Preparation containing besudil mesylate particles and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation containing besudil mesylate particles and a preparation method of the preparation. The particles of the present application comprise an internal phase of the particles, the internal phase of the particles comprising: a pellet core; the intermediate layer comprises besudil mesylate and a water-soluble dispersion carrier in a weight ratio of 1: (1-4), and the coating layer. According to the present invention, the active component and the water-soluble dispersion carrier form the solid dispersion through the fluidized bed granulation method, the coating material is used to coat the solid dispersion to prepare the particle internal phase, and compared with the common tablet, the particle preparation containing the particle preparation can significantly improve the dissolution rate, improve the bioavailability, and greatly reduce the stability risk. The preparation process is simple and stable, low in production cost and suitable for commercial production.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulation technology, specifically to a formulation containing besudil mesylate granules and its preparation method. Background Technology

[0002] Belumosudil mesylate is the first orally available, selective small-molecule inhibitor of ROCK2 (Rho-associated coiled-coil kinase 2), developed by Kadmon (a wholly owned subsidiary of Sanofi). ROCK2 is a molecular target involved in various autoimmune diseases, fibrosis, and neurodegenerative diseases. Belumosudil mesylate tablets were launched in the United States in July 2021 for the treatment of chronic graft-versus-host disease (cGVHD) in adults and children aged 12 years and older.

[0003] Besudil mesylate is a white to yellow, slightly hygroscopic powder. Its chemical name is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(prop-2-yl)acetamide methanesulfonate, with the molecular formula C26H24N6O2 (free base) and a molecular weight of 452.52 (free base). Its structural formula is:

[0004]

[0005] Besudil mesylate is a BCS class IV compound. It has poor water solubility, is pH dependent, is insoluble in most common organic solvents, slightly soluble in methanol and DMF, and soluble in DMSO.

[0006] Besudil mesylate has poor water solubility; its solubility in aqueous media is pH-dependent, leading to slow dissolution and release of the formulation. Furthermore, besudil mesylate is a BCS Class IV drug, and solubility is a key factor affecting its bioavailability. Tablets are also difficult to administer, and during in vivo release, the tablets must first absorb water, swell, and disintegrate into particles before further release, increasing the absorption barrier. In addition, while marketed products in various countries use high-density polyethylene bottles with added desiccants, according to FDA review reports, its dissolution rate still shows a decreasing trend during the stability period.

[0007] Therefore, there is an urgent need for a new type of besudil mesylate solid dosage form that improves patient compliance, has good stability, and reduces the risk of decreased dissolution rate during the stabilization period. Summary of the Invention

[0008] To address the aforementioned technical problems, this application provides a formulation containing besudil mesylate granules that ensures the stability of the finished product and good dissolution and release, as well as a method for its preparation.

[0009] To ensure good dissolution and release of formulations containing besudinil mesylate granules, this application prepares besudinil mesylate into an internal and external phase. The internal phase includes a core, an intermediate layer, and a coating layer. The active pharmaceutical ingredient is mixed with a water-soluble dispersion carrier to prepare a drug-containing solution, which is then sprayed onto the core through a fluidized bed. A suitable coating material is selected to coat the core, and the solution is then mixed with excipients. The resulting granules exhibit good stability, meet the required content, and demonstrate good dissolution and release during the stability period.

[0010] This application addresses at least one of the problems of the related technology in the following aspects.

[0011] Therefore, a first aspect of this application provides a formulation containing besudinil mesylate granules, the granules comprising an internal phase comprising: a core; an intermediate layer comprising besudinil mesylate and a water-soluble dispersion carrier in a weight ratio of 1:(1-4), the water-soluble dispersion carrier being povidone and / or acrylic resin; and a coating layer.

[0012] In some implementations, the weight ratio of besudil mesylate to the water-soluble dispersion carrier can be 1:1, 1:2, 1:3, or 1:4.

[0013] In some embodiments, the weight ratio of besudil mesylate to the coating material is 1:(0.05-0.5), such as 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc.

[0014] In some embodiments, the coating layer comprises a coating material selected from at least one of hydroxypropyl methylcellulose, polyvinyl alcohol-polyethylene glycol copolymer, and copovidone.

