An idoxaban solid pharmaceutical composition and a preparation method thereof

Abstract

The present application relates to a kind of idoxaban solid pharmaceutical compositions and its preparation method, provide a kind of idoxaban solid pharmaceutical compositions, it has simple process step, good compressibility, more optimal stability and less related substances, and the dissolution curve is consistent with the dissolution curve of commercially available pharmaceutical composition.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical compositions, and more specifically, to an edoxaban solid pharmaceutical composition containing a polyvinyl alcohol-polyethylene glycol copolymer and a method for preparing the same. Background Technology

[0002] The chemical name of edoxaban tosylate monohydrate is: N-(5-chloro-2-pyridinyl)-N'-[(1S,2R,4S)-4-[(dimethylamino)formyl]-2-[[4,5,6,7-tetrahydro-5-methylthiazo[5,4-C]pyridin-2-yl)formyl]amino]cyclohexyl]glyoxamide p-tosylate monohydrate. It is a selective inhibitor of coagulation factor Xa, reducing thrombin generation and thrombus formation. Its structural formula is as follows:

[0003]

[0004] Edoxaban tosylate shows good solubility in strongly acidic aqueous solutions, but its solubility decreases in neutral aqueous solutions (neutral buffer solutions, etc.), leading to a decline in clinical efficacy.

[0005] CN104324015B improves the dissolution of edoxaban tablets by coating them with one or more coating agents selected from hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose and polyvinyl alcohol. However, the tablets prepared by this coating agent have more impurities and poor stability.

[0006] CN108743556A also discloses an edoxaban tablet using Opadryl coating powder as the coating agent. However, the formulation of this patent is relatively complex, and the process steps are also relatively cumbersome. In particular, edoxaban is sprayed onto the filler in a dissolved form. On the one hand, edoxaban undergoes a dissolution and recrystallization process, which carries the risk of crystal form transformation. On the other hand, adding it in the form of a slurry makes it impossible to accurately control the final content in the tablet. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an edoxaban solid pharmaceutical composition, which features simple processing steps, good compressibility, superior stability, and fewer related substances. Furthermore, its dissolution profile is similar to that of commercially available pharmaceutical compositions. The dissolution curves are consistent.

[0008] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0009] On one hand, the present invention provides an edoxaban solid pharmaceutical composition comprising edoxaban, a filler, a disintegrant, a binder, a lubricant, and a coating agent, wherein the coating agent comprises... The adhesive is hydroxypropyl cellulose.

[0010] In some implementations, the edoxaban is edoxaban tosylate monohydrate.

[0011] In some embodiments, the solid pharmaceutical composition contains, by weight, 75-85 parts of edoxaban tosylate monohydrate, 200-300 parts of filler, 20-25 parts of disintegrant, 10-25 parts of binder, 2.5-5 parts of lubricant, and 10-25 parts of coating agent.

[0012] In some embodiments, the solid pharmaceutical composition contains 12-22 parts by weight of a coating agent.

[0013] In some embodiments, the solid pharmaceutical composition contains 14-20 parts by weight of a coating agent.

[0014] In some embodiments, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, or combinations thereof.

[0015] In some embodiments, the filler is mannitol and pregelatinized starch.

[0016] In some embodiments, the filler contains 150-200 parts by weight of mannitol and 50-100 parts by weight of pregelatinized starch.

[0017] In some embodiments, the disintegrant is selected from crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, or combinations thereof.

[0018] In some embodiments, the disintegrant is crospovidone.

[0019] In some embodiments, the lubricant is selected from magnesium stearate, calcium stearate, or combinations thereof.

[0020] In some implementations, the lubricant is magnesium stearate.

[0021] In some embodiments, the coating agent contains titanium dioxide, talc, ferric oxide, and Kollicoat.

[0022] In some embodiments, the coating agent contains, by weight, 5-20 parts titanium dioxide, 10-25 parts talc, and 1-15 parts yellow iron oxide. 50-100 servings.

[0023] In some embodiments, the coating agent contains, by weight, 10-15 parts titanium dioxide, 15-20 parts talc, 5-10 parts yellow iron oxide, and Kollicoat. 60-70 servings.

