An edoxaban tosylate orally disintegrating tablet and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a edoxaban tosylate oral disintegration tablet and a preparation method thereof. The edoxaban tosylate oral disintegration tablet is composed of granules and external auxiliary materials; the granules comprise the following components: edoxaban tosylate, a filler, a disintegrant 1, a binder and a solubilizer, wherein the disintegrant 1 is a mixture of crosslinked povidone and crosslinked sodium carboxymethyl cellulose, and the binder is hydroxypropyl methyl cellulose; the external auxiliary materials comprise the following components: a disintegrant 2, a flavoring agent, a coloring agent and a lubricant, wherein the disintegrant 2 is crosslinked povidone. The binder, the disintegrant and aspartic acid in a specific combination are used to realize the rapid drug release effect in cooperation, the blank rapid granules do not need to be prepared, the preparation process is simpler, and the edoxaban tosylate oral disintegration tablet has the characteristics of good taste.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an orally disintegrating tablet of edoxaban tosylate and its preparation method. Background Technology

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

[0003]

[0004] Chinese invention patent CN102791271A discloses an edoxaban ordinary tablet composition. However, in the granulation step of preparing this tablet, the maximum moisture content of the particles needs to be kept below 10%, otherwise the granulation effect will be affected. The granulation technology has high requirements, and ordinary tablets have a slow onset of action, which is not conducive to the use of patients with dysphagia and has poor compliance.

[0005] Chinese invention patent CN109996542A discloses an orally disintegrating tablet of edoxaban tosylate. However, in addition to preparing drug-containing granules using a fluidized bed, this orally disintegrating tablet also requires the preparation of blank rapidly disintegrating granules, which is complex and requires high-quality equipment.

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

[0007] The purpose of this invention is to provide an orally disintegrating tablet of edoxaban tosylate and its preparation method. The orally disintegrating tablet has a good taste, no gritty feeling, can disintegrate rapidly in the oral cavity, dissolves quickly, has stable physicochemical properties, and has a simple preparation process and low production cost.

[0008] To achieve the above objectives, on the one hand, the present invention provides an orally disintegrating tablet of edoxaban tosylate, wherein the orally disintegrating tablet of edoxaban tosylate is composed of granules and external excipients;

[0009] The particles comprise the following components: edoxaban tosylate, filler, disintegrant 1, binder, and solubilizer, wherein the disintegrant 1 is a mixture of crospovidone and crospovidone sodium carboxymethyl cellulose, and the binder is hydroxypropyl methylcellulose;

[0010] The external excipients include the following components: disintegrant 2, flavoring agent, coloring agent and lubricant, wherein the disintegrant 2 is crospovidone.

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

[0012] Preferably, the flavoring agent is selected from at least one of sodium saccharin, sucrose, fruit flavoring, 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; and the lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium stearate fumarate, talc, colloidal silica, 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 colorant is yellow iron oxide, and the lubricant is magnesium stearate.

[0014] Preferably, the adhesive is selected from at least one of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E3, and hydroxypropyl methylcellulose E50.

[0015] More preferably, the adhesive is selected from at least one of hydroxypropyl methylcellulose E15 and hydroxypropyl methylcellulose E3.

[0016] Preferably, the weight ratio of the toluenesulfonic acid edoxaban, 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 the toluenesulfonic acid edoxaban, 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 the toluenesulfonic acid edoxaban, 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, wherein the weight ratio of mannitol to microcrystalline cellulose is 154.84-159.44:55.5.

[0020] On the other hand, the present invention provides a method for preparing the above-mentioned edoxaban tosylate orally disintegrating tablets, comprising the following steps:

[0021] S1, edoxaban toluenesulfonate, 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, flavoring agent, coloring agent and lubricant, compress into tablets to obtain edoxaban tosylate orally disintegrating tablets.

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

[0024] The edoxaban tosylate orally disintegrating tablets of the present invention utilize specific types of binders, disintegrants, and solubilizers in the granule portion, resulting in a synergistic effect of enhanced disintegration. There is no need to prepare blank rapidly disintegrating granules or control the moisture content of the granules. Orally disintegrating tablets with a certain hardness and capable of rapid disintegration within 60 seconds can be obtained by using ordinary shear granulation. The preparation process is simpler, the production efficiency is higher, and the cost is lower. Attached Figure Description

[0025] Figure 1 The cumulative dissolution rate-time curves are for Examples 2, 3, 5 and Comparative Example 2.