[0015] In some embodiments, the particle size D90 of the intraparticle phase ranges from 155 to 430 μm, preferably from 220 to 380 μm.

[0016] In some embodiments, the pellet core includes a filler selected from one or more of microcrystalline cellulose, anhydrous dicalcium phosphate, corn starch, mannitol, lactose, and pregelatinized starch, preferably microcrystalline cellulose and / or anhydrous dicalcium phosphate.

[0017] In some embodiments, the pellet core further comprises a disintegrant selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, hydroxypropyl cellulose, and calcium carboxymethyl cellulose.

[0018] In some embodiments, the weight ratio of besudil mesylate to filler and disintegrant is 1:(0.3-3):(0.01-0.5), such as 1:0.3:0.01, 1:1:0.1, 1:2:0.1, 1:3:0.2, 1:3:0.5, etc.

[0019] In some embodiments, the particles further include an external phase, and the weight ratio of the internal phase to the external phase is (20-100):1, such as 20:1, 40:1, 60:1, 80:1, 100:1, etc.

[0020] In some embodiments, the external phase of the particles comprises a flavoring agent selected from one or more of orange flavoring, strawberry flavoring, vanilla flavoring, peppermint flavoring, raspberry flavoring, sucrose, aspartame, and acesulfame potassium; the external phase of the particles comprises a lubricant selected from one or more of magnesium stearate, stearic acid, micronized silica gel, talc, and sodium fumarate stearate, preferably magnesium stearate.

[0021] In some embodiments, the weight ratio of besudil mesylate to flavoring agent and lubricant is 1:(0.01-0.5):(0.003-0.2), such as 0.01:0.003, 0.02:0.006, 0.1:0.008, 0.2:0.01, 0.3:0.02, 0.4:0.1, 0.5:0.2, etc.

[0022] In some embodiments, the formulation is a granule, microparticle, capsule, or tablet; preferably a granule.

[0023] The second aspect of this application provides a method for preparing the besudinil mesylate granule formulation described in the first aspect of the application above, comprising the following steps:

[0024] S1: Preparation of drug-containing solution: Disperse besylate and water-soluble dispersion carrier in ethanol solution;

[0025] S2: Intraphase granulation: The filler and disintegrant are added into the fluidized bed, and the drug-containing solution prepared in step S1 is sprayed in for granulation and drying.

[0026] S3: Intra-particle phase coating: Prepare an ethanol solution of water-soluble material and coat the dry particles after granulation in step S2 to obtain intra-particle phase coated particles.

[0027] In some embodiments, preferably, the process further includes S4: mixing: taking the particles coated with the inner phase of the particles from step S3, wherein in some embodiments, the particle size D90 of besudil mesylate is 5-70 μm.

[0028] In some embodiments, the concentration of the ethanol solution used in the preparation method of the besudinil mesylate granules is 20%-40%.

[0029] The beneficial effects of this application include, but are not limited to:

[0030] (1) This application selects a water-soluble carrier as a dispersant and limits the weight ratio of besudil mesylate to the water-soluble dispersant carrier. It uses solid dispersion technology to prepare besudil mesylate drug-containing granules, which greatly improves the dissolution rate of besudil mesylate and avoids the use of surfactants, thus reducing the toxic side effects of the formulation.

[0031] (2) This application prepares granules into an internal phase and an external phase, wherein the internal phase includes: a core, an intermediate layer, and a coating layer, and further controls the particle size D90 range of the internal phase to be 165-415μm, thereby improving the material flowability and the overall particle mixing uniformity.

[0032] (3) In this application, a suitable coating material is selected to coat the besudil mesylate granules, and the weight ratio of the active ingredient to the coating material is limited. This ensures that the besudil mesylate has oxygen-barrier and moisture-proof properties after coating, thereby improving stability, and also ensures the dissolution effect of the formulation.

[0033] (4) The marketed besudil mesylate solid dosage form is a tablet, measuring 14.9*7.5mm and weighing 525mg. The tablet is relatively large, and the medication instructions clearly state that it should be swallowed whole and should not be cut, crushed, or chewed. The besudil mesylate granules involved in this application are mainly used for patients who have just undergone blood transplantation. The granules reduce the difficulty of administration and help improve patient compliance.

