A rivaroxaban tablet, preparation method and use
By combining trimethylamine-modified methylcellulose with other excipients, rivaroxaban tablets with high drug loading and high encapsulation efficiency were prepared, solving the problem of low drug loading and encapsulation efficiency in the existing technology and achieving efficient delivery and stability of rivaroxaban.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZIBO CENT HOSPITAL
- Filing Date
- 2023-12-25
- Publication Date
- 2026-05-29
AI Technical Summary
In the existing technology, the drug loading and encapsulation efficiency of rivaroxaban inclusion complexes are low, resulting in a significant reduction in their delivery efficiency.
Using trimethylamine-modified methylcellulose as the inclusion material, combined with lactose, starch, low-substituted hydroxypropyl cellulose and magnesium stearate, the preparation process was optimized to prepare rivaroxaban tablets with high drug loading and high encapsulation efficiency.
It improves the delivery efficiency of rivaroxaban inclusion complex, ensuring high dissolution, low impurity content and stability, and enhancing drug bioavailability.
Smart Images
Figure CN117752621B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a rivaroxaban tablet, its preparation method, and its uses. Background Technology
[0002] Rivaroxaban is a highly selective, dose-dependent novel oral anticoagulant that exerts its anticoagulant effect by inhibiting the intrinsic and extrinsic pathways that disrupt the coagulation cascade (FXa), thereby inhibiting thrombin production and thrombus formation. It is primarily indicated for: 1) adult patients undergoing elective hip or knee replacement surgery to prevent venous thrombosis (VTE); 2) the treatment of adult venous thrombosis (DVT) to reduce the risk of DVT recurrence and pulmonary embolism (PE) after acute DVT; and 3) adult patients with nonvalvular atrial fibrillation who have one or more risk factors (e.g., congestive heart failure, hypertension, age ≥75 years, diabetes, history of stroke or transient ischemic attack) to reduce the risk of stroke and systemic embolism.
[0003] Rivaroxaban is almost insoluble in water; at 25°C, its solubility in aqueous media is only 5-7 mg / L, resulting in poor in vitro dissolution and very low in vivo bioavailability. Common methods for improving the dissolution of poorly soluble drugs in existing technologies include: solid dispersions, cyclodextrin inclusion complexation, drug micronization, surfactant solubilization, microemulsion, and liposome technology.
[0004] Chinese patent CN114533899A discloses a rivaroxaban formulation and its preparation method, comprising rivaroxaban, cellulose, and pharmaceutically acceptable excipients. By preparing an inclusion complex intermediate and then further preparing it into a formulation, the problem of rivaroxaban's poor solubility is solved. However, the drug loading and encapsulation efficiency of the rivaroxaban inclusion complex in this technical solution are low, significantly reducing the delivery efficiency of rivaroxaban. Summary of the Invention
[0005] To address the shortcomings of existing technologies, this invention provides a rivaroxaban tablet composed of a rivaroxaban inclusion complex with high drug loading and high encapsulation efficiency. This solves the problem that the low drug loading and encapsulation efficiency of the rivaroxaban inclusion complex in existing technologies leads to a significant reduction in the delivery efficiency of rivaroxaban.
[0006] Specifically, the technical solution of the present invention is as follows:
[0007] The present invention provides a rivaroxaban tablet, the rivaroxaban tablet comprising: an inclusion complex containing rivaroxaban, lactose, starch, low-substituted hydroxypropyl cellulose, and magnesium stearate.
[0008] The inclusion complex containing rivaroxaban was prepared according to the following method:
[0009] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 2 to 5 parts by weight of trimethylamine, heat in a water bath at 40°C to 55°C and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0010] (2) Dissolve 3 to 7 parts by weight of trimethylamine-modified methylcellulose in methanol solution to prepare a solution with a mass fraction of 55% to 65%. Add a suspension containing 2 to 3 parts by weight of rivaroxaban in a pH=5.0 to 6.0 buffer solution, mix thoroughly, stir in a water bath at 45℃-55℃ for 1 to 5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0011] Trimethylamine contains nitrogen atoms, which can form hydrogen bonds of the type OH···N with the oxygen atoms in methylcellulose (CAS: 9004-67-5), thereby modifying it.