[0026] Figure 2 The cumulative dissolution rate-time curves are for Comparative Example 2, Comparative Example 3, Example 4 and Comparative Example 4.

[0027] Figure 3 The cumulative dissolution rate-time curves are for Comparative Examples 5, 6, 6 and 2. Detailed Implementation

[0028] Terminology and Declarations of this Invention:

[0029] 1. Articles “a,” “a kind,” and “the”: These include plural objects unless otherwise explicitly specified as a single (kind) object.

[0030] 2. Numerical Range: Unless otherwise expressly stated, all ranges or ratios disclosed herein shall be construed as including any and all subranges or subratios contained herein. For example, a stated range or ratio of 1 to 30 shall be considered to be included between the minimum value of 1 and the maximum value of 30, and includes any subranges or subratios, integers, decimals, or subranges or subratios consisting of integers or decimals, including endpoints.

[0031] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0032] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention were obtained through conventional commercial means. Unless otherwise specified, all contents mentioned below are mass contents. Unless otherwise specified, it is understood that the process was carried out at room temperature.

[0033] Information on some of the chemicals used in the embodiments and comparative examples of this invention is shown in Table 1:

[0034] Table 1

[0035] 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. Sodium croscarmellose Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Cross-linked polyvinylpyrrolidone XL ISP Chemicals LLC Aspartic acid Nanning Wintech Pharmaceutical Co., Ltd. Sodium saccharin Hunan Huana Pharmaceutical Chiral Drugs 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 the orally disintegrating toluene edoxaban provided in Examples 1-3 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 hydroxypropyl methylcellulose in purified water to prepare an aqueous solution with a concentration of approximately 2%.

[0042] Add the prescribed amounts of edoxaban toluenesulfonic acid, mannitol, microcrystalline cellulose, croscarmellose sodium, croscarmellose and aspartic acid to a wet granulation pot, start stirring and chopping to mix, and after mixing evenly, spray in an aqueous solution of hydroxypropyl methylcellulose to granulate. After granulation, the granules are dried and sized to obtain drug-containing granules.

[0043] 2) Preparation of orally disintegrating tablets:

[0044] Weigh the granules containing the drug, add the prescribed amount of excipients crospovidone, sodium saccharin, red or yellow iron oxide, and magnesium stearate, and mix them. Then compress the mixture according to the tablet weight to prepare the corresponding specification of edoxaban orally disintegrating tablets.

[0045] Example 4

[0046] Compared with Example 2, the only difference is that mannitol is replaced with 159.44 mg / tablet and hydroxypropyl methylcellulose E15 is replaced with 1 mg / tablet; all other doses are the same.

[0047] Example 5

[0048] Compared with Example 2, the only difference is that hydroxypropyl methylcellulose E15 is replaced with an equal weight of hydroxypropyl methylcellulose E3, and everything else is the same.

[0049] Example 6

[0050] Compared with Example 2, the only difference is that hydroxypropyl methylcellulose E15 is replaced with an equal weight of hydroxypropyl methylcellulose E50, and everything else is the same.

[0051] Comparative Examples 1 and 2 were commercially available edoxabantoin orally disintegrating tablets in 30mg and 60mg strengths, respectively. Manufacturer: Daiichi Sankyo Pharmaceutical Co., Ltd., Japan.

[0052] Comparative Example 3

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

[0054] Comparative Example 4

[0055] Compared with Example 2, the only difference is that mannitol is replaced with 158.24 mg / tablet and hydroxypropyl methylcellulose E15 is replaced with 2.2 mg / tablet, all other doses are the same.

[0056] Comparative Example 5

[0057] Compared with Example 2, the only difference is that mannitol is replaced with 162.84 mg / tablet and aspartic acid is replaced with 4 mg / tablet, all other doses are the same.

[0058] Comparative Example 6

[0059] Compared with Example 2, the only difference is that cross-linked sodium carboxymethyl cellulose is replaced with an equal mass of pregelatinized starch; all other aspects are the same.

[0060] Effect evaluation

[0061] 1. Tablet dissolution profile

[0062] The dissolution of the formulations in the examples and comparative examples in media at pH 4.5, 6.0, and 6.8 was investigated using Method II of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0063] The specific methods are as follows: rotation speed 50 rpm, medium 900 mL. Medium preparation methods: pH 4.5 phosphate buffer: weigh 6.81 g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000 mL, shake well; pH 6.0 phosphate buffer: weigh 4.19 g of anhydrous disodium hydrogen phosphate and 2.15 g of citric acid monohydrate, dissolve in degassed water and dilute to 1000 mL, shake well; pH 6.8 phosphate buffer: weigh 6.80 g of potassium dihydrogen phosphate and 0.90 g of sodium hydroxide, dissolve in water and dilute to 1000 mL, shake well.

