PAR-1 inhibitor enteric-coated preparation as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a PAR-1 inhibitor enteric-coated preparation as well as a preparation method and application thereof. The PAR-1 inhibitor is prepared into enteric-coated tablets or enteric-coated capsules by adding auxiliary materials and enteric-coated materials into a cyclodextrin inclusion compound, the cyclodextrin inclusion compound comprises a PAR-1 (Protein Activated Receptor 1) inhibitor, sodium sulfobutyl beta-cyclodextrin and a pH (Potential of Hydrogen) regulator. The auxiliary material comprises one or more of a filling agent, an adhesive, a disintegrating agent and a lubricating agent. And the adhesive is hydroxypropyl methyl cellulose E4M. According to the invention, a cyclodextrin inclusion technology is adopted, a pH regulator is added to improve the inclusion rate, the inclusion rate is combined with a suspending material hydroxypropyl methyl cellulose E4M, the cyclodextrin inclusion compound is solubilized, and the hydroxypropyl methyl cellulose E4M is beneficial for maintaining the supersaturated state of the raw material, so that the solubility of the raw material at an absorption part is improved to the maximum extent, and the bioavailability of the raw material is improved. The absorption is promoted; the bioavailability is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to enteric-coated formulations of PAR-1 inhibitors, their preparation methods, and applications. Background Technology

[0002] Thrombosis is a localized blood clot formed by abnormal blood aggregation. Based on its location, it can be divided into arterial thrombosis and venous thrombosis. Arterial thrombosis can lead to serious cardiovascular and cerebrovascular events such as myocardial infarction and stroke, while venous thrombosis can cause fatal pulmonary embolism. Currently, commonly used antithrombotic drugs in clinical practice mainly include three categories: anticoagulants, antiplatelet drugs, and thrombolytics. Among them, anticoagulants and antiplatelet drugs have relatively definite efficacy, but existing drugs still have significant limitations. In particular, traditional anticoagulants generally have drawbacks such as high bleeding risk, narrow therapeutic window, and the need for frequent monitoring, which severely limits their clinical application. Therefore, developing novel anticoagulants with higher safety, better efficacy, and convenient administration has become a current research focus.

[0003] Protease-activated receptor-1 (PAR-1) inhibitors hold significant potential for treating cardiovascular diseases. Patent CN117362279A discloses a PAR-1 inhibitor, its chiral synthesis method, and the preparation method and uses of its salt crystal form. The PAR-1 inhibitor is chemically named ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate. Due to its molecular structure, its solubility is strongly pH-dependent, and it is almost insoluble in the intestinal environment, resulting in low bioavailability and affecting therapeutic efficacy. Traditional preparation methods are insufficient to effectively improve its solubility. Therefore, providing a pharmaceutical enteric-coated formulation composition that can improve the solubility of PAR-1 inhibitors and its preparation method is of great significance. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide an enteric-coated formulation of a PAR-1 inhibitor, which significantly improves the solubility and bioavailability of the PAR-1 inhibitor through a cyclodextrin freeze-drying process and the addition of pH adjusters and suspending agents.

[0005] The present invention also provides a preparation method that is simple, easy to implement, and suitable for large-scale production.

[0006] The present invention also provides its application as a medicine for the prevention and / or treatment of thrombotic diseases.

[0007] The enteric-coated formulation of the PAR-1 inhibitor described in this invention has the chemical name of ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate, and its structural formula is shown in Formula I below:

[0008] Formula I; The PAR-1 inhibitor enteric-coated formulation is prepared as enteric-coated tablets or enteric-coated capsules by adding excipients and enteric materials to the PAR-1 inhibitor cyclodextrin inclusion complex. The PAR-1 inhibitor cyclodextrin inclusion complex is a mixture of PAR-1 inhibitor, sodium sulfobutyl betacyclodextrin, pH adjuster and water.

