Risedronate sodium tablet and preparation method thereof

Abstract

The present invention relates to a sodium risedronate tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations for osteoporosis. The sodium risedronate tablet of the present invention is composed of sodium risedronate, phospholipids, cholesterol, tartronic acid and pharmaceutically acceptable excipients. The present invention uses liposome technology to encapsulate sodium risedronate in liposomes, thereby reducing the possibility of sodium risedronate being degraded due to reactions such as oxidation and hydrolysis, and helping to improve the stability of the drug.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations for osteoporosis, and particularly relates to a risedronate sodium tablet and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Osteoporosis is a systemic bone disease characterized by low bone mass and damaged bone microstructure, which leads to increased bone brittleness and susceptibility to fractures. With the aging of the global population, the incidence of osteoporosis has shown a significant upward trend, which has had a serious impact on the quality of life of patients and increased the social medical burden. Therefore, the development of safe and effective anti-osteoporosis drugs is of great significance. Risedronate, as a third-generation bisphosphonate drug, has been widely used in the clinical treatment of osteoporosis. It effectively increases bone density and reduces the risk of fractures by inhibiting osteoclast-mediated bone resorption, and occupies an important position in the field of drug treatment of osteoporosis.

[0004] During the preparation and storage process, risedronate sodium often faces hygroscopic problems due to its good water solubility and strong hygroscopicity, which brings many challenges to the production, storage and administration of its tablets. The hygroscopicity of risedronate sodium makes it easy to absorb moisture under conditions of high ambient humidity, resulting in a decrease in the stability of the drug ingredients in the tablets. After absorbing moisture, risedronate sodium may undergo hydrolysis, thereby affecting the efficacy of the drug. In addition, moisture absorption may also lead to deterioration of the appearance and mechanical properties of the tablets, such as softening, sticking, breaking or agglomeration, affecting the appearance and user experience of the tablets.

[0005] In order to overcome the above problems, the traditional preparation process often takes the following measures: first, by controlling the humidity of the preparation environment, the exposure of sodium risedronate to a high humidity environment is minimized; second, appropriate excipients are used, such as fillers with strong moisture resistance, excipients with low hygroscopicity, and certain moisture-proof packaging materials; third, an effective moisture barrier is formed through an appropriate coating process to prevent the drug from contacting with external moisture. A Chinese patent with publication number CN 101601661A discloses a sodium risedronate tablet, which is prepared by a powder direct tableting method and includes the following components based on the total weight of the tablet: sodium risedronate 2-20wt%, filler 70-90wt%, binder 3-6wt%, disintegrant 2-8wt%, glidant 1-4wt% and lubricant 0.2-1wt%. This solution reduces the high temperature and high humidity drying step in the preparation process, avoids the introduction of impurities, and improves the stability of the drug. A Chinese patent with publication number CN 104721165 A discloses a sodium risedronate coated tablet composition and a preparation method thereof, which contains auxiliary materials such as chitosan, hydroxypropyl methylcellulose, polyethylene glycol, and microcrystalline cellulose, and reduces the content of related substances through coating technology.

[0006] However, although these methods have alleviated the hygroscopicity problem to a certain extent, they have not fundamentally solved the hygroscopicity problem of risedronate sodium tablets. In the prior art, there are still certain technical difficulties in improving the stability and hygroscopicity of risedronate sodium tablets, especially under the premise of maintaining their efficacy and mechanical strength. Summary of the invention

[0007] The disadvantages of the prior art are overcome. The present invention utilizes liposome technology to prepare a risedronate sodium tablet with high stability.

[0008] Specifically, the risedronate sodium tablets are composed of risedronate sodium, phospholipids, cholesterol, tartronic acid and pharmaceutically acceptable excipients. The mass ratio of risedronate sodium, egg yolk phospholipids, cholesterol and tartronic acid is 10:8~15:1~5:0.2~0.8. The pharmaceutically acceptable excipients include but are not limited to fillers, disintegrants, lubricants, flavoring agents and coating materials.

[0009] Furthermore, the phospholipid is egg yolk phospholipid and / or soybean phospholipid.