[0034] (5) The besudil mesylate granules provided in this application do not require secondary dispersion, thus improving bioavailability; the content is uniform and stable, and easy to separate, which is beneficial for patients to make dosage adjustments according to the progression of chronic graft-versus-host disease and adverse reactions. The side effects of the drug are significantly reduced compared to tablets.

[0035] (6) The method for preparing besudil mesylate granules provided in this application is simple and easy to control; it requires no special production equipment, has low requirements for production lines, and is suitable for industrialization and promotion. Attached Figure Description

[0036] Figure 1 The graphs show the accelerated dissolution curves over 6 months for Example 1, Comparative Examples 2, 4, 5, and 6, and the original reference formulation. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of this application clearer, the following embodiments are provided for further detailed explanation. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of this application.

[0038] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as understood by any person skilled in the art to which this application pertains. The terminology used to describe this application is intended only to describe a particular implementation and is not intended to limit the scope of the teachings.

[0039] Technical terms appearing in this application are used as they are common sense or as they would be understood by someone skilled in the art. Where certain terms have a specific meaning, their definitions will be given below in the context of their use.

[0040] The following embodiments are used to further illustrate the advantages and features of this method, and are not intended to limit this application. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions.

[0041] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. Unless otherwise specified, all quantitative analysis experiments in the following examples were performed in triplicate, and the results were averaged.

[0042] Example 1

[0043] According to the formulation of besudinil mesylate granules (1000 sachets) in Table 1 below, the active ingredient content in the granules is 200mg / sachet, calculated as besudinil.

[0044] Table 1

[0045]

[0046] In Table 1 above, the weight ratio of besudinil mesylate to the water-soluble dispersion carrier is approximately 1:1.53, where the dispersion carrier is povidone; the weight ratio of besudinil mesylate to the coating material is approximately 1:0.082; and the weight ratio of the internal phase to the external phase of the particles is approximately 25.67:1.

[0047] The preparation steps include the following steps S1 to S5:

[0048] S1: Preparation of drug-containing solution: Besudil mesylate is pulverized by air jet milling to D90 = 20 μm. The pulverized besudil mesylate and water-soluble dispersion carrier are then dispersed in a 30% (v / v) ethanol solution and stirred to homogenize the suspension.

[0049] S2: Intra-phase granulation: The filler and disintegrant are added to a fluidized bed and sprayed with the drug-containing solution prepared in step S1 for granulation. During the spraying process, the fan flow rate is set to 1600-2200 m³ / h. 3 The spraying rate is [number] h, and the material temperature is controlled to not exceed 40℃ during the spraying process. After spraying, hot air drying is carried out in the fluidized bed until the material moisture content is ≤1.5%.

[0050] S3: Intra-phase coating: Prepare an ethanol solution of coating material and spray it onto the dry particles after granulation in step S2 for coating. After completion, dry the particles to a moisture content of ≤2.0% and granulate them using a Φ3.0mm stainless steel sieve to obtain intra-phase coated particles with a particle size D90 of 218μm.

[0051] S4: Mixing the inner and outer phases of the granules: Take the inner phase coated granules from step S3, mix them with the flavoring agent, add them to the hopper mixer, set the speed to 10.00 rpm, mix for 10 minutes, then add the lubricant, set the speed to 10.00 rpm, mix for 3 minutes, and you will get the finished product of besudil mesylate granules.

[0052] Example 2

[0053] The difference between the prescription in this embodiment and that in Embodiment 1 is:

[0054] The weight ratio of besudinil mesylate to the water-soluble dispersion carrier is approximately 1:2; the weight ratio of besudinil mesylate to the coating material is approximately 1:0.1; and the weight ratio of the internal phase to the external phase is approximately 35.36:1; the flavoring agents are aspartame, orange flavoring, and peppermint flavoring; the lubricant is magnesium stearate. The preparation method is the same as in Example 1. The internal phase coated particles obtained in step S3 have a particle size D90 of 321 μm. Besudinil mesylate granules (1000 sachets) were prepared according to the proportions in Table 2 below, with the active ingredient content in the granules being 200 mg / sachet.