[0009] The mass ratio of the PAR-1 inhibitor to sodium sulfobutylbetacyclodextrin is 1:10~40, and the pH of the sodium sulfobutylbetacyclodextrin aqueous solution in the cyclodextrin inclusion complex is adjusted to 1.0~3.0 using a pH adjuster.

[0010] The pH adjuster is one or more of citric acid, gallic acid, sorbic acid, maleic acid, fumaric acid, succinic acid, and tartaric acid, with citric acid being preferred.

[0011] The excipients include one or more of fillers, binders, disintegrants, and lubricants.

[0012] The filler is one or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, and starch, preferably pregelatinized starch.

[0013] The adhesive is hydroxypropyl methylcellulose E4M, and the mass ratio of the PAR-1 inhibitor to the adhesive is 1:2~20.

[0014] The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose (L-HPC). Crospovidone is preferred.

[0015] The lubricant is selected from one or more of magnesium stearate, silicon dioxide, talc, and sodium stearate fumarate, preferably magnesium stearate.

[0016] Preferably, the raw materials for PAR-1 inhibitor enteric-coated capsules are: 5 parts PAR-1 inhibitor raw material, 150 parts sodium sulfobutyl betacyclodextrin, 10 parts citric acid, 42 parts pregelatinized starch, 50 parts hydroxypropyl methylcellulose E4M, and 3 parts magnesium stearate lubricant.

[0017] The method for preparing the enteric-coated formulation of the PAR-1 inhibitor of the present invention comprises the following steps: a) Weigh out sodium sulfobutyl betacyclodextrin, dissolve it in purified water, add pH adjuster to adjust pH, and prepare sodium sulfobutyl betacyclodextrin aqueous solution; b) Weigh the PAR-1 inhibitor and add it to the sodium sulfobutyl betacyclodextrin aqueous solution in step a), stir for more than 3 hours, pre-freeze at -80℃ for 12 hours, transfer to a freeze dryer, and after drying, pulverize and pass through a 40-mesh sieve to obtain the PAR-1 inhibitor cyclodextrin inclusion complex. c1) After the PAR-1 inhibitor cyclodextrin inclusion complex from step b) is mixed with excipients and compressed into tablets, enteric coating is performed using an enteric material that can be dissolved at pH 5.5 or higher to obtain PAR-1 inhibitor enteric tablets. or; c2) The PAR-1 inhibitor cyclodextrin inclusion complex from step b) is mixed with excipients and filled into enteric-coated gelatin empty capsules that can dissolve at pH 5.5 or higher to obtain PAR-1 inhibitor enteric-coated capsules.

[0018] The mass ratio of sodium sulfobutyl betacyclodextrin to water in step a) is 1:3~5.

[0019] The enteric material mentioned in step c1) is Euterich, preferably Euterich L30d-55.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The present invention optimizes the solubility of the active pharmaceutical ingredient. Due to the molecular structure characteristics of the active pharmaceutical ingredient, there is a problem of low solubility. The present invention improves the solubility of the active pharmaceutical ingredient by using cyclodextrin inclusion technology and adding sodium sulfobutyl betacyclodextrin and pH adjuster.

[0021] (2) This invention improves the bioavailability of the active pharmaceutical ingredient. Due to the molecular structure characteristics of the active pharmaceutical ingredient, there is a problem of low solubility. This invention innovatively combines cyclodextrin inclusion complex with hydroxypropyl methylcellulose E4M, a suspending agent. The cyclodextrin inclusion complex solubilizes the active pharmaceutical ingredient, while hydroxypropyl methylcellulose E4M helps maintain the supersaturated state of the active pharmaceutical ingredient, thereby maximizing the solubility of the active pharmaceutical ingredient at the absorption site and promoting absorption and improving bioavailability. Attached Figure Description

[0022] Figure 1 The dissolution curves are for Example 1 and Comparative Examples 1-3 in pH 6.8 medium. Figure 2 The dissolution curves for pH 6.8 media in Examples 2-5 are shown. Figure 3 The figures are dissolution curves in the pH 6.8 medium for Examples 6-9.