[0024] In some embodiments, the edoxaban solid pharmaceutical composition is in the form of tablets.

[0025] On the other hand, the present invention provides a method for preparing an edoxaban solid pharmaceutical composition, comprising the following steps: dissolving a binder in water to obtain a slurry; mixing edoxaban with a filler and a disintegrant according to the prescribed amount, adding the slurry and granulating in a fluidized bed, drying, sizing, adding a lubricant and mixing, compressing to obtain a tablet core, and coating to obtain the final product.

[0026] In some embodiments, the preparation method includes the following steps: dissolving hydroxypropyl cellulose in water to obtain a slurry; mixing edoxaban tosylate monohydrate with mannitol, pregelatinized starch and cross-linked povidone according to the prescribed amount, adding the slurry, granulating in a fluidized bed, drying, sizing, adding magnesium stearate and mixing, compressing to obtain a tablet core, and coating to obtain the final product.

[0027] In some implementations, the core has a hardness of 10-20 kg.

[0028] In some implementations, the core has a hardness of 10-15 kg.

[0029] Beneficial effects: The edoxaban solid pharmaceutical composition provided by this invention has better compressibility, produces fewer impurities, and has better stability. Furthermore, its dissolution profile is similar to that of commercially available pharmaceutical compositions. The dissolution curves are consistent.

[0030] Unless otherwise defined in this invention, the scientific and technical terms associated with this invention shall have the meanings understood by one of ordinary skill in the art. Attached Figure Description

[0031] Figure 1 The figure shown is the dissolution curve of Example 1.

[0032] Figure 2 The figure shown is the dissolution curve of Example 2.

[0033] Figure 3 The figure shown is the dissolution curve of Example 3. Detailed Implementation

[0034] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer with the description. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0035] The embodiments of the present invention are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0036] Example 1: Investigation of Core Hardness

[0037] Hydroxypropyl cellulose was dissolved in water to prepare a homogeneous slurry. According to the prescribed dosage, edoxaban tosylate monohydrate was mixed evenly with mannitol, pregelatinized starch, and crospovidone. This mixture was then added to the slurry and granulated in a fluidized bed. After drying and sizing, magnesium stearate was added and mixed. The mixture was then compressed into tablets. The tablet cores were tested for hardness using a hardness tester, yielding cores with hardnesses of 6 kg, 11 kg, and 14 kg, respectively (Core 1, Core 2, and Core 3). The formulation composition is shown in Table 1.

[0038] Table 1

[0039]

[0040] For dissolution curve comparison, this product was used. Dissolution and release assay (Chinese Pharmacopoeia 2015 Edition, General Chapter 0931, Method II) was performed using 900 ml of pH 6.6 phosphate buffer as the dissolution medium and a rotation speed of 50 rpm. Samples were taken at 10, 15, 20, 30, 45, and 60 minutes for testing, and the cumulative dissolution rate was calculated. Dissolution data are shown in Table 2.

[0041] Chromatographic conditions: Octadecylsilane-bonded silica gel or a column of equivalent performance was used as the packing material; phosphate buffer / acetonitrile was used as the mobile phase; the column temperature was 40℃; the detection wavelength was 290nm; and the injection volume was 10μL. The dissolution amount was calculated based on peak area using the external standard method. The results are shown in Table 2, and the dissolution curve is shown in [Figure 1]. Figure 1 Since Tween was added to solubilize the solution after sampling at 45 min during the dissolution process, the dissolution data at 60 min are not included in the calculation of the similarity factor f2.

[0042] Table 2

[0043] Chip 1 71.4 78.9 81.1 84.3 90.1 93.3 Chip 2 70.0 75.3 79.7 84.6 89.4 90.8 Chip 3 66.6 72.8 77.8 82.8 88.5 93.0

[0044] As shown in Table 2, there is no significant difference in the dissolution rate of tablets with different hardnesses under the conditions of the present invention.

