Edoxaban tosylate orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an esdoxaban tosylate orally disintegrating tablet and a preparation method thereof. The ludoxaban tosylate orally disintegrating tablet is prepared from particles and external auxiliary materials, the particles comprise the following components: indedoxaban tosylate, a filler, a disintegrating agent 1, an adhesive and a solubilizer, the disintegrating agent 1 is a mixture of polyvinylpolypyrrolidone and croscarmellose sodium, and the adhesive is hydroxypropyl methylcellulose; the external auxiliary materials comprise the following components: a disintegrating agent 2, a flavoring agent, a coloring agent and a lubricating agent, wherein the disintegrating agent 2 is polyvinylpolypyrrolidone. The adhesive, the disintegrating agent and the asparaginic acid which are specifically combined are adopted to synergistically realize a rapid drug release effect, blank rapid granules do not need to be prepared, the preparation process is simpler, and meanwhile, the composition has the characteristic of good taste.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an edoxaban tosylate orodisintegrating tablet and a preparation method thereof. Background Art

[0002] Edoxaban is a selective inhibitor of activated coagulation factor Xa that inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. It is currently used to treat adult patients with non-valvular atrial fibrillation with one or more risk factors (such as congestive heart failure, hypertension, age ≥75 years, diabetes, previous history of stroke or transient ischemic attack) to prevent stroke and systemic embolism, as well as to treat deep vein thrombosis and pulmonary embolism in adults and prevent their recurrence. The chemical structure of Edoxaban is as follows:

[0003]

[0004] Chinese invention patent CN102791271A discloses an edoxaban common tablet composition. However, the maximum water content of the granules needs to be kept below 10% during the preparation and granulation step of the tablets, otherwise the granulation effect will be affected. The granulation technology requirements are relatively high, and the common tablets take effect slowly, which is not conducive to the use of patients with dysphagia and has poor compliance.

[0005] Chinese invention patent CN109996542A discloses an edoxaban tosylate orally disintegrating tablet. However, in addition to using a fluidized bed to prepare drug-containing granules, the orally disintegrating tablet also requires the additional preparation of blank rapidly disintegrating granules, resulting in a complex preparation process and high equipment requirements.

[0006] In summary, it is necessary to develop an edoxaban tosylate orally disintegrating tablet that better meets clinical use needs, has a simple preparation process, and is suitable for modern industrial mass production. Summary of the invention

[0007] The purpose of the present invention is to provide an edoxaban tosylate orodisintegrating tablet and a preparation method thereof. The orodisintegrating tablet has a good mouthfeel, is free of gritty feeling, can be rapidly disintegrated in the oral cavity, has rapid dissolution, has stable physical and chemical properties, and has a simple preparation process and low production cost.

[0008] To achieve the above object, on the one hand, the present invention provides an edoxaban toluenesulfonate orodisintegrating tablet, wherein the edoxaban toluenesulfonate orodisintegrating tablet is composed of particles and external excipients;

[0009] The granules include the following ingredients: edoxaban tosylate, a filler, a disintegrant 1, a binder and a solubilizer, wherein the disintegrant 1 is a mixture of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose, and the binder is hypromellose;

[0010] The external auxiliary materials include the following ingredients: disintegrant 2, flavoring agent, colorant and lubricant, wherein the disintegrant 2 is cross-linked polyvinylpyrrolidone.

[0011] Preferably, the filler is at least one of mannitol and microcrystalline cellulose, and the solubilizer is at least one of aspartic acid and glutamic acid.

[0012] Preferably, the flavoring agent is selected from at least one of saccharin sodium, sucrose, fruit flavor, aromatic syrup, aspartame, sucralose, and acesulfame potassium; the coloring agent is selected from at least one of red iron oxide, yellow iron oxide, titanium dioxide, carmine, sunset yellow, turmeric, and theaflavins; the lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, colloidal silicon dioxide, and hydrogenated vegetable oil.

[0013] More preferably, the filler is a mixture of mannitol and microcrystalline cellulose, the solubilizer is aspartic acid, the flavoring agent is sodium saccharin, the coloring agent is yellow iron oxide, and the lubricant is magnesium stearate.

[0014] Preferably, the binder is selected from at least one of hypromellose E15, hypromellose E3 and hypromellose E50.

[0015] More preferably, the binder is selected from at least one of hypromellose E15 and hypromellose E3.

[0016] Preferably, the weight ratio of edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is 80.8:210.34-214.94:33.63:1-1.6:8-12:9.27:4.8:0.36:7.2.