[0023] Figure 4 The figures are dissolution curves of the pH 6.8 medium in Examples 10-15.

[0024] Figure 5 The figures are dissolution curves of the pH 6.8 medium in Examples 16-19.

[0025] Figure 6 The figures are dissolution curves of the pH 6.8 medium in Examples 20-23. Detailed Implementation

[0026] The present invention will be further described below with reference to the embodiments.

[0027] Unless otherwise specified, all raw materials used in the examples were commercially available.

[0028] The active pharmaceutical ingredient (API) used in the examples and comparative examples was prepared using the method described in Example 1 of patent CN117362279A.

[0029] Example 1 and Comparative Examples 1-3 The mass ratio of the raw materials for the PAR-1 inhibitor enteric-coated formulation is shown in Table 1 below: Table 1. Mass ratio of raw materials for PAR-1 inhibitor enteric-coated formulations in Examples 1 and Comparative Examples 1-3

[0030] The method for preparing the enteric-coated formulation of the PAR-1 inhibitor includes the following steps: a) Weigh out citric acid and cyclodextrin, dissolve them in purified water, and prepare a cyclodextrin solution containing citric acid; the mass ratio of cyclodextrin to water is 1:4. b) Weigh the PAR-1 inhibitor and add it to the cyclodextrin solution in step a), stir for 3 hours, pre-freeze at -80℃ for 12 hours, transfer to a freeze dryer, and after drying, pulverize and pass through a 40-mesh sieve to obtain the PAR-1 inhibitor cyclodextrin inclusion complex. c2) The cyclodextrin inclusion complex from step b) is mixed with fillers, binders, and lubricants and filled into enteric-coated gelatin empty capsules that can dissolve at pH 5.5 or higher to obtain PAR-1 inhibitor enteric-coated capsules.

[0031] The test data for Example 1 and Comparative Examples 1-3 are shown in Table 2 below: Table 2 Test data for Example 1 and Comparative Examples 1-3

[0032] As the results showed, sodium sulfobutylbetacyclodextrin, as an inclusion complex carrier, significantly improved the bioavailability of the PAR-1 inhibitor in rats. Dissolution curves of Example 1 and Comparative Examples 1-3 in pH 6.8 medium are shown below. Figure 1 As shown.

[0033] Examples 2-5 The preparation method of the pharmaceutical composition is the same as in Example 1, except that: the amount of sodium sulfobutyl betacyclodextrin was investigated, the mass of API and other raw materials was expressed in parts by weight, and the mass ratio of raw materials for the PAR-1 inhibitor enteric-coated formulations in Examples 2-5 is shown in Table 3.

[0034] Table 3. Mass ratio of raw materials for PAR-1 inhibitor enteric-coated formulations in Examples 2-5

[0035] The test data for Examples 2-5 are shown in Table 4 below: Table 4 Test data for Examples 2-5

[0036] As the results show, when the mass ratio of PAR-1 inhibitor to sodium sulfobutylbetacyclodextrin is 1:10~40, the final dissolution rate of the sample is greater than 80%. At a ratio of 1:5, the dissolution rate is less than 50%, and at 1:60, the dissolution rate is consistent with that of 1:10~40. However, due to the large amount of sodium sulfobutylbetacyclodextrin used, further preparation of capsules or tablets is more difficult. Therefore, a mass ratio of PAR-1 inhibitor to sodium sulfobutylbetacyclodextrin of 1:10~40 is preferred. The dissolution curves in pH 6.8 medium for Examples 2~5 are shown below. Figure 2 As shown.

[0037] Examples 6-9 The formulation and preparation method of the pharmaceutical composition are the same as in Example 1, except that citric acid was used to adjust the pH of the sodium sulfobutyl betacyclodextrin aqueous solution to different values ​​for investigation. The pH values ​​of the sodium sulfobutyl betacyclodextrin aqueous solution in Examples 6-9 are shown in Table 5.