[0010] The present invention also provides a preparation method of the risedronate sodium tablets, comprising the following steps: dissolving phospholipids, cholesterol and tartronic acid in an organic solvent, performing vacuum rotary evaporation in a water bath at 30°C to 45°C to obtain a thin film, adding a buffer solution containing the risedronate sodium to hydrate, ultrasonicating, performing vacuum rotary evaporation until 1 / 2 of the solution volume remains, adjusting the solution pH to 7.5±0.2, continuing vacuum rotary evaporation until 1 / 3 of the solution volume remains, freeze drying, adding pharmaceutically acceptable excipients, and preparing tablets.

[0011] Furthermore, the organic solvent is selected from one of ethanol, methanol and chloroform. The buffer solution is selected from one of phosphate buffer solution, citrate buffer solution and carbonate buffer solution, and the pH of the buffer solution is 5.0-6.5. The freeze-drying procedure is: pre-freezing at -35°C±5°C for 6-10h, sublimation drying at -20°C±5°C for 10-14h, and desorption drying at 15°C±5°C for 8-12h.

[0012] Compared with the prior art, the technical effects of the present invention are:

[0013] (1) The present invention forms a physical barrier by encapsulating risedronate sodium in liposomes. The double-layer membrane structure of liposomes can reduce the direct contact between the drug and external environmental factors (such as moisture, oxygen, etc.), thereby reducing the possibility of drug degradation due to oxidation, hydrolysis and other reactions, and helping to improve the stability of the drug.

[0014] (2) During the preparation process, the present invention undergoes multiple vacuum rotary evaporation and ultrasonic treatments to enable risedronate sodium to be better dispersed in the liposomes, and by controlling the volume of the solution, it helps to form a stable liposome structure, thereby further protecting the drug.

[0015] (3) Succinic acid plays two roles in the present invention. On the one hand, succinic acid participates in the formation process of liposome membrane, interacts with phospholipids and cholesterol, regulates the fluidity and stability of liposome membrane, and improves the drug loading and encapsulation rate of risedronate sodium liposome. On the other hand, it also helps to reduce the moisture absorption of risedronate sodium tablets and improve stability.

[0016] (4) The present invention prepares risedronate sodium liposomes in a weakly acidic environment and then adjusts the pH to about 7.5, so that risedronate sodium is in its most stable chemical state, reducing the possibility of chemical reactions such as hydrolysis and decomposition of the drug due to excessive acidity or alkalinity. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : Drug loading and encapsulation efficiency of risedronate sodium liposome freeze-dried powder of Example 1 to Example 3 and Comparative Example 1 to Comparative Example 4.

[0018] Figure 2 : Content stability of risedronate sodium tablets of Example 1 to Example 4 and Comparative Example 1 to Comparative Example 5. DETAILED DESCRIPTION

[0019] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 Risedronate Sodium Tablets

[0021] formula:

[0022]

[0023] Preparation method:

[0024] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is formed. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution, perform ultrasonication, and evaporate under reduced pressure until 1 / 2 of the solution volume remains. Adjust the solution pH to 7.5±0.2, and continue to evaporate under reduced pressure until 1 / 3 of the solution volume remains. Freeze-dry: pre-freeze at -35℃ for 8h, sublimation drying at -20℃ for 12h, desorption drying at 15℃ for 10h, add pharmaceutically acceptable excipients, and prepare tablets.

[0025] Example 2 Risedronate Sodium Tablets

[0026] formula:

[0027]

[0028] Preparation method:

[0029] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is obtained. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution. Ultrasound is performed, and the solution is evaporated under reduced pressure until 1 / 2 of the volume of the solution remains. The pH of the solution is adjusted to 7.5±0.2. The solution is evaporated under reduced pressure until 1 / 3 of the volume of the solution remains. Freeze-dry: pre-freeze at -40℃ for 6h, sublimation drying at -25℃ for 10h, desorption drying at 10℃ for 8h, and pharmaceutically acceptable excipients are added to prepare tablets.

[0030] Example 3 Risedronate Sodium Tablets

[0031] formula:

[0032]

[0033] Preparation method:

[0034] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is obtained. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution. Ultrasound is performed, and the solution is evaporated under reduced pressure until 1 / 2 of the volume of the solution remains. The pH of the solution is adjusted to 7.5±0.2. The solution is evaporated under reduced pressure until 1 / 3 of the volume of the solution remains. Freeze-dry: pre-freeze at -30℃ for 10h, sublimation drying at -15℃ for 14h, desorption drying at 20℃ for 12h, and pharmaceutically acceptable excipients are added to prepare tablets.