[0012] In a preferred embodiment, the trimethylamine is 3 parts by weight.
[0013] In a preferred embodiment, the water bath heating temperature in step (1) is 45°C to 50°C.
[0014] In a preferred embodiment, the trimethylamine-modified methylcellulose is 5 parts by weight and the rivaroxaban is 2.5 parts by weight.
[0015] In a preferred embodiment, the methanol solution in step (2) is an aqueous methanol solution with a mass fraction of 70-85%.
[0016] In several embodiments, the buffer solution is a phosphate buffer solution.
[0017] In a preferred embodiment, step (2) involves preparing a solution with a mass fraction of 60%.
[0018] In several embodiments, the formulation of the rivaroxaban tablets, calculated in parts by weight, is as follows:
[0019] It contains 10 parts of rivaroxaban inclusion complex, 100-200 parts of starch, 30-70 parts of lactose, 8-20 parts of substituted hydroxypropyl cellulose, and 0.4-4 parts of magnesium stearate.
[0020] In a preferred embodiment, the formulation of the rivaroxaban tablets, calculated in parts by weight, is as follows:
[0021] It contains 10 parts of rivaroxaban inclusion complex, 150 parts of starch, 50 parts of lactose, 12 parts of substituted hydroxypropyl cellulose, and 2 parts of magnesium stearate.
[0022] A second objective of this invention is to provide the use of the above-mentioned rivaroxaban tablets in the preparation of anticoagulant drugs.
[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0024] This invention utilizes trimethylamine-modified methylcellulose as an inclusion material to encapsulate rivaroxaban, optimizing the preparation process and solving the problems of low drug loading and encapsulation efficiency of rivaroxaban inclusion compounds in existing technologies. It provides a rivaroxaban tablet composed of a rivaroxaban inclusion compound with high drug loading and high encapsulation efficiency, thus improving the delivery efficiency of the rivaroxaban inclusion compound. Verification shows that the rivaroxaban tablets provided by this invention have high dissolution, few impurities, and are stable. Attached Figure Description
[0025] Figure 1 Effects of different pH values on drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes
[0026] Figure 2 Effects of different concentrations of trimethylamine-modified methylcellulose methanol aqueous solution on drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes.
[0027] Figure 3 Dissolution curves of rivaroxaban tablets in Examples 1-3
[0028] Figure 4 Curves showing the change in total content of related substances in accelerated tests of rivaroxaban tablets in Examples 1-3 and Comparative Examples 1-3 Detailed Implementation
[0029] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.
