Melasartan potassium granules and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides a Milsartan potassium particle and a preparation method thereof, the Milsartan potassium particle comprises the following components by weight: 80-90 parts of Milsartan potassium, 255-276 parts of mannitol, 6-15 parts of a latent solvent, 5-10 parts of a pH regulator, 5-16 parts of a coating agent, 7-19 parts of a flavoring agent, and 4-12 parts of a flow aid; wherein the latent solvent is selected from one or more than two of glycerol, propylene glycol, polyethylene glycol 300 and polyethylene glycol 400; the coating agent is prepared from a mixture of polyvinyl alcohol polyethylene glycol copolymer and polyvinyl alcohol, copovidone S630, glycerol triacetate and titanium dioxide in a mass ratio of 45: (20-30): (8-12): (18-22). The granular preparation provided by the invention is good in taste and stability, high in dissolution rate and high in dissolution rate.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and relates to amlodipine potassium granules and a preparation method thereof. BACKGROUND

[0002] Amlodipine potassium is a prodrug of azilsartan, which can be rapidly converted into azilsartan after oral absorption. Azilsartan, as an angiotensin II receptor antagonist, blocks the angiotensin II receptor, thereby inhibiting vasoconstriction and reducing peripheral vascular tension to achieve a blood pressure lowering effect. At present, the marketed dosage form of amlodipine potassium is only tablets.

[0003] Amlodipine potassium, as a potent and selective antagonist, has a significant and persistent blood pressure lowering effect in vivo compared with other angiotensin II receptor antagonist drugs. However, amlodipine potassium belongs to BCS Class IV drugs, has low solubility and is almost insoluble in water. Solubility is a key factor affecting the bioavailability of amlodipine potassium. In addition, tablets are difficult to take, and need to be absorbed and swollen and disintegrated into granules before being released in the body, which increases the absorption barrier. Furthermore, amlodipine potassium is an ester salt, which is easily hydrolyzed into azilsartan during the stability period, and has slightly poor chemical stability.

[0004] The original research patent with the publication number CN101677961A discloses that the microenvironment of the active substance is improved by adding a pH adjuster to improve stability and dissolution. However, this method is slightly complex, and the tablets need to be dried under reduced pressure for 16 hours before packaging, which is a relatively harsh production condition. Moreover, the original research marketed product still needs to be packaged in a high-density polyethylene bottle with an additional 2-box cylindrical desiccant package to ensure product stability. Meanwhile, the granular preparation disclosed in the patent has insufficient taste and stability.

[0005] The Chinese patent application with the publication number CN119424358A discloses a method for improving dissolution and stability and improving taste. Amlodipine potassium microtablets are filled into hollow capsules to isolate the special odor and moisture of amlodipine potassium, improve patient compliance and preparation stability. Moreover, the bioavailability can be improved by increasing the specific surface area of the microtablets compared with ordinary tablets. However, the volume of the capsule-filled preparation is increased, which is not conducive to swallowing for elderly hypertensive patients, and the capsule shell is prone to crosslinking and aging during the stability period. The Chinese patent application with the publication number CN119564629A discloses amlodipine potassium tablets and a preparation method thereof. A moisture-proof coating liquid is used to coat amlodipine potassium tablets. The moisture absorption of the prepared amlodipine potassium tablets is significantly reduced, and the stability is good. However, the patent application focuses on tablets and does not focus on the improvement needs of granular preparations. The patent adds a pH adjuster in the coating composition, which is prone to moisture absorption and has a large amount, which has an adverse effect on stability.

[0006] Granules are the urgent needs of patients with poor compliance, such as elderly patients, patients with difficulty in swallowing and poor compliance, who often have difficulty in swallowing tablets / capsules; granules can be directly washed or sprinkled on food, solving the pain of "swallowing", and can accurately dose (such as 20 mg, 40 mg), which is convenient for patients with large body weight difference and small dose starting. At the same time, granules have the potential for development and expansion, and can be further developed into compound granules, and can be packaged into single-dose bags, which is suitable for primary hospitals and home scenarios.

