Tablet containing risedronate sodium and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a risedronate sodium-containing tablet and application thereof. The risedronate sodium tablet is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol and other auxiliary materials, the prepared tablet is good in dissolution effect, the content of risedronate sodium in the tablet is high through an acceleration test, the mass of related substances is low, and the risedronate sodium tablet is suitable for further expanded production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tablet containing sodium risedronate and its uses. Background Art

[0002] Osteoporosis (OP) is a metabolic bone disease characterized by reduced bone mineral density, destruction of bone tissue microstructure, and increased fracture risk. With the intensification of population aging, osteoporosis has become an important public health issue globally, especially with a relatively high incidence in the elderly population. According to data from the World Health Organization (WHO), osteoporosis affects approximately 200 million people worldwide, with the majority of patients being women. The main feature of osteoporosis is bone mass reduction, leading to fragile bones and an increased risk of fractures. Common fracture sites include the spine, hip, and forearm, especially hip fractures, which have become the focus of clinical attention due to their severe consequences and treatment difficulties. The occurrence of osteoporosis is related to multiple factors such as genetic factors, eating habits, lack of exercise, smoking, alcoholism, and changes in hormone levels. As people age, bone mineral density gradually decreases, especially in postmenopausal women, where the incidence of osteoporosis increases significantly due to the decline in estrogen levels.

[0003] The main drugs for the treatment of osteoporosis include bisphosphonates: These are the first-choice drugs for treating osteoporosis, such as alendronate sodium (Fosamax), zoledronic acid (Reclast), etc. Selective estrogen receptor modulators (SERMs) such as tamoxifen (Evista) and raloxifene (Fareston). Parathyroid hormone (PTH) drugs: such as teriparatide (Forteo). Vitamin D and calcium supplements: For osteoporosis patients, supplementing sufficient calcium and vitamin D is a basic treatment measure. New biopharmaceutical drugs such as anti-RANKL monoclonal antibody (denosumab, trade name Prolia) have also been widely used. The prevention and treatment of osteoporosis are of great significance for ensuring human health and quality of life.

[0004] Sodium risedronate is a third-generation bisphosphonate drug developed by Procter & Gamble Company in the United States. It is used for the prevention and treatment of osteoporosis in postmenopausal women. Its chemical name is: 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid monosodium salt, and the structural formula is Formula I:

[0005]

[0006] Esculetin consists of five rings, including a six-membered ring (ring E) and a five-membered ring (ring A). The other three rings (rings B, C, and D) are connected by covalent bonds to form a complex structure. It is a natural active compound extracted from Aesculus hippocastanum and is widely used in many fields such as medicine, health products, and cosmetics due to its unique pharmacological properties. The main pharmacological effects of esculetin include anti-inflammatory, improving blood circulation, anti-tumor, antioxidant, etc., so it has broad application prospects.

[0007] In the prior art, there is no report on preparing risedronate sodium and esculetin into a pharmaceutical composition for use, and even less on preparing them into tablets for relevant efficacy verification experiments. Summary of the Invention

[0008] Based on the deficiencies of the prior art, a tablet containing risedronate sodium is provided, which solves the defect of high content of related substances in risedronate sodium and is suitable for further clinical application expansion.

[0009] Specifically, the inventors solved the problem through the following technical solutions:

[0010] The first object of the present invention is to provide a tablet containing risedronate sodium, which is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol, disintegrant, and lubricant; calculated by weight, specifically as follows:

[0011]

[0012]

[0013] Further, the disintegrant is selected from one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone; the lubricant is selected from one of talc powder, magnesium stearate, and sodium dodecyl sulfate.

[0014] Further, the disintegrant is selected from sodium carboxymethyl starch; the lubricant is selected from magnesium stearate.

[0015] In a preferred embodiment of the present invention, the tablet is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol, disintegrant, and lubricant; calculated by weight, specifically as follows:

[0016]

[0017] The second object of the present invention is to provide the preparation process of the tablet:

[0018] 1) Dissolve monoethanolamine, esculetin, and risedronate sodium in an organic solvent, stir and mix evenly continuously, and rotary evaporate to dryness to obtain a mixture for standby;

[0019] 2) Mix the risedronate sodium mixture and chitosan evenly, then add sorbitol and mix evenly. Finally, add the disintegrant and lubricant and mix evenly before tabletting.

[0020] In a preferred embodiment of the present invention, the organic solvent is selected from one of glacial acetic acid, chloroform, and trichloromethane, and preferably the organic solvent is selected from glacial acetic acid.