[0038] Table 5. pH values ​​of sodium sulfobutyl betacyclodextrin aqueous solutions in Examples 6-9

[0039] The test data for Examples 6-9 are shown in Table 6 below: Table 6 Test data for Examples 6-9

[0040] As the results showed, when the pH of the sodium sulfobutyl betacyclodextrin aqueous solution was adjusted to 1.0–3.0, the bioavailability in the rat samples was greater than 70%. When the pH was less than 1.0 or greater than 3.0, the bioavailability was less than 60%. Therefore, the preferred amount of pH adjuster was sufficient to adjust the pH of the sodium sulfobutyl betacyclodextrin aqueous solution to 1.0–3.0. The dissolution curves in the pH 6.8 medium for Examples 6–9 are shown below. Figure 3 As shown.

[0041] Examples 10-15 The formulation and preparation method of the pharmaceutical composition are the same as in Example 1, except that the types of pH adjusters are studied, the formulation and process are the same as in Example 1, and the selection of pH adjusters is shown in Table 7.

[0042] Table 7. Mass ratio of raw materials for PAR-1 inhibitor enteric-coated formulations in Examples 10-15

[0043] The test data for Examples 10-15 are shown in Table 8 below: Table 8 Test data for Examples 10-15

[0044] As the results show, when the pH adjusters were gallic acid, sorbic acid, maleic acid, fumaric acid, succinic acid, and tartaric acid, the final dissolution rate of the samples in the pH 6.8 medium was greater than 70%, but slightly lower than that of citric acid. Therefore, citric acid is preferred. The dissolution curves in the pH 6.8 medium for Examples 10-15 are shown below. Figure 4 As shown.

[0045] Examples 16-19 The preparation method of the pharmaceutical composition is the same as in Example 1, except that the amount of binder was investigated, the mass of raw materials such as API was expressed in parts by weight, and the mass ratio of raw materials of PAR-1 inhibitor enteric-coated formulations in Examples 16-19 is shown in Table 9.

[0046] Table 9. Mass ratio of raw materials for PAR-1 inhibitor enteric-coated formulations in Examples 16-19

[0047] The test data for Examples 16-19 are shown in Table 10 below: Table 10 Test data for Examples 16-19

[0048] As the results show, the bioavailability of the PAR-1 inhibitor to hydroxypropyl methylcellulose E4M was greater than 70% in rat samples when the mass ratio was 1:2 to 20, less than 50% when the ratio was 1:30, and less than 40% after removing hydroxypropyl methylcellulose E4M. Therefore, a mass ratio of PAR-1 inhibitor to hydroxypropyl methylcellulose E4M of 1:2 to 20 is preferred. The dissolution curves in pH 6.8 medium for Examples 16-19 are shown below. Figure 5 As shown.

[0049] Examples 20-23 The preparation method of the pharmaceutical composition is the same as in Example 1, except that: the type of filler is investigated, the mass of raw materials such as API is expressed in parts by weight, and the mass ratio of raw materials of PAR-1 inhibitor enteric-coated formulations in Examples 20-23 is shown in Table 11.

[0050] Table 11. Mass ratio of raw materials for PAR-1 inhibitor enteric-coated formulations in Examples 20-23

[0051] The test data for Examples 20-23 are shown in Table 12 below: Table 12 Test data for Examples 20-23

[0052] As the results show, after adjusting the filler to microcrystalline cellulose, mannitol, lactose, and starch, the final dissolution rate of the sample was approximately 80%. The dissolution curves for pH 6.8 media in Examples 20-23 are shown below. Figure 6 As shown.

[0053] Examples 24-26 The preparation method of the pharmaceutical composition is the same as in Example 1, except that after the total mixed granules are prepared, the effects of tablets, capsules and whether or not they are coated with enteric coating on bioavailability are investigated. The process and dissolution data of Examples 24 to 26 are shown in Table 13.