[0007] Therefore, there is an urgent need for a new irbesartan potassium granule preparation to improve patient medication compliance, and good solubility and stability to improve bioavailability. SUMMARY

[0008] The present application provides a kind of irbesartan potassium granule and preparation method thereof, the present application provides irbesartan potassium granule dosage form, the granule preparation taste and stability are good, and high dissolution rate, dissolution rate is fast.

[0009] The technical scheme of the present application is as follows: An irbesartan potassium granule is composed of the following components by weight: 80-90 parts of irbesartan potassium, 255-276 parts of mannitol, 6-15 parts of latent solvent, 5-10 parts of pH regulator, 5-16 parts of coating agent, 7-19 parts of flavoring agent and 4-12 parts of flow aid; The latent solvent is selected from one or more of glycerol, propylene glycol, polyethylene glycol 300 and polyethylene glycol 400. The coating agent is composed of a polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol mixture, copovidone S630, triacetin and titanium dioxide in a mass ratio of 40-50:20-30:8-12:18-22.

[0010] The polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol mixture are purchased from BASF (BASF SE) Protect (model).

[0011] Preferably, the coating agent is composed of a polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol mixture, copovidone S630, triacetin and titanium dioxide in a mass ratio of 45:25:10:20.

[0012] Preferably, the pH regulator is composed of 4-8 parts of an acidic regulator and 1.3-2 parts of an alkaline regulator, the acidic regulator is fumaric acid and / or citric acid, and the alkaline regulator is sodium hydroxide and / or meglumine.

[0013] Preferably, the flavoring agent is selected from one or more of orange flavor, strawberry flavor, vanilla flavor, peppermint flavor, raspberry flavor, sucrose, aspartame and acesulfame.

[0014] Preferably, the flow agent is selected from one or more of stearic acid, magnesium stearate and silicon dioxide.

[0015] Preferably, the pH regulator consists of 4-8 parts of fumaric acid and 1.3-2 parts of sodium hydroxide.

[0016] Preferably, the flavoring agent consists of 2-4 parts of orange flavor and 15-17 parts of aspartame.

[0017] Preferably, the flow agent is magnesium stearate.

[0018] The present application also provides a preparation method of the above-mentioned irbesartan potassium granules, comprising the following steps: S1: dissolving the latent solvent and the pH regulator in purified water to prepare a wetting agent solution; dissolving the coating agent in purified water to prepare a coating liquid; S2: sieving the irbesartan potassium and mannitol, adding them into a fluidized bed, spraying the wetting agent solution to granulate, primary drying, then spraying the coating liquid to coat the granules, secondary drying, to obtain coated granules; S3: mixing the prepared coated granules with the flow agent and the flavoring agent, to obtain the irbesartan potassium granules.

[0019] Preferably, in the step S1, the latent solvent and the pH regulator are dissolved in 25-35 times the total mass of the two in purified water. Further preferably, the latent solvent and the pH regulator are dissolved in 30 times the total mass of the two in purified water.

[0020] Preferably, in the step S1, the coating agent is dissolved in 5-10 times the mass of the coating agent in purified water. Further preferably, the coating agent is dissolved in 9 times the mass of the coating agent in purified water.

[0021] Preferably, in the step S2, the fluidized bed granulation parameters are as follows: air inlet amount 1000-4000 m 3 / h, air inlet temperature 30-70℃, atomization pressure 0.05-0.2Mpa, liquid supply speed 15-50rpm, material temperature 28-45℃.

[0022] Preferably, in the step S2, the fluidized bed granulation parameters are as follows: air inlet amount 3000 m 3 / h, air inlet temperature 60℃, atomization pressure 0.14Mpa, liquid supply speed 35rpm, material temperature 28-32℃.