[0055] Table 2

[0056]

[0057] Example 3

[0058] The difference between the prescription in this embodiment and that in Embodiment 1 is:

[0059] The weight ratio of besudinil mesylate to the water-soluble dispersion carrier is approximately 1:3; the weight ratio of besudinil mesylate to the coating material is approximately 1:0.2; and the weight ratio of the internal phase to the external phase is approximately 40:1. The water-soluble dispersion carrier is acrylic resin; the disintegrant is croscarmellose sodium; and the filler is anhydrous calcium hydrogen phosphate. The preparation method is the same as in Example 1. The particle size D90 of the internal phase coated particles obtained in step S3 is 397 μm. Besudinil mesylate granules (1000 bags) were prepared according to the proportions in Table 3 below, with the active ingredient content in the granules being 200 mg / bag (based on besudinil).

[0060] Table 3

[0061]

[0062]

[0063] Example 4

[0064] The difference between the prescription in this embodiment and that in Embodiment 1 is:

[0065] The weight ratio of besudinil mesylate to the water-soluble dispersion carrier is approximately 1:4; the weight ratio of besudinil mesylate to the coating material is approximately 1:0.3; and the weight ratio of the internal phase to the external phase is approximately 50:1; and the water-soluble dispersion carrier is copovidone. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 408 μm. Besudinil mesylate granules (1000 bags) were prepared according to the proportions in Table 4 below, and the content of the active ingredient in the granules, calculated as besudinil, is 200 mg / bag.

[0066] Table 4

[0067]

[0068] Example 5

[0069] The difference between the prescription in this embodiment and that in Embodiment 1 is:

[0070] The weight ratio of besudinil mesylate to the water-soluble dispersion carrier is approximately 1:2.5; the weight ratio of besudinil mesylate to the coating material is approximately 1:0.5; and the weight ratio of the internal phase to the external phase is approximately 60:1; the water-soluble dispersion carrier is a polyvinyl alcohol-polyethylene glycol copolymer. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 353 μm. Besudinil mesylate granules (1000 bags) were prepared according to the proportions in Table 5 below, and the content of the active ingredient in the granules, calculated as besudinil, is 200 mg / bag.

[0071] Table 5

[0072]

[0073]

[0074] Comparative Example 1

[0075] The difference between this comparative example and the formulation of Example 1 is that the weight ratio of besudinil mesylate to the coating material is approximately 1:0.6. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 251 μm. Besudinil mesylate granules (1000 sachets) were prepared according to the proportions in Table 6 below, with the active ingredient content in the granules being 200 mg / sachet based on besudinil.

[0076] Table 6

[0077]

[0078] Comparative Example 2

[0079] The difference between the formulation of this comparative example and that of Example 1 is:

[0080] The weight ratio of besudinil mesylate to the coating material is approximately 1:0.04. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 124 μm. Besudinil mesylate granules (1000 sachets) were prepared according to the proportions in Table 7 below, and the content of the active ingredient in the granules, calculated as besudinil, is 200 mg / sachet.

[0081] Table 7

[0082]

[0083]

[0084] Comparative Example 3

[0085] The difference between the formulation of this comparative example and that of Example 1 is:

[0086] The weight ratio of besudinil mesylate to the water-soluble carrier is approximately 1:4.5. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 444 μm. Besudinil mesylate granules (1000 sachets) were prepared according to the proportions in Table 8 below, with the active ingredient content in the granules being 200 mg / sachet based on besudinil.

[0087] Table 8

[0088]

[0089] Comparative Example 4

[0090] The difference between the formulation of this comparative example and that of Example 1 is:

[0091] The weight ratio of besudinil mesylate to the water-soluble carrier is approximately 1:0.5. The preparation method is the same as in Example 1, and the particle size D90 of the internal phase coated particles obtained in step S3 is 99.7 μm. Besudinil mesylate granules (1000 sachets) were prepared according to the proportions in Table 9 below, with the active ingredient content in the granules being 200 mg / sachet based on besudinil.