[0021] Furthermore, the tablet preparation process is as follows:

[0022] 1) Dissolve monoethanolamine, aesculetin, and risedronate sodium in glacial acetic acid, continuously stir and mix evenly, and rotary evaporate to dryness to obtain a mixture for standby;

[0023] 2) Mix the risedronate sodium mixture and chitosan evenly, then add sorbitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and magnesium stearate and mix evenly before tabletting.

[0024] Furthermore, in the most preferred embodiment of the present invention, the tablet is composed of risedronate sodium, aesculetin, monoethanolamine, chitosan, sorbitol, sodium carboxymethyl starch, and magnesium stearate; calculated by weight, it is specifically as follows:

[0025]

[0026] Furthermore, the tablet preparation process is as follows:

[0027] 1) Dissolve monoethanolamine, aesculetin, and risedronate sodium in glacial acetic acid, continuously stir and mix evenly, and rotary evaporate to dryness to obtain a mixture for standby;

[0028] 2) Mix the risedronate sodium mixture and chitosan evenly, then add sorbitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and magnesium stearate and mix evenly before tabletting.

[0029] The third object of the present invention is to provide the use of the tablet in the preparation of a drug for treating postmenopausal osteoporosis.

[0030] Compared with the prior art, the present invention has achieved unexpected technical effects.

[0031] A tablet of aesculetin and risedronate sodium is provided. The dissolution of the risedronate sodium tablet in water reaches more than 80% at the 5th minute, which can meet the requirements of the 2020 edition of the Chinese Pharmacopoeia standard. Through accelerated experiments, it is found that the content of related substances of risedronate sodium in Examples 1-3 of the present invention is relatively low, which is better than other examples. Description of the Drawings

[0032] Figure 1: Comparison of the content of the active substance in the accelerated test at the 0th, 1st, 2nd, 3rd, and 6th months for each example.

[0033] Figure 2 : Comparison of the dissolution in the accelerated test at the 0th, 1st, 2nd, 3rd, and 6th months for each example.

[0034] Figure 3 : Comparison of the related substances in the accelerated test at the 0th, 1st, 2nd, 3rd, and 6th months for each example.

[0035] Detailed implementation mode

[0036] The present invention discloses a tablet containing sodium risedronate and its use. Those skilled in the art can draw on the content of this article and appropriately change the process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included within the scope of the present invention. The methods and applications of the present invention have been described through comparative examples, and relevant personnel can obviously make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0037] Example 1: A tablet containing sodium risedronate and its preparation method are as follows

[0038] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Monoethanolamine 0.2 Chitosan 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0039] The preparation method is as follows:

[0040] 1) Dissolve the prescribed amounts of monoethanolamine, esculetin, and sodium risedronate in glacial acetic acid, continuously stir and mix evenly, and rotary evaporate to dryness to obtain a mixture for standby;

[0041] 2) Mix the sodium risedronate mixture evenly with chitosan, then add sorbitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and magnesium stearate and mix evenly, and then press into tablets.

[0042] Example 2: A tablet containing sodium risedronate and its preparation method are as follows

[0043] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Monoethanolamine 0.2 Chitosan 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0044] The preparation method is the same as that of Example 1.

[0045] Other steps are the same as those of Example 1.

[0046] Example 3: A tablet containing sodium risedronate and its preparation method are as follows

[0047] Material Name Weight (g) Risedronate Sodium 5 Esculetin 0.5 Monoethanolamine 0.1 Chitosan 100 Sorbitol 20 Sodium Carboxymethyl Starch 8 Magnesium Stearate 1

[0048] The preparation method is the same as that of Example 1.

[0049] Example 4: A tablet containing risedronate sodium and its preparation method are as follows

[0050] Material Name Weight (g) Risedronate Sodium 5 Esculetin 0.5 Monoethanolamine 0.1 Chitosan 100 Sorbitol 20 Low-Substituted Hydroxypropyl Cellulose 8 Magnesium Stearate 1

[0051] The preparation method is the same as that in Example 1.

[0052] Comparative Example 1: A tablet containing risedronate sodium and its preparation method are as follows. The preparation method is the same as that in Example 1.

[0053] Material Name Weight (g) Risedronate Sodium 5 Monoethanolamine 0.2 Chitosan 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0054] Comparative Example 2: A tablet containing risedronate sodium and its preparation method are as follows

[0055] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Chitosan 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0056] The preparation method is the same as that in Example 1.