[0023] Preferably, in the step S3, the mixing speed is 8-12rpm, and the mixing time is 3-8min.

[0024] Preferably, in the step S1, the sieving is 24-mesh sieving.

[0025] Preferably, the particle size D90 of the potassium ambrisentan in step S2 is ≤10 μm, and the particle size D50 is ≤5 μm.

[0026] Preferably, both the primary drying and the secondary drying are performed until the moisture content is ≤0.8%.

[0027] The beneficial effects of the technical solution of the present application are as follows: 1. The potassium ambrisentan granules provided by the present application use glycerol, propylene glycol, polyethylene glycol 300 or polyethylene glycol 400 as a latent solvent, which improves the solubility of potassium ambrisentan, and avoids the use of surfactants and other solubilizers, thereby reducing the toxic and side effects of the preparation.

[0028] 2. Potassium ambrisentan has a rather unpleasant odor, and swallowing is difficult due to the odor. The present application uses granule coating technology and adds a flavoring agent, which not only improves the odor, but also improves the stability of the preparation through coating.

[0029] 3. The potassium ambrisentan granules provided by the present application have improved bioavailability and are easy to take, which is beneficial to improving the compliance of patients in taking the medicine.

[0030] 4. The preparation method of the potassium ambrisentan granules provided by the present application is one-step granulation in a fluidized bed, which is simple to operate and easy to control, does not require special production equipment, has low requirements for the production line, and is suitable for industrialization and popularization. BRIEF DESCRIPTION OF DRAWINGS

[0031] The present application will be further described in detail below in combination with the drawings and specific embodiments.

[0032] Figure 1 The figure is a dissolution curve of the medicine of the present application. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification controls. If a term in the present specification is found missing or ambiguous, it can be interpreted as a term commonly used in the field of the present application. In the present application, the experimental methods or test methods involved in the embodiments, if not specifically stated, are the conventional methods in the prior art, and the name and / or abbreviation thereof are the conventional names in the field, which are very clear and definite in the field of use, and the skilled person in the art can understand the conventional process steps and use the corresponding equipment according to the conventional conditions or the conditions recommended by the manufacturer. The various instruments, equipment, raw materials or reagents used in the embodiments of the present application are not specially limited in terms of source, and are conventional products that can be purchased through regular commercial channels, or can be prepared according to the conventional methods well known to those skilled in the art.

[0035] Example 1 A meixanatan potassium granule, the prescription of which is shown in Table 1 below.

[0036] Table 1

[0037] The preparation method of the meixanatan potassium granule comprises the following steps: S1: Dissolve the latent solvent and the pH adjuster in purified water in an amount of 30 times the total mass of the two, stir to dissolve, and configure into a wetting agent solution; Dissolve the coating agent in purified water in an amount of 9 times the mass of the coating agent, stir to homogenize the solution, and configure into a coating liquid; S2: Crush the meixanatan potassium to D90≤10μm, D50≤5μm, mix with the filler through a 24 mesh sieve, then add to a fluidized bed, spray the wetting agent solution for granulation, primary drying, dry to a granule moisture content≤0.8%, then spray the coating liquid for granule coating, secondary drying, dry to a granule moisture content≤0.8%, to obtain coated granules; the fluidized bed granulation parameters are as follows: inlet air flow 3000m 3 / h, inlet air temperature 60℃, atomization pressure 0.14Mpa, liquid supply speed 35rpm, material temperature 30℃; S3: Mix the prepared coated granules with the glidant and the flavoring agent in a hopper mixer at a speed of 10rpm for 5min, to obtain the meixanatan potassium granule.

[0038] Example 2 A meixanatan potassium granule, the prescription of which is shown in Table 2 below.

[0039] Table 2

[0040] The preparation method of the meixenatate potassium granules is the same as that of Example 1.

[0041] Example 3 A meixenatate potassium granule, the prescription of which is shown in Table 3 below.