[0030] I. Examples and Comparative Examples: Rivaroxaban Tablets
[0031] Example 1 Rivaroxaban Tablets
[0032] Preparation of inclusion complexes containing rivaroxaban:
[0033] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 3 parts by weight of trimethylamine, heat in a water bath at 45℃~50℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0034] (2) Dissolve 5 parts by weight of trimethylamine-modified methylcellulose in a 70%–85% methanol aqueous solution to prepare a 60% solution. Add a suspension containing 2.5 parts by weight of rivaroxaban in a pH 5.0–6.0 phosphate buffer solution, mix thoroughly, stir in a water bath at 45℃–55℃ for 1–5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0035] Preparation of rivaroxaban tablets:
[0036] The inclusion complex containing 10 parts by weight of rivaroxaban, 150 parts by weight of starch, 50 parts by weight of lactose, and 12 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and then 2 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0037] Example 2 Rivaroxaban Tablets
[0038] Preparation of inclusion complexes containing rivaroxaban:
[0039] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 2 parts by weight of trimethylamine, heat in a water bath at 40℃~45℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0040] (2) Dissolve 5 parts by weight of trimethylamine-modified methylcellulose in a 70%–85% methanol aqueous solution to prepare a 55% solution. Add a suspension containing 2 parts by weight of rivaroxaban in a pH 5.0–6.0 phosphate buffer solution, mix thoroughly, stir in a 45℃–55℃ water bath for 1–5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0041] Preparation of rivaroxaban tablets:
[0042] The inclusion complex containing 10 parts by weight of rivaroxaban, 100 parts by weight of starch, 70 parts by weight of lactose, and 8 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and 0.4 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0043] Example 3 Rivaroxaban Tablets
[0044] Preparation of inclusion complexes containing rivaroxaban:
[0045] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 5 parts by weight of trimethylamine, heat in a water bath at 50℃~55℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0046] (2) Dissolve 5 parts by weight of trimethylamine-modified methylcellulose in a 70%–85% methanol aqueous solution to prepare a 65% solution. Add a suspension containing 3 parts by weight of rivaroxaban in a pH 5.0–6.0 phosphate buffer solution, mix thoroughly, stir in a 45℃–55℃ water bath for 1–5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0047] Preparation of rivaroxaban tablets:
[0048] The inclusion complex containing 10 parts by weight of rivaroxaban, 200 parts by weight of starch, 30 parts by weight of lactose, and 20 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and then 4 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0049] Comparative Example 1: Rivaroxaban Tablets
[0050] Preparation of inclusion complexes containing rivaroxaban:
[0051] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 3 parts by weight of trimethylamine, heat in a water bath at 45℃~50℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0052] (2) Dissolve 1 part by weight of trimethylamine-modified methylcellulose in a 70%–85% methanol aqueous solution to prepare a 60% solution. Add a suspension containing 2.5 parts by weight of rivaroxaban in a pH 5.0–6.0 phosphate buffer solution, mix thoroughly, stir in a water bath at 45℃–55℃ for 1–5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0053] Preparation of rivaroxaban tablets:
[0054] The inclusion complex containing 10 parts by weight of rivaroxaban, 150 parts by weight of starch, 50 parts by weight of lactose, and 12 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and then 2 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0055] Comparative Example 2: Rivaroxaban Tablets
[0056] Preparation of inclusion complexes containing rivaroxaban:
[0057] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 3 parts by weight of trimethylamine, heat in a water bath at 45℃~50℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0058] (2) Dissolve 5 parts by weight of trimethylamine-modified methylcellulose in a 55% methanol aqueous solution to prepare a 60% solution. Add a suspension containing 2.5 parts by weight of rivaroxaban in a pH 5.0-6.0 phosphate buffer solution, mix thoroughly, stir in a water bath at 45℃-55℃ for 1-5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0059] Preparation of rivaroxaban tablets:
[0060] The inclusion complex containing 10 parts by weight of rivaroxaban, 150 parts by weight of starch, 50 parts by weight of lactose, and 12 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and then 2 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0061] Comparative Example 3 Rivaroxaban Tablets
[0062] Preparation of inclusion complexes containing rivaroxaban:
[0063] (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 3 parts by weight of trimethylamine, heat in a water bath at 45℃~50℃ and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose.
[0064] (2) Dissolve 5 parts by weight of trimethylamine-modified methylcellulose in an aqueous ethanol solution with a mass fraction of 70% to 85% to prepare a solution with a mass fraction of 60%. Add a suspension containing 2.5 parts by weight of rivaroxaban in a phosphate buffer solution with a pH of 5.0 to 6.0, mix thoroughly, stir in a water bath at 45℃ to 55℃ for 1 to 5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
[0065] Preparation of rivaroxaban tablets:
[0066] The inclusion complex containing 10 parts by weight of rivaroxaban, 150 parts by weight of starch, 50 parts by weight of lactose, and 12 parts by weight of substituted hydroxypropyl cellulose are pulverized and passed through an 80-mesh sieve, mixed, and then 2 parts by weight of pulverized and sieved magnesium stearate are added. The mixture is then directly compressed into tablets to obtain rivaroxaban tablets.