[0045] Example 2: Investigation of the coating agent

[0046] Using the preparation method of Example 1, tablet cores were obtained by controlling the hardness range to 10-15 kg during tablet compression. These cores were then coated, the difference being that a self-developed coating agent and a Kollicoat coating agent were used respectively. 03F42132 (i.e., the coating agent with hydroxypropyl methylcellulose as the main component as described in CN104324015B); coating was performed to obtain Formula 1, Formula 2 and Formula 3. The composition of the formulas is shown in Table 3, and the composition of the self-developed coating agent is shown in Table 4.

[0047] Table 3

[0048]

[0049] The preparation method of the self-developed coating agent is as follows: Titanium dioxide, talc, yellow iron oxide, and... (The text abruptly ends here, so the translation stops as well.) The mixture was then stirred to obtain a uniform yellow solid powder.

[0050] Table 4

[0051]

[0052] The dissolution profiles of Formulation 1, Formulation 2, and the reference formulation in pH 6.6 phosphate buffer were detected using the same method as in Example 1. The results are shown in Table 5. Figure 2 .

[0053] Among them, the reference formulation, edoxaban tosylate tablets It is sourced from Daiichi Sankyo Co., Ltd. of Japan, with a specification of 60mg. The two batches are Reference Preparation I and Reference Preparation II, respectively.

[0054] Table 5

[0055] Prescription 1 62.0 75.7 81.6 87.3 91.4 97.9 80 Prescription 2 56.9 73.5 79.6 85.8 89.5 95.3 76 Reference preparation II 58.2 75.7 83.1 89.5 93.6 99.4 /

[0056] The results showed that the dissolution rate of the tablets coated with Formula 2 was slower than that of Formula 1, and the dissolution data of Formula 1 was closer to that of the original drug.

[0057] Example 3: Investigation of Weight Gain from Coating

[0058] The preparation method of Formula 1 was used to obtain tablet cores after compression. The effect of different coating weight gain of the self-developed coating powder on dissolution was investigated. The average tablet weight of 100 preheated tablet cores was calculated as the initial tablet weight. Coating was stopped when the amount of coating solution reached the theoretical weight gain of 3.5% and 5.0%. Formulas 4 and 5 were obtained, as shown in Table 6.

[0059] Table 6

[0060]

[0061] Using the same method as in Example 1, the dissolution profiles of each formulation and the reference formulation in pH 6.6 phosphate buffer were determined. The results are shown in Table 7 and... Figure 3 .

[0062] Table 7

[0063] Prescription 4 64.8 72.8 76.7 82.2 86.5 96.5 74 Prescription 5 62.2 70.2 75.5 81.2 86.8 88.4 79 Reference preparation I 61.5 71.2 73.2 78.5 82.9 85.9 /

[0064] The results showed that qualified edoxaban tosylate tablets could be obtained with a coating agent dosage in the range of 10-25 mg, preferably 12-22 mg, and more preferably 14-20 mg, and the dissolution behavior was similar to that of the original formulation.

[0065] Example 4: Detection of related substances

[0066] Related substances were determined for prescriptions 1 and 3.

[0067] The determination of related substances was performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512).

[0068] Take appropriate amounts of the coated tablets of Formula 1 and Formula 3 respectively, weigh them accurately, add an appropriate amount of solvent to dissolve them, and dilute quantitatively to prepare a solution containing approximately 1.2 mg of edoxaban per ml, which is used as the test solution.

[0069] Accurately measure 1 ml of the reference solution and place it in a 200 ml volumetric flask. Dilute to the mark with solvent and shake well.

[0070] For system suitability solution, take appropriate amounts of edoxaban tosylate reference standard and impurity I reference standard, dissolve them in solvent and quantitatively dilute to prepare a solution containing approximately 1.2 mg of edoxaban and 2.4 μg of impurity I per ml, which is used as the positioning solution.

[0071] Chromatographic conditions: Octadecylsilane-bonded silica gel or equivalent column; phosphate buffer-acetonitrile as mobile phase; detection wavelength of 290 nm; column temperature of 40 °C; sample chamber temperature of 10 °C; injection volume of 10 μL.

[0072] Upon testing, impurity I with the following structure was detected in prescription 3 at a content of 0.05%, while it was not detected in prescription 1; no other impurities were detected in either prescription 1 or prescription 3.