[0017] More preferably, the weight ratio of edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is: 80.8: 210.34-214.34: 33.63: 1.6: 8-12: 9.27: 4.8: 0.36: 7.2.

[0018] More preferably, the weight ratio of edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is: 80.8:214.34:33.63:1.6:8:9.27:4.8:0.36:7.2.

[0019] Preferably, the disintegrant 1 is a mixture of mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is 154.84-159.44:55.5.

[0020] In another aspect, the present invention provides a method for preparing the above-mentioned edoxaban tosylate orodisintegrating tablets, comprising the following steps:

[0021] S1, edoxaban tosylate, filler, disintegrant 1, solubilizer, binder and water are mixed, wet granulated, dried, and granulated to obtain granules;

[0022] S2. Mix the granules obtained in step S1 with disintegrant 2, a flavoring agent, a colorant and a lubricant, and compress the mixture into tablets to obtain edoxaban tosylate orodisintegrating tablets.

[0023] Compared with the prior art, the beneficial effects of the present invention include:

[0024] The drug-containing granules of the edoxaban tosylate orodisintegrating tablets of the present invention adopt specific types of binders, disintegrants and solubilizers, which produce a synergistic effect of enhanced disintegration. There is no need to additionally prepare blank rapidly disintegrating granules or control the water content of the granules. Orodisintegrating tablets with a certain hardness and capable of rapid disintegration within 60 seconds can be obtained by ordinary shear granulation. The preparation process is simpler, the production efficiency is higher and the cost is lower. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a cumulative dissolution rate-time curve diagram of Example 2, Example 3, Example 5 and Comparative Example 2.

[0026] Figure 2 It is the cumulative dissolution rate-time curve diagram of Comparative Example 2, Comparative Example 3, Example 4 and Comparative Example 4.

[0027] Figure 3 It is a cumulative dissolution rate-time curve diagram of Comparative Example 5, Comparative Example 6, Example 6 and Comparative Example 2. DETAILED DESCRIPTION

[0028] Terms and Claims of the Present Invention:

[0029] 1. The articles “a”, “an” and “the” include plural referents unless expressly limited to one or more referents otherwise.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] The information of some chemicals used in the examples and comparative examples of the present invention is shown in Table 1:

[0034] Table 1

[0035] name source Edoxaban Tosylate Zhejiang Supor Pharmaceutical Co., Ltd. Hydroxypropyl methylcellulose SH-E15 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Hydroxypropyl methylcellulose E3 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Hydroxypropyl methylcellulose E50 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Mannitol 50C Roquette Freres Pregelatinized starch SH-DP Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Microcrystalline Cellulose SH-101 Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Croscarmellose Sodium Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Crospovidone XL ISP Chemicals LLC Aspartic acid Nanning Evonik Meishi Pharmaceutical Co., Ltd. Saccharin Sodium Hunan Warner Pharmaceutical Chiral Drug Co., Ltd. Yellow Iron Oxide 1651 Ningbo Yipin Biotechnology Co., Ltd. Red Iron Oxide 3651 Ningbo Yipin Biotechnology Co., Ltd. Magnesium Stearate SH-YM-M Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0036] The formulations of edoxaban tosylate orodisintegrating tablets provided in Examples 1 to 3 are shown in Table 2 (“-” indicates that the substance is not contained).

[0037] Table 2

[0038]

[0039] Preparation method:

[0040] 1) Preparation of drug-containing granules:

[0041] Dissolve the prescribed amount of hypromellose in purified water to prepare an aqueous solution with a concentration of about 2%.

[0042] Add the prescribed amount of edoxaban tosylate, mannitol, microcrystalline cellulose, croscarmellose sodium, crospovidone and aspartic acid into the wet granulation pot, start stirring and chopping, mix, and after mixing evenly, spray the aqueous solution of hypromellose to granulate. After granulation, the particles are dried and granulated to obtain drug-containing particles.

[0043] 2) Preparation of orally disintegrating tablets:

[0044] The drug-containing granules are weighed, and the prescribed amount of additional excipients, such as crospovidone, sodium saccharin, red iron oxide or yellow iron oxide, and magnesium stearate, are added and mixed, and then tablets are pressed according to the tablet weight to prepare edoxaban orodisintegrating tablets of corresponding specifications.

[0045] Example 4

[0046] Compared with Example 2, the only difference is that mannitol is used at 159.44 mg / tablet and hypromellose E15 is used at 1 mg / tablet, and the rest are the same.

[0047] Example 5

[0048] Compared with Example 2, the only difference is that the same weight of hypromellose E3 is used instead of hypromellose E15, and the rest is the same.