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

[0065] Table 3

[0066]

[0067] Table 4

[0068]

[0069]

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

[0071] Based on the above experimental results, it can be seen that the orally disintegrating tablets of edoxaban tosylate prepared in this invention exhibit superior dissolution characteristics compared to commercially available formulations at different pH levels. At pH 6.8, the dissolution rate of the orally disintegrating tablets of this invention reaches over 40% in 5 minutes and over 70% in 30 minutes, demonstrating rapid tablet dissolution without gelation. When pregelatinized starch is added as a disintegrant to the drug-containing granules, or when the ratio of hydroxypropyl methylcellulose and aspartic acid in the drug-containing granules is adjusted to 1:8, 1.1:4, or 1:2.5, or when the type of disintegrant or binder is changed, the tablet dissolution rate decreases.

[0072] 2. Analysis of related substance stability data for tablets

[0073] The stability of related substances in the orally disintegrating tablets of the examples and comparative examples was investigated separately. The stability was determined by high-performance liquid chromatography (HPLC) according to General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. The specific detection scheme is as follows:

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

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

[0076] Reference solution: Weigh an appropriate amount of edoxaban tosylate reference standard accurately, dissolve it in a solvent and quantitatively release it to prepare a solution containing approximately 2.4 μg of edoxaban per 1 mL.

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

[0078] Table 5

[0079] 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] Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0081] Calculation: The content of each impurity was calculated based on the peak area of ​​the Idoxaban using 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 table above, after 6 months of acceleration, the maximum single impurity and total impurity content of commercially available edoxaban tosylate orally disintegrating tablets increased significantly, and the impurity growth was large. In contrast, the impurity content of the orally disintegrating tablets prepared in Examples 1 and 2 remained basically unchanged, indicating that the formulation of the present invention has better stability.

[0087] 3. Evaluation of tablet taste and texture

[0088] Ten volunteers were recruited to evaluate the taste and mouthfeel of the edoxaban tosylate orally disintegrating tablets prepared in each example and comparative example (stored for 0 days and accelerated storage for 6 months). 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, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An orally disintegrating tablet of edoxaban tosylate, characterized in that, The orally disintegrating tablets of edoxaban tosylate consist of granules and external excipients. The particles are composed of the following components: edoxaban tosylate, filler, disintegrant 1, binder and solubilizer, wherein the filler is a mixture of mannitol and microcrystalline cellulose, the weight ratio of mannitol to microcrystalline cellulose is 154.84-159.44:55.5, the disintegrant 1 is a mixture of crospovidone and crospovidone sodium carboxymethyl cellulose, the binder is hydroxypropyl methylcellulose, and the solubilizer is aspartic acid; The external excipients consist of the following components: disintegrant 2, flavoring agent, coloring agent and lubricant, wherein the disintegrant 2 is crospovidone; The weight ratio of the toluenesulfonic acid edoxaban, 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. The preparation method of the aforementioned edoxaban tosylate orally disintegrating tablets includes the following steps: S1, edoxaban toluenesulfonate, 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, flavoring agent, coloring agent and lubricant, compress into tablets to obtain edoxaban tosylate orally disintegrating tablets.

2. The orally disintegrating tablets of edoxaban tosylate according to claim 1, characterized in that, The flavoring agent is selected from at least one of sodium saccharin, sucrose, fruit flavoring, 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 stearate fumarate, talc, colloidal silica, and hydrogenated vegetable oil.

3. The orally disintegrating tablets of edoxaban tosylate according to claim 1, characterized in that, The flavoring agent is sodium saccharin, the coloring agent is yellow iron oxide, and the lubricant is magnesium stearate.

4. The orally disintegrating tablets of edoxaban tosylate according to claim 1, characterized in that, The adhesive is selected from at least one of hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E3, and hydroxypropyl methylcellulose E50.

5. The orally disintegrating tablets of edoxaban tosylate according to claim 1, characterized in that, The weight ratio of the toluenesulfonic acid edoxaban, 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.

6. The orally disintegrating tablets of edoxaban tosylate according to claim 5, characterized in that, The weight ratio of the toluenesulfonic acid edoxaban, 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.

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