[0092] Table 9

[0093]

[0094] Comparative Example 5

[0095] The difference between the formulation of this comparative example and that of Example 1 is that the formulation uses the original reference formulation and is prepared as granules. Besudil mesylate granules (500 sachets) were prepared according to the proportions in Table 10 below, with the active ingredient content in the granules being 200 mg / sachet, calculated as besudil.

[0096] Table 10

[0097]

[0098] The preparation process includes the following steps:

[0099] S1: Preparation of adhesive: Disperse hydroxypropyl methylcellulose in purified water and stir until completely dissolved;

[0100] S2: Granulation: Besudil mesylate, filler, and disintegrant are added to a fluidized bed and mixed evenly. The binder prepared in step S1 is then sprayed in for granulation. During the spraying process, the fan flow rate is set to 1600-2200 m³ / h. 3 The spraying rate is [number] h, and the material temperature is controlled to not exceed 40℃ during the spraying process. After spraying, hot air drying is carried out in the fluidized bed until the material moisture content is ≤1.5%; granulation is performed using a Φ3.0mm stainless steel sieve, and the particle size D90 is 102μm.

[0101] S3: Total Mixing: Take the granulated drug-containing granules and mix them with the flavoring agent. Add the mixture to the hopper mixer, set the speed to 10.00 rpm, and mix for 10 minutes. Then add the lubricant, set the speed to 10.00 rpm, and mix for 3 minutes to obtain the finished product of besylate granules.

[0102] Comparative Example 6

[0103] The formulation of this comparative example is the same as that of Example 1, except that the preparation method is different, using a conventional wet granulation process.

[0104] The preparation steps include the following steps S1 to S5:

[0105] S1: Premix: Weigh the active ingredients, fillers, disintegrants, and coating materials and place them in a wet granulator for mixing. Set the stirring speed to medium and the shearing speed to low for 5 minutes.

[0106] S2: Granulation: The water-soluble dispersion carrier is dispersed in purified water, stirred and clarified, and then atomized and added to the premixed material. When adding by spray, set medium speed stirring and medium speed shearing. After complete addition, granulate for 1 minute and pass through a Φ8.0mm stainless steel sieve.

[0107] S3: Drying: Place the wet granules in a fluidized bed dryer to dry to a moisture content ≤3.0%, and then pass them through a Φ3.0mm stainless steel sieve for granulation. The particle size D90 is 104μm;

[0108] S4: Blending: After granulation, blend the granules with flavoring agents and lubricants to obtain the finished product.

[0109] Example 1: Testing of finished product content and content uniformity

[0110] Finished product content testing:

[0111] High performance liquid chromatography was used to detect the content of the active ingredient besuldil mesylate in the besuldil mesylate granules prepared in Examples 1 to 5 and Comparative Examples 1 to 6, according to the detection conditions in Table 11 below. The detection results are shown in Table 12 below.

[0112] Table 11: Chromatographic conditions for content detection

[0113]

[0114] Content uniformity test:

[0115] According to the content uniformity test method in Part IV, 0941 of the 2020 edition of the Chinese Pharmacopoeia, the content uniformity of the besudil mesylate granules prepared in Examples 1 to 5 and Comparative Examples 1 to 6 was tested, and the test results are shown in Table 12 below.

[0116] Table 12: Results of Active Ingredient Content Detection and Content Uniformity Detection

[0117]

[0118]