[0054] Table 13 Process and dissolution data for Examples 24-26

[0055] The test data for Examples 1, 24-26 are shown in Table 14 below: Table 14 Test data for Examples 1, 24-26

[0056] As the results showed, the bioavailability of enteric-coated tablets or capsules in dogs was significantly higher than that of ordinary tablets or capsules, with enteric-coated tablets or capsules having a bioavailability greater than 65% and ordinary tablets or capsules having a bioavailability less than 50%.

Claims

1. An enteric-coated formulation of a PAR-1 inhibitor, characterized in that, The chemical name of the PAR-1 inhibitor is ethyl((3aR,4aR,5S,6R,8aR,9R,9aS)-9-((E)(-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-5,8-dimethyl-3-oxododecanonaphtho[2,3-c]furan-6-yl)carbamate sulfate, and its structural formula is shown in Formula I below: Formula I; The PAR-1 inhibitor enteric-coated formulation is prepared as enteric-coated tablets or enteric-coated capsules by adding excipients and enteric materials to the PAR-1 inhibitor cyclodextrin inclusion complex. The PAR-1 inhibitor cyclodextrin inclusion complex is a mixture of PAR-1 inhibitor, sodium sulfobutyl betacyclodextrin, pH adjuster and water.

2. The enteric-coated formulation of the PAR-1 inhibitor according to claim 1, characterized in that, The mass ratio of the PAR-1 inhibitor to sodium sulfobutylbetacyclodextrin is 1:10~40.

3. The enteric-coated formulation of the PAR-1 inhibitor according to claim 1, characterized in that, The pH of the sodium sulfobutyl betacyclodextrin aqueous solution in the cyclodextrin inclusion complex was adjusted to 1.0-3.0 using a pH adjuster.

4. The enteric-coated formulation of the PAR-1 inhibitor according to claim 3, characterized in that, The pH adjuster is one or more of citric acid, gallic acid, sorbic acid, maleic acid, fumaric acid, succinic acid, and tartaric acid.

5. The enteric-coated formulation of the PAR-1 inhibitor according to claim 1, characterized in that, The excipients include one or more of fillers, binders, disintegrants, and lubricants.

6. The enteric-coated formulation of the PAR-1 inhibitor according to claim 5, characterized in that, The filler is one or more of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, and starch.

7. The enteric-coated formulation of the PAR-1 inhibitor according to claim 5, characterized in that, The adhesive is hydroxypropyl methylcellulose E4M, and the mass ratio of the PAR-1 inhibitor to the adhesive is 1:2~20.

8. A method for preparing an enteric-coated formulation of a PAR-1 inhibitor according to any one of claims 1 to 7, characterized in that, It includes the following steps: a) Weigh out sodium sulfobutyl betacyclodextrin, dissolve it in water, add a pH adjuster to adjust the pH, and prepare an aqueous solution of sodium sulfobutyl betacyclodextrin. b) Weigh the PAR-1 inhibitor and add it to the sodium sulfobutyl betacyclodextrin aqueous solution in step a). After stirring and dissolving, pre-freeze the solution and then transfer it to a freeze dryer. After drying, pulverize and sieve the solution to obtain the PAR-1 inhibitor cyclodextrin inclusion complex. c1) After the PAR-1 inhibitor cyclodextrin inclusion complex from step b) is mixed with excipients and compressed into tablets, enteric coating is performed using an enteric material that can be dissolved at pH 5.5 or higher to obtain PAR-1 inhibitor enteric tablets. or; c2) The PAR-1 inhibitor cyclodextrin inclusion complex from step b) is mixed with excipients and filled into enteric-coated empty capsules that can dissolve at pH 5.5 or higher to obtain PAR-1 inhibitor enteric-coated capsules.

9. The use of an enteric-coated formulation of a PAR-1 inhibitor according to any one of claims 1 to 7 in a medicament for the prevention and / or treatment of thrombotic diseases.

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