[0042] Table 3

[0043] The preparation method of the meixenatate potassium granules is the same as that of Example 1.

[0044] Example 4 A meixenatate potassium granule, the prescription of which is shown in Table 4 below.

[0045] Table 4

[0046] The preparation method of the meixenatate potassium granules is the same as that of Example 1.

[0047] Example 5 A meixenatate potassium granule, the prescription of which is shown in Table 5 below.

[0048] Table 5

[0049] The preparation method of the meixenatate potassium granules is the same as that of Example 1.

[0050] Example 6 A meixenatate potassium granule, the prescription of which is shown in Table 6 below.

[0051] Table 6

[0052] The preparation method of the meixenatate potassium granules is the same as that of Example 1.

[0053] Example 7 A meixenatate potassium granule, the prescription of which is shown in Table 7 below.

[0054] Table 7

[0055] The preparation method of the meixenatate potassium granules comprises the following steps: S1: dissolving the latent solvent and the pH regulator in purified water with a total mass of 25 times that of the two, stirring to dissolve, and configuring into a wetting agent solution; dissolving the coating agent in purified water with a mass of 10 times that of the coating agent, stirring to homogenize the solution, and configuring into a coating liquid; S2: The meixenatan potassium is crushed to D90≤10 μm, D50≤5 μm, mixed with the filler and passed through a 24 mesh sieve, then added to a fluidized bed, sprayed with the wetting agent solution for granulation, primary drying, dried to a granule moisture content≤0.8%, then sprayed with the coating liquid for granule coating, secondary drying, dried to a granule moisture content≤0.8%, to obtain coated granules; the fluidized bed granulation parameters are as follows: air inlet 4000 m 3 / h, air inlet temperature 30°C, atomization pressure 0.2 Mpa, liquid supply speed 50 rpm, material temperature 28°C; S3: The prepared coated granules are mixed with the glidant and flavoring agent in a hopper mixer, at a speed of 8 rpm, for 8 min, to obtain meixenatan potassium granules.

[0056] Example 8 A meixenatan potassium granule, with the following prescription shown in Table 8.

[0057] Table 8

[0058] The preparation method of the meixenatan potassium granule comprises the following steps: S1: The latent solvent and pH adjuster are dissolved in purified water at 35 times the total mass of the two, stirred to dissolve, and configured into a wetting agent solution; The coating agent is dissolved in purified water at 5 times the mass of the coating agent, stirred to homogenize the solution, and configured into a coating liquid; S2: The meixenatan potassium is crushed to D90≤10 μm, D50≤5 μm, mixed with the filler and passed through a 24 mesh sieve, then added to a fluidized bed, sprayed with the wetting agent solution for granulation, primary drying, dried to a granule moisture content≤0.8%, then sprayed with the coating liquid for granule coating, secondary drying, dried to a granule moisture content≤0.8%, to obtain coated granules; the fluidized bed granulation parameters are as follows: air inlet 4000 m 3 / h, air inlet temperature 30°C, atomization pressure 0.2 Mpa, liquid supply speed 50 rpm, material temperature 28°C; S3: The prepared coated granules are mixed with the glidant and flavoring agent in a hopper mixer, at a speed of 8 rpm, for 8 min, to obtain meixenatan potassium granules.

[0059] Comparative Example 1 Compared with Example 1, the only difference is that the latent solvent is not added, and the amount of mannitol is correspondingly increased, as shown in Table 9 below.