[0067] II. Yield of trimethylamine-modified methylcellulose
[0068] The yields of the trimethylamine-modified methylcellulose prepared in Examples 1-3 were calculated:
[0069] Table 1. Yield of trimethylamine-modified methylcellulose
[0070] Yield (%) of trimethylamine-modified methylcellulose Example 1 92.62 Example 2 91.34 Example 3 90.08
[0071] In this embodiment of the invention, trimethylamine-modified methylcellulose is used as the inclusion material of the inclusion complex. The results show that the yield of trimethylamine-modified methylcellulose is high, which can provide a guarantee for the subsequent preparation of inclusion complexes containing rivaroxaban.
[0072] III. Drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes
[0073] Drug loading, encapsulation efficiency, and leakage rate are the main indicators for evaluating the quality of inclusion compounds. Drug loading refers to the percentage of drug weight encapsulated in the inclusion compound. Encapsulation efficiency refers to the weight percentage of drug in the inclusion compound relative to the amount of feed added. Leakage rate indicates the change in encapsulation efficiency during storage (in this experiment, the storage conditions for leakage rate were: temperature 40±2℃, relative humidity 75%±5%, and time 1 month). The drug loading, encapsulation efficiency, and leakage rate of the inclusion compounds containing rivaroxaban in Examples 1-3 and Comparative Examples 1-3 were measured and calculated.
[0074] Table 2. Drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes.
[0075] Drug loading (%) Encapsulation efficiency (%) Leakage rate (%) Example 1: Inclusion complex containing rivaroxaban 22.54 90.84 0.16 Example 2 Inclusion complex containing rivaroxaban 21.31 90.05 0.20 Example 3 Inclusion complex containing rivaroxaban 22.10 90.51 0.21 Comparative Example 1: Inclusion complex containing rivaroxaban 15.35 80.62 1.72 Comparative Example 2: Inclusion complex containing rivaroxaban 18.04 82.57 0.63 Comparative Example 3: Inclusion complex containing rivaroxaban 17.26 82.09 0.91
[0076] Compared with the drug loading and encapsulation efficiency of the rivaroxaban inclusion complex disclosed in Chinese Patent CN114533899 A, the rivaroxaban-containing inclusion complex prepared by this invention has high quality and stability, with a drug loading of over 21% and an encapsulation efficiency of over 90%, which greatly improves the efficiency of the inclusion complex in delivering the active ingredient rivaroxaban, and represents a significant advancement.
[0077] IV. Single-factor experiments
[0078] 1. Effects of different pH values on drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes.
[0079] All other conditions were the same as those in Example 1. pH was used as a variable factor to investigate the effects of different pH values on the drug loading, encapsulation efficiency, and leakage rate of the rivaroxaban-containing inclusion complex. The storage conditions for leakage rate in this experiment were: temperature 40±2℃, relative humidity 75%±5%, for one month.
[0080] like Figure 1 As shown, the rivaroxaban-containing inclusion complexes prepared within the pH range of 5.0–6.0 are of high quality and stable, exhibiting high drug loading and encapsulation efficiency as well as low leakage rate.
[0081] 2. Effects of different concentrations of trimethylamine-modified methylcellulose methanol aqueous solution on drug loading, encapsulation efficiency, and leakage rate of rivaroxaban-containing inclusion complexes.
[0082] All other conditions were the same as those in Example 1. The concentration of trimethylamine-modified methylcellulose methanol aqueous solution was used as a variable factor to investigate the effect of different concentrations of trimethylamine-modified methylcellulose methanol aqueous solution on the drug loading, encapsulation efficiency, and leakage rate of the inclusion complex containing rivaroxaban. The storage conditions for leakage rate in this experiment were: temperature 40±2℃, relative humidity 75%±5%, and time 1 month.