[0073] Impurity I is 2-{[(1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamyl)-5-(dimethylcarbamoyl)cyclohexyl]carbamoyl}-5-methyl-4,5,6,7-tetrahydro[1,3]thiazo[5,4-c]pyridine-5-oxide, with the following structural formula:

[0074]

[0075] It is evident that the self-developed coating agent of this invention has fewer impurities.

[0076] Example 5

[0077] Formula 1 was prepared in two batches, designated Batch 1 and Batch 2. Stability was investigated under accelerated and long-term conditions, respectively. Dissolution was measured and compared with the reference formulation, edoxaban tosylate tablets. Reference formulation II was compared.

[0078] Dissolution testing was performed using this product according to the Dissolution and Release Test Method (Chinese Pharmacopoeia 2015 Edition, General Chapter 0931, Method II), with 900 ml of pH 6.0 phosphate buffer as the dissolution medium and a rotation speed of 50 rpm. The dissolution rate was measured after 30 minutes, and the limit was 75% of the labeled amount. The dissolution results are shown in Tables 8-9 below.

[0079] Table 8

[0080] Batch 1 89％ 89％ Batch 2 88％ 88％ Reference preparation II 91％ 82％

[0081] Table 9

[0082] Batch 1 89％ 87％ Batch 2 88％ 86％ Reference preparation II 91％ 85％

[0083] Dissolution results under accelerated and long-term testing conditions showed that, under accelerated conditions (40℃±2℃, RH75%±5%), the 3-month dissolution rate of the edoxaban tosylate pharmaceutical composition of the present invention was consistent with that at 0℃, but the dissolution rate of reference formulation II decreased from 91% to 82%. Under long-term conditions (25℃±2℃, RH60%±5%), the dissolution rate of the edoxaban tosylate pharmaceutical composition of the present invention decreased less, indicating that the edoxaban pharmaceutical composition of the present invention has better stability.

Claims

1. An edoxaban solid pharmaceutical composition comprising edoxaban, a filler, a disintegrant, a binder, a lubricant, and The coating agent is characterized in that, The binder is hydroxypropyl cellulose, the filler is mannitol and pregelatinized starch, the disintegrant is crospovidone, the lubricant is magnesium stearate, and the edoxaban is edoxaban tosylate monohydrate. By weight, the solid pharmaceutical composition contains 80.8 parts of edoxaban tosylate monohydrate, 198.4 parts of mannitol (filler), 84 parts of pregelatinized starch (filler), 21.4 parts of disintegrant, 12.2 parts of binder, 3.2 parts of lubricant, and 20 parts of coating agent. The coating agent consists of titanium dioxide, talc, ferric oxide, and Kollicoat IR. ® The coating agent, based on its total weight, comprises 12 parts titanium dioxide, 18 parts talc, 6 parts yellow iron oxide, and Kollicoat IR. ® 64 copies.

2. A pharmaceutical composition as claimed in claim 1, characterized in that, The edoxaban solid pharmaceutical composition is in the form of tablets.

3. A method for preparing the pharmaceutical composition as described in claim 1 or 2, characterized in that, Includes the following steps: Dissolve the binder in water to obtain a slurry; mix edoxaban with filler and disintegrant according to the prescription amount, add to the slurry, granulate in a fluidized bed, dry, granulate, add lubricant and mix, compress to obtain tablet core, and then coat.

4. A method for preparing the pharmaceutical composition as described in claim 3, characterized in that, The process includes the following steps: dissolving hydroxypropyl cellulose in water to obtain a slurry; mixing edoxaban tosylate monohydrate with mannitol, pregelatinized starch and cross-linked povidone according to the prescribed amount, adding the slurry, granulating in a fluidized bed, drying, sizing, adding magnesium stearate and mixing, compressing to obtain a tablet core, and coating to obtain the final product.

5. A method for preparing the pharmaceutical composition as described in claim 3 or 4, characterized in that, The hardness of the core is 10-20 kg.

6. A method for preparing the pharmaceutical composition as described in claim 5, characterized in that, The hardness of the core is 10-15 kg.

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