[0060] Table 9

[0061] The preparation method of the meixenatan potassium granule comprises the following steps: S1: Dissolve the pH adjuster in 30 times the total mass of purified water, stir to dissolve, and prepare a wetting agent solution; Dissolve the coating agent in 9 times its mass of purified water, stir to homogenize the solution, and prepare a coating liquid; S2: Crush the irbesartan potassium to D90≤10 μm, D50≤5 μm, mix with the filler through a 24-mesh sieve, and then add to a fluidized bed, spray the wetting agent solution to granulate, primary dry, dry to a granule moisture content≤0.8%, then spray the coating liquid to coat the granules, secondary dry, dry to a granule moisture content≤0.8%, to obtain coated granules; the fluidized bed granulation parameters are as follows: inlet air flow 3000 m 3 / h, inlet air temperature 60°C, atomization pressure 0.14 Mpa, liquid supply speed 35 rpm, material temperature 30°C; S3: Mix the prepared coated granules with the glidant and flavoring agent in a hopper mixer at a speed of 10 rpm for 5 min, to obtain the irbesartan potassium granules.

[0062] Comparative Example 2 Compared with Example 1, the only difference is that no granule coating is performed, as shown in Table 10 below.

[0063] Table 10

[0064] The preparation method of the irbesartan potassium granules comprises the following steps: S1: Dissolve the pH adjuster in 30 times the total mass of purified water, stir to dissolve, and prepare a wetting agent solution; Dissolve the coating agent in 9 times its mass of purified water, stir to homogenize the solution, and prepare a coating liquid; S2: Crush the irbesartan potassium to D90≤10 μm, D50≤5 μm, mix with the filler through a 24-mesh sieve, and then add to a fluidized bed, spray the wetting agent solution to granulate, primary dry, dry to a granule moisture content≤0.8%, to obtain dry granules; the fluidized bed granulation parameters are as follows: inlet air flow 3000 m 3 / h, inlet air temperature 60°C, atomization pressure 0.14 Mpa, liquid supply speed 35 rpm, material temperature 30°C; S3: Mix the prepared dry granules with the glidant and flavoring agent in a hopper mixer at a speed of 10 rpm for 5 min, to obtain the irbesartan potassium granules.

[0065] Comparative Example 3 Compared with Example 1, the only difference is that the prescription is different, and the prescription is the original preparation, as shown in Table 11 below.

[0066] Table 11

[0067] Preparation process: S1: Preparation of the binder: Dissolve the pH adjuster and the binder in 30 times the total mass of purified water, respectively, and stir to dissolve.

[0068] S2: Granulation: Crush the milrinone to D90≤10 μm, D50≤5 μm, mix with mannitol through a 24 mesh sieve, and then add to the fluidized bed. Spray the wetting agent solution to granulate. Primary drying is performed until the granule moisture content is ≤0.8%. Then spray the coating liquid to coat the granules. Secondary drying is performed until the granule moisture content is ≤0.8%. The fluidized bed granulation parameters are as follows: air inlet amount 3000 m 3 / h, air inlet temperature 60°C, atomization pressure 0.14 Mpa, liquid supply speed 35 rpm, material temperature 30°C.

[0069] S3: Total mixing: Add the disintegrating agent and the filler microcrystalline cellulose to the hopper mixer after drying the granules. Set the rotation speed to 10 rpm and mix for 5 min. Then add the glidant magnesium stearate. Set the rotation speed to 10 rpm and mix for 5 min. The milrinone granules are obtained.

[0070] Comparative Example 4 The prescription of Example 3 of the patent application CN 119564629 A is the same as that of the milrinone tablet, except for the preparation method. The specific prescription is shown in Table 12 below: Table 12

[0071] The stomach-soluble film coating premix is a composition of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc in a weight ratio of 10:6:5:4. The polyvinyl alcohol is type 05-88, and the polyethylene glycol is polyethylene glycol 4000.