[0083] Figure 2 As shown, single-factor experiments have shown that the inclusion complex containing rivaroxaban prepared from a methylcellulose methanol aqueous solution modified with trimethylamine at a mass fraction of 55%–65% has high quality and stability.
[0084] V. Dissolution of Rivaroxaban Tablets
[0085] Using water as the medium and a volume of 900 ml, the dissolution rate of rivaroxaban tablets in Examples 1-3 was determined, and dissolution curves were plotted. Figure 3 The results showed that the present invention overcomes the defect that rivaroxaban is poorly soluble in water, making dissolution difficult. The rivaroxaban tablets of the present invention dissolve rapidly, uniformly, and with high dissolution rate.
[0086] VI. Related substance content of rivaroxaban tablets
[0087] The content of related substances was determined for rivaroxaban tablets of Examples 1-3 and Comparative Examples 1-3. Accelerated test: The tablets were placed in commercial packaging at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th months of the test period to determine the total content of related substances.
[0088] like Figure 4 As shown, the rivaroxaban tablets in Examples 1-3 of this invention have low levels of related substances, and the content of related substances remains basically unchanged in accelerated tests, indicating high stability.
Claims
1. A rivaroxaban tablet, characterized in that, The rivaroxaban tablets comprise: an inclusion complex containing rivaroxaban, lactose, starch, low-substituted hydroxypropyl cellulose, and magnesium stearate; The inclusion complex containing rivaroxaban was prepared according to the following method: (1) Dissolve 10 parts by weight of methylcellulose in water, slowly add anhydrous ethanol containing 2 to 5 parts by weight of trimethylamine, heat in a water bath at 40°C to 55°C and reflux to remove 2 / 3 of the solution, cool, and let stand to evaporate naturally to obtain trimethylamine modified methylcellulose. (2) Dissolve 3-7 parts by weight of trimethylamine-modified methylcellulose in a methanol aqueous solution with a mass fraction of 70-85% to prepare a solution with a mass fraction of 55%-65%. Add a suspension containing 2-3 parts by weight of rivaroxaban buffer solution with pH=5.0-6.0, mix thoroughly, stir in a water bath at 45℃-55℃ for 1-5 hours, and dry under reduced pressure to obtain the inclusion complex containing rivaroxaban.
2. The rivaroxaban tablets according to claim 1, characterized in that, The trimethylamine is in parts by weight of 3.
3. The rivaroxaban tablet according to claim 1, characterized in that, The water bath heating temperature in step (1) is 45℃~50℃.
4. The rivaroxaban tablet according to claim 1, characterized in that, The trimethylamine-modified methylcellulose is 5 parts by weight, and the rivaroxaban is 2.5 parts by weight.
5. The rivaroxaban tablet according to claim 1, characterized in that, The buffer solution is a phosphate buffer solution.
6. The rivaroxaban tablet according to claim 1, characterized in that, In step (2), a solution with a mass fraction of 60% is prepared.
7. The rivaroxaban tablet according to claim 1, characterized in that, The formulation of the rivaroxaban tablets, calculated in parts by weight, is as follows: It contains 10 parts of rivaroxaban inclusion complex, 100-200 parts of starch, 30-70 parts of lactose, 8-20 parts of substituted hydroxypropyl cellulose, and 0.4-4 parts of magnesium stearate.
8. The rivaroxaban tablet according to claim 7, characterized in that, The formulation of the rivaroxaban tablets, calculated in parts by weight, is as follows: It contains 10 parts of rivaroxaban inclusion complex, 150 parts of starch, 50 parts of lactose, 12 parts of substituted hydroxypropyl cellulose, and 2 parts of magnesium stearate.
9. Use of the rivaroxaban tablets of claim 1 in the preparation of anticoagulant drugs.