[0119] The above content results show that: the besudinil mesylate content in Examples 1-5 is all above 98%, and the content uniformity is all below 4.2; in Comparative Example 1, the weight ratio of besudinil mesylate to coating material is approximately 1:0.6. Compared to the weight ratio in Examples 1-5, a larger amount of coating material was used to prepare the internal phase of the coated particles, resulting in a besudinil mesylate content below 98% and a content uniformity as high as 6.1; in Comparative Example 2, the weight ratio of besudinil mesylate to coating material is approximately 1:0.04. Compared to the weight ratio in Examples 1-5, a smaller amount of coating material was used to prepare the internal phase of the coated particles, resulting in a besudinil mesylate content of 99.4%, but a content uniformity as high as 7.5; in Comparative Example 3, the besudinil mesylate content is higher than that of the water-soluble carrier. The weight ratio of besylate to water-soluble carrier in Comparative Example 4 is approximately 1:4.5. Compared to the weight ratio of besylate to water-soluble carrier in Examples 1-5, a larger amount of water-soluble carrier is used to prepare the inner phase of the coated particles. The content of besylate is less than 98%, and the content uniformity is 5.1. However, the particle size D90 of the coated particles in the inner phase is 444 μm. The weight ratio of besylate to water-soluble carrier in Comparative Example 4 is approximately 1:0.5. Compared to the weight ratio of besylate to water-soluble carrier in Examples 1-5, a smaller amount of water-soluble carrier is used to prepare the inner phase of the coated particles. The content of besylate is less than 98%, and the content uniformity is as high as 8.9. However, the particle size D90 of the coated particles in the inner phase is 99.7 μm. The formulation of Comparative Example 5 uses the original formulation. Comparative Example 6 uses the formulation of Example 1 and employs a conventional wet formulation process.

[0120] In summary, the prepared besudil mesylate granules met the standards in both the examples and comparative examples in terms of content detection. However, the content uniformity test results for the comparative example were larger than those for the examples. Therefore, controlling the amount of water-soluble dispersion carrier and coating material, as well as the particle size of the internal phase coating particles, within the range of 155-430 μm, can ensure the flowability of the particles. Particles that are too large or too small will result in slightly poor flowability.

[0121] Example 2: Dissolution Test

[0122] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, 0931, Method II), 900 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 60 rpm. Samples of 10 mL were taken at 5, 10, 15, 30, 45, and 60 min, and replenishment was performed. The cumulative dissolution amount per bag was calculated by high-performance liquid chromatography. The test results are shown in Table 15 below. The dissolution of besudinil mesylate granules prepared in Examples 1 to 5 and Comparative Examples 1 to 6, as well as the original reference formulation (the original domestically marketed product, Yilaike, specification 200 mg / tablet), was tested.

[0123] Table 15: Accelerated Dissolution Test Results at Day 0

[0124]

[0125] Table 16: Results of accelerated dissolution test after 3 months

[0126]

[0127] Table 17: Results of accelerated dissolution test after 6 months

[0128]

[0129] The dissolution results in the table above show that:

[0130] In Examples 1-5, the weight ratio of besudinil mesylate to the water-soluble dispersion carrier was 1:(1-4), the weight ratio of besudinil mesylate to the coating material was 1:(0.05-0.5), and the particle size D90 of the internal phase ranged from 155 to 430 μm. The dissolution and release were relatively fast, meeting the requirements of very rapid dissolution, and the dissolution and release were relatively fast during the stability study, which was superior to the original reference formulation.

[0131] In Comparative Example 1, the weight ratio of besudil mesylate to the coating material was approximately 1:0.6. Compared to the weight ratio in Examples 1-5, a larger amount of coating material was used to prepare the internal phase of the coated particles. Based on the accelerated dissolution results at day 0, the dissolution rate before 15 minutes was slower than that of the original reference formulation, and even slower than the dissolution rates of Examples 1-5. Based on the accelerated dissolution results at 3 months and 6 months, the dissolution rate of Comparative Example 1 was slower than that of Examples 1-5.

[0132] In Comparative Example 2, the weight ratio of besudil mesylate to the coating material was approximately 1:0.04. Compared to the weight ratio of the two in Examples 1-5, a larger amount of coating material was used to prepare the internal phase of the coated particles. According to the accelerated dissolution results at 0 days, the dissolution rate before 15 minutes was better than that of the original reference formulation and comparable to that of Examples 1-5. However, according to the accelerated dissolution results at 3 months and 6 months, the dissolution rate of Comparative Example 2 was slower than that of Examples 1-5.