[0072] The preparation method is as follows: S1: Dissolve the binder and the pH adjuster in 30 times the total mass of purified water, and stir to dissolve to prepare a wetting agent solution. Dissolve the coating composition in 9 times the mass of purified water, and stir to homogenize the solution to prepare a coating liquid. S2: Crush the milrinone to D90≤10 μm, D50≤5 μm, mix with mannitol through a 24 mesh sieve, and then add to the fluidized bed. Spray the wetting agent solution to granulate. Primary drying is performed until the granule moisture content is ≤0.8%. Then spray the coating liquid to coat the granules. Secondary drying is performed until the granule moisture content is ≤0.8%. The coated granules are obtained. The fluidized bed granulation parameters are as follows: air inlet amount 3000 m 3 / h, air inlet temperature 60°C, atomization pressure 0.14 Mpa, liquid supply speed 35 rpm, material temperature 30°C. S3: The prepared coated granules were added into the hopper mixer with disintegrating agent, microcrystalline cellulose PH112, and mixed for 5 min at a speed of 10 rpm. Then, lubricant magnesium stearate was added and mixed for 5 min at a speed of 10 rpm, to obtain the irbesartan granules.

[0073] Comparative Example 5 Comparative Example 5

[0074] Table 13

[0075] The preparation method of the irbesartan granules was the same as in Example 1.

[0076] Comparative Example 6 Comparative Example 6

[0077] Table 14

[0078] The preparation method of the irbesartan granules was the same as in Example 1.

[0079] Comparative Example 7 Comparative Example 7

[0080] Table 15

[0081] The preparation method of the irbesartan granules was the same as in Example 1.

[0082] Detection of taste The taste of the irbesartan granules prepared in Examples 1-8 and Comparative Examples 1-4 above and the original preparation was detected by integrated score evaluation method (ISEM), and the results are shown in Table 16 below.

[0083] Table 16: Results of taste detection

[0084] Note: The original preparation is a tablet, which is directly purchased from the market and taken as a whole. No evaluation is made because there is no grittiness or stickiness.

[0085] From the taste detection results in Table 16 above, it can be seen that: The average scores of the granules of meixenatan potassium prepared in Examples 1-8 are all above 90. In Comparative Example 1, no latent solvent is added, which only slightly affects the taste, and the average score is still above 90. In Comparative Example 2, no granule coating is performed, although there are flavoring agents, the special smell of meixenatan potassium is still not completely covered, and the smell and taste scores are slightly low, which are 84 and 80, respectively. In Comparative Example 3, the composition is consistent with the original research tablet, no taste masking is performed, and the adhesive hydroxypropyl cellulose is added, which increases the viscosity of the solution, so the smell, taste and stickiness scores are all low. In Comparative Example 4, only granule coating is performed to mask the taste, and no flavoring agent is added, so the smell and taste scores are slightly low, which are 80 and 81, respectively.

[0086] In summary, the use of coating to mask the taste in the present application effectively improves the smell and taste of the preparation, and the special effect of the flavoring agent can effectively improve the taste. The taste of the finally obtained product is better than that of the original research preparation.

[0087] Stability detection of detection example 2 1. The meixenatan potassium granules prepared in Examples 1-6 and Comparative Examples 1-7 above are packaged using polyester / aluminum / polyethylene pharmaceutical composite film. The packaged samples and the original research preparation (with the same packaging form) are placed together in severe conditions (50°C, 75% RH), and the change in related substances during the stability period is investigated, and the results are as follows in Table 17.

[0088] The detection method of related substances is high performance liquid chromatography (ChP 2020 edition four-part general rule 0512). The limit requirement is: impurity AQK-4A≤0.20%; azilsartan≤4.5%; impurity AQK-6C≤0.50%; impurity AQK-6D≤0.25%; other single impurities≤0.20%; total amount of impurities (excluding azilsartan)≤2.0%.

[0089] Table 17 Stability detection results

[0090] Note: “ND” represents not detected.