[0035] Example 4 Risedronate sodium coated tablets

[0036] formula:

[0037]

[0038] Preparation method:

[0039] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is formed. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution, perform ultrasonication, and evaporate under reduced pressure until 1 / 2 of the solution volume remains. Adjust the solution pH to 7.5±0.2, and continue to evaporate under reduced pressure until 1 / 3 of the solution volume remains. Freeze-dry: pre-freeze at -35℃ for 8h, sublimation drying at -20℃ for 12h, desorption drying at 15℃ for 10h, add pharmaceutically acceptable excipients, and prepare tablets.

[0040] Comparative Example 1 Risedronate Sodium Tablets

[0041] formula:

[0042]

[0043] Preparation method:

[0044] Dissolve phospholipids and cholesterol in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is formed, add a phosphate buffer solution of pH=5.8 containing sodium rifdronate to hydrate, sonicate, evaporate under reduced pressure until 1 / 2 of the solution volume remains, adjust the solution pH to 7.5±0.2, continue to evaporate under reduced pressure until 1 / 3 of the solution volume remains, freeze-dry: pre-freeze at -35℃ for 8h, sublimation dry at -20℃ for 12h, desorption dry at 15℃ for 10h, add pharmaceutically acceptable excipients, and prepare tablets.

[0045] Comparative Example 2 Risedronate Sodium Tablets

[0046] formula:

[0047]

[0048] Preparation method:

[0049] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is formed. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution, perform ultrasonication, and evaporate under reduced pressure until 1 / 2 of the solution volume remains. Adjust the solution pH to 7.5±0.2, and continue to evaporate under reduced pressure until 1 / 3 of the solution volume remains. Freeze-dry: pre-freeze at -35℃ for 8h, sublimation drying at -20℃ for 12h, desorption drying at 15℃ for 10h, add pharmaceutically acceptable excipients, and prepare tablets.

[0050] Comparative Example 3 Risedronate Sodium Tablets

[0051] formula:

[0052]

[0053] Preparation method:

[0054] Dissolve phospholipids, cholesterol and glycolic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is obtained. Add a phosphate buffer solution with pH=5.8 containing sodium rifdronate to hydrate the solution. Ultrasound is performed, and the solution is evaporated under reduced pressure until 1 / 2 of the volume of the solution remains. Adjust the pH of the solution to 7.5±0.2, and continue to evaporate under reduced pressure until 1 / 3 of the volume of the solution remains. Freeze-dry: pre-freeze at -35℃ for 8h, sublimation drying at -20℃ for 12h, desorption drying at 15℃ for 10h, and add pharmaceutically acceptable excipients to prepare tablets.

[0055] Comparative Example 4 Risedronate Sodium Tablets

[0056] formula:

[0057]

[0058] Preparation method:

[0059] Dissolve phospholipids, cholesterol and succinic acid in a mixed solvent of chloroform and ethanol (volume ratio of 4:1), and evaporate under reduced pressure in a water bath at 30℃~45℃ until a thin film is formed. Add a phosphate buffer solution of pH=5.8 containing sodium rifdronate to hydrate the solution. Ultrasound is performed, and reduced pressure rotary evaporation is continued until 1 / 3 of the solution volume remains. Freeze-dry: pre-freeze at -35℃ for 8h, sublimation drying at -20℃ for 12h, desorption drying at 15℃ for 10h, and pharmaceutically acceptable excipients are added to prepare tablets.

[0060] Comparative Example 5: Commercially available risedronate sodium tablets (National Medicine Standard H20140091)

[0061] Drug loading and encapsulation efficiency of risedronate sodium liposome freeze-dried powder

[0062] Drug loading refers to the ratio of the weight (or amount) of the drug in the liposome to the total weight (or amount) of the liposome. Encapsulation efficiency refers to the ratio of the amount of drug encapsulated by the liposome to the total amount of drug (including encapsulated and unencapsulated drugs), which reflects the encapsulation ability of the liposome for the drug. Risedronate sodium liposome lyophilized powder refers to the product after freeze-drying in the preparation method.