[0133] In Comparative Example 3, the weight ratio of besudinil mesylate to the water-soluble carrier was approximately 1:4.5. Compared to the weight ratio of the two in Examples 1-5, a larger amount of water-soluble carrier was used to prepare the inner phase of the coated particles. In Comparative Example 4, the weight ratio of besudinil mesylate to the water-soluble carrier was approximately 1:0.5. Compared to the weight ratio of the two in Examples 1-5, a smaller amount of water-soluble carrier was used to prepare the inner phase of the coated particles. Based on the dissolution results at 0 days, 3 months, and 6 months, the dissolution rates of Comparative Examples 3 and 4 were slower than those of Examples 1-5.

[0134] Comparative Example 5 used the original reference formulation; Comparative Example 6 used the formulation from Example 1 and employed a conventional wet-process formulation. Based on the accelerated dissolution results at 0 days, 3 months, and 6 months, the dissolution rate of Comparative Example 5 was slower than that of Examples 1-5.

[0135] In summary, the prepared besudinil mesylate granules exhibited the following dissolution rates: excessive coating material resulted in a slow dissolution rate, while insufficient coating material slowed the dissolution rate during stability studies. Furthermore, both excessively high and low proportions of the water-soluble dispersion carrier relative to besudinil mesylate negatively impacted the dissolution rate of the granules, slowing its release. Additionally, the formulation composition and preparation process of the granules also influenced their dissolution rate.

[0136] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A preparation containing particles of BESIGLIPTIN methanesulfonate, characterized in that, The granules comprise an intragranular phase, which comprises: a core; an intermediate layer comprising besivance and a water-soluble dispersion carrier in a weight ratio of 1: (1-4), the water-soluble dispersion carrier being povidone and / or acrylic resin; and a coating layer.

2. The formulation of claim 1, wherein, The weight ratio of the besivance to the coating material is 1: (0.05-0.5).

3. The formulation of claim 1, wherein, The coating layer comprises a coating material selected from at least one of hypromellose, polyvinyl alcohol-polyethylene glycol copolymer and copolyvidone.

4. The particles of BESUROFEL mesylate according to claim 1, wherein The particle size D90 of the intragranular phase ranges from 155 to 430 μm.

5. The formulation of claim 1, wherein The core comprises a filler selected from any one or more of microcrystalline cellulose, anhydrous dibasic calcium phosphate, corn starch, mannitol, lactose, pregelatinized starch, preferably microcrystalline cellulose and / or anhydrous dibasic calcium phosphate; Preferably, the core further comprises a disintegrant selected from any one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, hydroxypropyl cellulose, carboxymethyl cellulose calcium.

6. The formulation of claim 5, wherein, The weight ratio of the besivance to the filler and disintegrant is 1: (0.3-3): (0.01-0.5).

7. The formulation of any one of claims 1-6, wherein, The granules further comprise an extragranular phase, and the weight ratio of the intragranular phase to the extragranular phase is (20-100): 1; Preferably, the extragranular phase comprises a flavoring agent selected from any one or more of orange flavor, strawberry flavor, vanilla flavor, peppermint flavor, raspberry flavor, sucrose, aspartame, acesulfame potassium; Preferably, the extragranular phase comprises a lubricant selected from any one or more of magnesium stearate, stearic acid, colloidal silicon dioxide, talc, sodium stearyl fumarate, preferably magnesium stearate.

8. The formulation of any one of claims 1-7, wherein, The preparation is granules, microparticles, capsules or tablets; preferably granules.

9. Process for the preparation of the preparation according to any one of claims 1 to 8, characterized in that, It comprises the following process steps: S1: preparation of a drug-containing solution: dispersing besivance and a water-soluble dispersion carrier in an ethanol solution; S2: granulation of the intragranular phase: placing a filler and a disintegrant into a fluidized bed and spraying the drug-containing solution prepared in step S1 for granulation and drying; S3: coating of the intragranular phase: preparing an ethanol solution of a water-soluble material and coating the dry granules after granulation in step S2, to obtain intragranular phase coated granules; Preferably, it further comprises S4: mixing: mixing the intragranular phase coated granules in step S3 with a flavoring agent and a lubricant, to obtain the finished product of besivance granules.

10. A process for the preparation of a formulation as claimed in claim 8, characterized in that, The particle size D90 of the besivance in step S1 is 5-70 μm, and the concentration of the ethanol solution is 20%-40%.

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