[0091] From the related substance detection results in Table 17 above under severe conditions, it can be seen that: The total impurities of the meixenatan potassium particles prepared in Examples 1-6 were all below 0.9% after being stored at 50°C for 60 days; the preparation process of Comparative Example 1 was the same as that of the examples, and after granule coating, the total impurities of the sample were 0.77% after being stored under severe conditions for 60 days, and the growth level was not higher than that of the original preparation. The total impurities of the sample of Comparative Example 2, which was not coated with granules, increased from 0.16% to 1.63% after being stored for 60 days, and the growth rate was greater than that of Examples 1-6. The prescription composition of Comparative Example 3 used the prescription of the original reference preparation, and according to the results of the related substances at 0 days and under severe conditions for 60 days, the impurity growth level of Comparative Example 3 was significantly higher. Comparative Example 4, i.e., using the prescription of the original reference preparation, coated the granules with a coating powder of polyvinyl alcohol as the film-forming agent and a pH adjuster, and the related substances increased to 1.15%, which was lower than that of Comparative Example 3 but still greater than that of Examples 1-6. The reason was that 40% of the hygroscopic and permeable pH adjuster was added to the coating composition, and the amount was large, so it affected the water-blocking and moisture-proof effect of polyvinyl alcohol. Comparative Example 5 lacked copolyvidone S630 in the coating agent composition compared with Example 1, and the total impurities increased from 0.14% to 1.03% after being stored for 60 days, which was higher than that of Examples 1-6. Comparative Example 6 had no polyvinyl alcohol polyethylene glycol copolymer and polyvinyl alcohol mixture in the coating agent composition, and the total impurities increased from 0.13% to 1.25% after being stored for 60 days, which was higher than that of Examples 1-6. Comparative Example 7 replaced copolyvidone S630 with povidone K30 in the coating agent composition, and the total impurities increased to 1.01% after being stored for 60 days, which was higher than that of Examples 1-6 and the original preparation.

[0092] 2. Stability test of simulated granules after transportation, jolting and shaking Comparative Example 5 used polyvinyl alcohol polyethylene glycol copolymer and polyvinyl alcohol mixture as the film-forming agent in the coating agent composition, which had a strong moisture-proof effect, and the impurity growth level was still higher than that of Examples 1-6 after being stored for 60 days. The reason was that the coating composition lacked copolyvidone S630, which had a slightly poor film-forming effect, and there was a risk of coating layer density, and the stability risk of the sample increased after transportation and handling. Therefore, a stability test of simulated granules after transportation, jolting and shaking was designed to verify the above analysis.

[0093] Take 50 ml small medicine bottles with lids, and accurately add the same weight (8 g) of samples into each bottle, and tightly cap the bottle. The experimental group fixes the medicine bottles on a vortex shaker, and shakes at a speed of 30 rpm for 15 minutes. Use polyester / aluminum / polyethylene pharmaceutical composite film packaging. Place the packaged samples in severe conditions (50°C, 75% RH), and observe the changes in related substances during the stability test.

[0094] Among them, 2 medicine bottles are set in the experimental group, and both are subjected to shaking treatment. The 2 medicine bottles of the experimental group correspond to the samples of Example 1 and Comparative Example 5, respectively. The stability of the samples without shaking treatment is compared with that of the control group, and the results are shown in Table 18.

[0095] Table 18 Stability test results

[0096] Note: "ND" represents not detected.

[0097] The results show that: The impurity growth trend of the test sample of Example 1 is basically consistent with the control group, while the total impurity of the experimental sample of Comparative Example 5 increases from 0.14% to 1.49%, which is significantly higher than that of the control sample.

[0098] In summary, the prepared meixenatate potassium granules are coated with a certain amount of coating powder with better moisture-proof effect, thereby isolating the active ingredients from water vapor and oxygen, reducing the risk of meixenatate potassium hydrolysis and oxidation, and making the preparation more stable.

[0099] Dissolution curve detection of Test Example 3 According to the dissolution and release determination method (second method in Chinese Pharmacopoeia 2020 Edition Volume IV 0931), with pH 6.8 + Tween 80 as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the law. At 5, 10, 15, 20 and 30 min, 10 mL of sample was taken and supplemented with liquid, and the cumulative dissolution of each bag was calculated by high performance liquid chromatography. The test results are shown in Table 19 below, and the dissolution curve is shown in Figure 1 The dissolution of meixenatate potassium granules prepared in Examples 1 to 6 and Comparative Examples 1 to 4 above and the original research drug was detected.