[0049] Example 6

[0050] Compared with Example 2, the only difference is that the same weight of hypromellose E50 is used instead of hypromellose E15, and the rest is the same.

[0051] Comparative Example 1 and Comparative Example 2 are commercially available edoxaban tosylate orodisintegrating tablets of 30 mg and 60 mg, respectively, with trade names: Manufacturer: Daiichi Sankyo Pharmaceutical Co., Ltd.

[0052] Comparative Example 3

[0053] Compared with Example 2, the only difference is that 148.04 mg / tablet of mannitol is used and 10.8 mg / tablet of pregelatinized starch is added to the disintegrant 1, and the rest are the same.

[0054] Comparative Example 4

[0055] Compared with Example 2, the only difference is that 158.24 mg / tablet of mannitol is used instead, and 2.2 mg / tablet of hypromellose E15 is used instead, and the rest are the same.

[0056] Comparative Example 5

[0057] Compared with Example 2, the only difference is that 162.84 mg / tablet of mannitol is used instead, and 4 mg / tablet of aspartic acid is used instead, and the rest are the same.

[0058] Comparative Example 6

[0059] Compared with Example 2, the only difference is that the same mass of pregelatinized starch is used instead of cross-linked sodium carboxymethyl cellulose, and the rest is the same.

[0060] Effect evaluation

[0061] 1. Tablet dissolution curve

[0062] The second method of 0931 of the fourth general rule of the "Chinese Pharmacopoeia" 2020 edition was adopted to investigate the dissolution of the examples and comparative examples in media of pH 4.5, 6.0, and 6.8, respectively.

[0063] The specific method is: rotation speed 50rpm, medium 900mL. Medium preparation method: pH4.5 phosphate buffer: weigh 6.81g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000mL, shake well, and obtain; pH6.0 phosphate buffer: weigh 4.19g of anhydrous disodium hydrogen phosphate, 2.15g of citric acid monohydrate, dissolve in degassed water and dilute to 1000mL, shake well, and obtain; pH6.8 phosphate buffer: weigh 6.80g of potassium dihydrogen phosphate, 0.90g of sodium hydroxide, dissolve in water and dilute to 1000mL, shake well, and obtain.

[0064] The dissolution of the orally disintegrating tablets of each example and comparative example was tested at 5, 10, 15, 30 and 45 minutes respectively. The dissolution test data of the 30 mg edoxaban tablets are shown in Table 3, and the dissolution test data of the 60 mg edoxaban tablets are shown in Table 4.

[0065] Table 3

[0066]

[0067] Table 4

[0068]

[0069]

[0070] The dissolution curves of Example 2-Example 6 and Comparative Example 2-Comparative Example 6 are as follows: Figure 1 , Figure 2 , Figure 3 shown.

[0071] According to the above experimental results, the orodisintegrating tablets of edoxaban tosylate prepared by the present invention show better dissolution characteristics than commercially available preparations at different pH values. At pH 6.8, the orodisintegrating tablets of the present invention have a dissolution rate of more than 40% in 5 minutes and more than 70% in 30 minutes. The tablets dissolve quickly and no gelation occurs. When pregelatinized starch is added as a disintegrant to the drug-containing granules, or the dosage ratio of hydroxypropyl methylcellulose and aspartic acid in the drug-containing granules is adjusted to 1:8, 1.1:4, 1:2.5, or the types of disintegrants and binders are changed, the tablet dissolution rate decreases.

[0072] 2. Investigation of stability data of tablet related substances

[0073] The stability of the related substances of the orally disintegrating tablets of the examples and comparative examples was investigated respectively, and the high performance liquid chromatography method 0512 of the general rules of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia was used for determination. The specific detection scheme is as follows:

[0074] Solvent: water-acetonitrile (50:50).

[0075] Test solution: Take 4 tablets (30 mg) or 5 tablets (60 mg) of this product and place them in a 100 mL (30 mg) or 250 mL (60 mg) volumetric flask. Add an appropriate amount of solvent and sonicate for about 15 minutes to dissolve edoxaban. Cool, dilute to the scale with solvent, shake well, centrifuge, filter, and take the filtrate.

[0076] Reference solution: Take an appropriate amount of Edoxaban Tosylate Reference, weigh accurately, dissolve in solvent and quantitatively release to prepare a solution containing approximately 2.4 μg of Edoxaban per 1 mL.

