glidant, and a disintegrant for the second time, and then adding a lubricant for the third time to obtain a total mixed powder for pramipexole hydrochloride tablets; S3, tableting the total mixed powder of pramipexole hydrochloride tablets obtained in step S2 to obtain pramipexole hydrochloride tablets.

3. The pramipexole hydrochloride tablets according to claim 2, characterized in that: In step S1, the solution is an aqueous solution, and the weight fraction of the adhesive in the adhesive solution is 1%-10%.

4. The pramipexole hydrochloride tablets according to claim 2 or claim 3, characterized in that: In step S1, the binder is selected from at least one of povidone, starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

5. The pramipexole hydrochloride tablets according to claim 2, characterized in that: In step S1, the particle size of the mannitol is required to be D85=150 μm; the mixing is dry mixing for 4-6 min; the granulation is shear granulation for 1-3 min; the drying is drying to a moisture content of ≤2%; and the granulation is granulated using a sieve with an aperture of 0.6-1 mm.

6. The pramipexole hydrochloride tablets according to claim 2, characterized in that: In step S2, the weight ratio of the auxiliary particles, pramipexole hydrochloride, filler, glidant, disintegrant and lubricant is 64.15-79.9: 0.2-0.3: 12.85-37.35: 1.1-1.3: 0.95-1.15: 0.8-1.

2.

7. The pramipexole hydrochloride tablets according to claim 2 or claim 6, characterized in that: In step S2, the filler is selected from at least one of microcrystalline cellulose and lactose; the glidant is selected from at least one of silicon dioxide, talc, and aluminum silicate; the disintegrant is selected from at least one of starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; the lubricant is selected from at least one of magnesium stearate, stearic acid, sodium stearyl fumarate, and hydrogenated castor oil.

8. The pramipexole hydrochloride tablets according to claim 2, characterized in that: In step S2, the first mixing time is 8-12 minutes, the second mixing time is 28-32 minutes, and the third mixing time is 2-4 minutes; The first mixing comprises the following steps: mixing 40% to 60% by weight of the auxiliary particles obtained in step S1 with pramipexole hydrochloride, and then adding the remaining amount of the auxiliary particles and mixing.

9. A method for preparing pramipexole hydrochloride tablets according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1. Mixing the formulated amount of mannitol and microcrystalline cellulose, adding a binder solution, granulating, drying, and granulating to obtain auxiliary granules; S2, mixing the auxiliary particles obtained in step S1 with a formula amount of pramipexole hydrochloride for the first time, then adding a formula amount of filler, glidant, and disintegrant for a second time, and then adding a formula amount of lubricant for a third time to obtain a total mixed powder of pramipexole hydrochloride tablets; S3, tableting the total mixed powder of pramipexole hydrochloride tablets obtained in step S2 to obtain pramipexole hydrochloride tablets.

10. The preparation method according to claim 9, characterized in that: The step S4 is also included: S4, performing aluminum-plastic packaging on the pramipexole hydrochloride tablets obtained in step S3 to obtain packaged pramipexole hydrochloride tablets.

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