[0100] Table 19 Dissolution curve test results

[0101] From the above Table 19 and Figure 1 Dissolution curve test results show that: Examples 1-6 use a certain amount of latent solvent, and the dissolution endpoint can reach more than 95%; Comparative Example 1 does not add latent solvent, and the dissolution rate and dissolution platform are reduced, and the 30 min cumulative dissolution is only 93%; Comparative Example 2 does not perform granule coating, and although the dissolution platform meets the requirements, the early dissolution rate is slightly faster, and the 5-10 min dissolution rate is nearly 20% faster than the original research formulation; Comparative Example 3 has the same prescription composition as the original research reference formulation, and does not contain latent solvent, and the platform is slightly lower than that of Comparative Example 1, only 94%.

[0102] The above is only a preferred embodiment of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A granulate of Myrbetriq® (mirabegron) potassium characterized in that, The raw material is composed of the following components by weight: 80-90 parts of milrinone, 255-276 parts of mannitol, 6-15 parts of a latent solvent, 5-10 parts of a pH regulator, 5-16 parts of a coating agent, 7-19 parts of a flavoring agent, and 4-12 parts of a flow agent. The latent solvent is selected from one or more of glycerol, propylene glycol, polyethylene glycol 300, and polyethylene glycol 400. The coating agent is composed of a mixture of polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol in a mass ratio of 45:20-30:8-12:18-22, copovidone S630, triacetin, and titanium dioxide.

2. The meixian potassium granules according to claim 1, characterized in that, The pH regulator is composed of 4-8 parts of an acidic regulator and 1.3-2 parts of an alkaline regulator, wherein the acidic regulator is fumaric acid and / or citric acid, and the alkaline regulator is sodium hydroxide and / or meglumine.

3. The meixian potassium granules according to claim 1, characterized in that, The flavoring agent is selected from one or more of orange flavor, strawberry flavor, vanilla flavor, mint flavor, raspberry flavor, sucrose, aspartame, and acesulfame potassium.

4. The meixian potassium granules according to claim 1, characterized in that, The flow agent is selected from one or more of stearic acid, magnesium stearate, and silicon dioxide.

5. The meixian potassium granules according to claim 1, characterized in that, The pH regulator is composed of 4-8 parts of fumaric acid and 1.3-2 parts of sodium hydroxide.

6. The meixian potassium granules according to claim 1, characterized in that, The flavoring agent is composed of 2-4 parts of orange flavor and 15-17 parts of aspartame.

7. The meixian potassium granules according to claim 1, characterized in that, The flow agent is magnesium stearate.

8. The process for preparing meixian tan potassium granules according to any one of claims 1 to 7, characterized in that, The method comprises the following steps: S1: dissolving the latent solvent and the pH regulator in purified water to prepare a wetting agent solution; The coating agent is dissolved in purified water to prepare a coating liquid; S2: sieving the milrinone and mannitol, adding them to a fluidized bed, spraying the wetting agent solution to granulate, primary drying, then spraying the coating liquid to coat the granules, secondary drying, to obtain coated granules; S3: mixing the prepared coated granules with the flow agent and the flavoring agent to obtain milrinone granules.

9. The process for preparing the meixan potassium granules according to claim 8, characterized by, The fluidized bed granulation parameters in the step S2 are as follows: air inlet amount 1000-4000 m 3 / h, air inlet temperature 30-70℃, atomization pressure 0.05-0.2 Mpa, liquid supply speed 15-50 rpm, material temperature 28-45℃.

10. The process for preparing the meixan potassium granules according to claim 8, characterized by, Both the primary drying and the secondary drying are performed until the moisture content is less than or equal to 0.8%.

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