[0077] Chromatographic conditions: octadecyl bonded silica gel was used as the filler (Welch Ultimate-XB-C18 4.6 mm × 250 mm, 5 μm); ammonium acetate buffer (1.54 g of ammonium acetate was dissolved in water and diluted to 1000 mL, and the pH value was adjusted to 4.5 with acetic acid) was used as the mobile phase A, acetonitrile was used as the mobile phase B, and the flow rate was 1.0 mL per minute; the column temperature was 40°C; the wavelength was 290 nm; the injection volume was 10 μL; the injector temperature was 8°C, and the gradient elution method was shown in Table 5.

[0078] Table 5

[0079] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 5 88 12 19 80 20 45 80 20 50 30 70 55 30 70 56 100 0 65 100 0

[0080] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0081] Calculation: The content of each impurity was calculated using the edoxaban peak area according to the external standard method. The test results are shown in Table 6 below.

[0082] Table 6

[0083]

[0084]

[0085]

[0086] According to the data in the above table, after 6 months of accelerated treatment, the maximum single impurity and total impurity contents of the commercially available edoxaban tosylate orodisintegrating tablets increased significantly, with a large increase in impurities, while the impurity contents of the orodisintegrating tablets prepared in Examples 1 and 2 remained basically unchanged, indicating that the preparation of the present invention has better stability.

[0087] 3. Evaluation of tablet taste

[0088] Ten volunteers were recruited to evaluate the taste and mouthfeel of the edoxaban tosylate orodisintegrating tablets (stored for 0 days and accelerated stored for 6 months) prepared in each example and comparative example. The results are shown in Table 7.

[0089] Table 7

[0090]

[0091] 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. An edoxaban tosylate orodisintegrating tablet, characterized in that: The edoxaban tosylate orodisintegrating tablets are composed of granules and external excipients; The granules include the following ingredients: edoxaban tosylate, a filler, a disintegrant 1, a binder and a solubilizer, wherein the disintegrant 1 is a mixture of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose, and the binder is hypromellose; The external auxiliary materials include the following ingredients: disintegrant 2, flavoring agent, colorant and lubricant, wherein the disintegrant 2 is cross-linked polyvinylpyrrolidone.

2. The edoxaban tosylate orodisintegrating tablet according to claim 1, characterized in that: The filler is at least one of mannitol and microcrystalline cellulose, and the solubilizer is at least one of aspartic acid and glutamic acid.

3. The edoxaban tosylate orodisintegrating tablet according to claim 1, characterized in that: The flavoring agent is selected from at least one of saccharin sodium, sucrose, fruit flavor, aromatic syrup, aspartame, sucralose, and acesulfame potassium; the coloring agent is selected from at least one of red iron oxide, yellow iron oxide, titanium dioxide, carmine, sunset yellow, turmeric, and theaflavins; the lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, colloidal silicon dioxide, and hydrogenated vegetable oil.

4. The orodisintegrating tablet of edoxaban tosylate according to claim 2 or claim 3, characterized in that The filler is a mixture of mannitol and microcrystalline cellulose, the solubilizer is aspartic acid, the flavoring agent is saccharin sodium, the colorant is yellow iron oxide, and the lubricant is magnesium stearate.

5. The edoxaban tosylate orodisintegrating tablet according to claim 1, characterized in that: The binder is selected from at least one of hypromellose E15, hypromellose E3 and hypromellose E50.

6. The orodisintegrating tablet of edoxaban tosylate according to claim 1, characterized in that The weight ratio of the edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is 80.8:210.34-214.94:33.63:1-1.6:8-12:9.27:4.8:0.36:7.

2.

7. The edoxaban tosylate orodisintegrating tablet according to claim 6, characterized in that: The weight ratio of the edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is: 80.8: 210.34-214.34: 33.63: 1.6: 8-12: 9.27: 4.8: 0.36: 7.

2.

8. The edoxaban tosylate orodisintegrating tablet according to claim 7, characterized in that: The weight ratio of the edoxaban tosylate, filler, disintegrant 1, binder, solubilizer, disintegrant 2, flavoring agent, colorant and lubricant is: 80.8:214.34:33.63:1.6:8:9.27:4.8:0.36:7.

2.

9. The edoxaban tosylate orodisintegrating tablet according to claim 1, characterized in that: The disintegrant 1 is a mixture of mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is 154.84-159.44:55.

5.

10. The method for preparing the edoxaban tosylate orodisintegrating tablets according to any one of claims 1 to 9, characterized in that: The following steps are involved: S1, edoxaban tosylate, filler, disintegrant 1, solubilizer, binder and water are mixed, wet granulated, dried, and granulated to obtain granules; S2. Mix the granules obtained in step S1 with disintegrant 2, a flavoring agent, a colorant and a lubricant, and compress the mixture into tablets to obtain edoxaban tosylate orodisintegrating tablets.

Images