[0063] Figure 1 The drug loading and encapsulation efficiency of the risedronate sodium liposome lyophilized powder of Example 1 to Example 3 and Comparative Example 1 to Comparative Example 4 are shown. The results show that compared with Comparative Example 1 to Comparative Example 4, the drug loading and encapsulation efficiency of the risedronate sodium liposome lyophilized powder of Example 1 to Example 3 are higher, which means that more drugs are contained in the liposomes of the same mass, which improves the utilization efficiency of the drugs and improves the accuracy and effectiveness of drug delivery.

[0064] Stability of risedronate sodium tablets

[0065] The risedronate sodium tablets of Example 1 to Example 4 and Comparative Example 1 to Comparative Example 5 were packaged as sold on the market, placed at a temperature of 40±2° C. and a relative humidity of 75%±5% for 6 months, and samples were taken at the end of the first month, the second month, the third month, and the sixth month during the test period, and the risedronate sodium content was detected according to the high performance liquid chromatography method in the Chinese Pharmacopoeia.

[0066] Figure 2 The content stability of risedronate sodium tablets of Examples 1 to 4 and Comparative Examples 1 to 5 is shown. It is shown that the risedronate sodium tablets of Examples 1 to 4 of the present invention exhibit high stability, and the content of the active ingredient remains substantially unchanged in the accelerated test.

[0067] Risedronate sodium tablets hygroscopicity

[0068] The risedronate sodium tablets of Example 1 to Example 4 and Comparative Example 1 to Comparative Example 5 were placed at a temperature of 40±2° C. and a relative humidity of 75%±5% for 10 days and 30 days, and their moisture absorption and weight gain were measured to determine the hygroscopicity.

[0069] Table 1 Hygroscopic weight gain of risedronate sodium tablets (%)

[0070]

[0071] Table 1 shows the moisture absorption and weight gain of risedronate sodium tablets of Examples 1 to 4 and Comparative Examples 1 to 5, indicating that the risedronate sodium tablets of Examples 1 to 4 of the present invention absorb less moisture after contacting with moisture in the external environment, and the risk of drug degradation due to hydrolysis reaction during storage is low, and the chemical stability of the drug is high.

Claims

1. A risedronate sodium tablet, characterized in that: The risedronate sodium tablets are composed of risedronate sodium, phospholipids, cholesterol, tartronic acid and pharmaceutically acceptable excipients in a mass ratio of 10:8-15:1-5:0.2-0.8; The preparation method of the risedronate sodium tablets comprises: dissolving phospholipids, cholesterol and tartronic acid in an organic solvent, performing vacuum rotary evaporation in a water bath at 30°C to 45°C until a thin film is obtained, adding a buffer solution containing the risedronate sodium to hydrate, performing ultrasonication, performing vacuum rotary evaporation until 1 / 2 of the solution volume remains, adjusting the solution pH to 7.5±0.2, continuing vacuum rotary evaporation until 1 / 3 of the solution volume remains, freeze drying, adding pharmaceutically acceptable excipients, and preparing tablets.

2. The risedronate sodium tablet according to claim 1, characterized in that: The mass ratio of risedronate sodium, phospholipid, cholesterol and tartronic acid is 10:10:2:0.

5.

3. The risedronate sodium tablet according to claim 1, characterized in that: The pharmaceutically acceptable excipients are fillers, disintegrants, lubricants, flavoring agents, and coating materials.

4. The risedronate sodium tablet according to claim 1, characterized in that: The phospholipids are egg yolk phospholipids and / or soybean phospholipids.

5. The risedronate sodium tablet according to claim 1, characterized in that: The organic solvent is selected from one of ethanol, methanol and chloroform.

6. The risedronate sodium tablet according to claim 1, characterized in that: The buffer solution is selected from one of a phosphate buffer solution, a citrate buffer solution and a carbonate buffer solution.

7. The risedronate sodium tablet according to claim 1, characterized in that: The pH of the buffer solution is 5.0-6.

5.

8. The risedronate sodium tablet according to claim 1, characterized in that: The freeze-drying procedure is: pre-freezing at -35°C±5°C for 6~10h, sublimation drying at -20°C±5°C for 10~14h, and desorption drying at 15°C±5°C for 8~12h.

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