[0057] Comparative Example 3: A tablet containing risedronate sodium and its preparation method are as follows

[0058] Material Name Weight (g) Risedronate Sodium 5 Esculetin 5 Monoethanolamine 0.05 Chitosan 50 Sorbitol 128 Sodium Carboxymethyl Starch 8 Magnesium Stearate 2

[0059] The preparation method is the same as that in Example 1.

[0060] Comparative Example 4: A tablet containing risedronate sodium and its preparation method are as follows

[0061] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Monoethanolamine 0.2 Lactose 150 Xylitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0062] The preparation method is the same as that in Example 1.

[0063] Comparative Example 5: A tablet containing risedronate sodium and its preparation method are as follows

[0064] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Monoethanolamine 0.2 Microcrystalline Cellulose 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0065] The preparation method is the same as that in Example 1.

[0066] Comparative Example 6: A tablet containing risedronate sodium and its preparation method are as follows

[0067] Material Name Weight (g) Risedronate Sodium 5 Esculetin 1 Monoethanolamine 0.2 Chitosan 150 Sorbitol 30 Sodium Carboxymethyl Starch 10 Magnesium Stearate 2

[0068] The preparation method is as follows:

[0069] 1) Dissolve the prescribed amounts of monoethanolamine, esculetin and risedronate sodium in methanol, adjust the pH value to 5, continuously stir and mix evenly, and rotary evaporate to dryness to obtain a mixture for standby;

[0070] 2) Mix the risedronate sodium mixture and chitosan evenly, then add sorbitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and magnesium stearate and mix evenly before tabletting.

[0071] The particle sizes in the tablets finally prepared using different dissolution solvents are uneven and cannot meet the basic requirements of the tablets. There are serious mottles on the 5th day during storage. Therefore, it is not necessary to determine the dissolution and related substances.

[0072] Comparative Example 7: A tablet containing risedronate sodium and its preparation method are as follows

[0073]

[0074]

[0075] The preparation method is the same as that of Example 1.

[0076] At the 1st month, the content of related substances in the tablets reached 3.4%. Therefore, the subsequent related experiments were abandoned.

[0077] Verification Example 1: Dissolution and content of related substances of the tablets of the present invention

[0078] 2.1 Determination of dissolution of risedronate sodium tablets

[0079]

Dissolution determination

[0080] 2.2 Content detection

[0081]

Content determination

[0082] 2.3 Determination of related substances

[0083] Determination of related substances: Preparation of test solution: Crush the tablets of the examples, grind them into fine powder. Take an appropriate amount of the fine powder (equivalent to about 10.0 mg of risedronate sodium), weigh it accurately, place it in a 50 mL volumetric flask, add 19 mL of acetonitrile, sonicate for 10 minutes to dissolve risedronate sodium, add 0.07 moL / L phosphoric acid solution (adjust the pH value to 2.5 with triethylamine) to the scale, shake well, filter, and take the subsequent filtrate as the test solution.

[0084] Preparation of reference solution: Accurately measure 1 mL, place it in a 100 mL volumetric flask, dilute it to the scale with the mobile phase, shake well, and use it as the reference solution. Perform the test according to the high performance liquid chromatography method (General Principles 0512). Use octadecylsilane chemically bonded silica gel as the filler; use 0.07 moL / L phosphoric acid solution (adjust the pH value to 2.5 with triethylamine)-acetonitrile (62:38) as the mobile phase; the detection wavelength is 257 nm.

[0085] The number of theoretical plates calculated based on the risedronate sodium peak is not less than 2000, and the resolution between the risedronate sodium peak and the adjacent impurity peak should meet the requirements.

[0086] Accurately measure 20 μL of each of the above two solutions, inject them into the liquid chromatograph respectively, and record the chromatogram until 2 times the retention time of the main peak.

[0087] Accelerated test conditions: According to the commercial packaging, after the accelerated test (placed under the conditions of temperature 40 ± 2 °C and relative humidity 75% ± 5%), samples are taken and the above-mentioned dissolution is detected at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month during the test period.

[0088] 2.4 Results

[0089] Accelerated test conditions: According to the commercial packaging, after the accelerated test (placed under the conditions of temperature 40 ± 2 °C and relative humidity 75% ± 5%), samples are taken and the above-mentioned dissolution is detected at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month during the test period.

[0090] Figure 1 : By comparing the content of the active substance in the accelerated test of each example at the 0th, 1st, 2nd, 3rd, and 6th months, it can be seen that the effective substances of Examples 1-3 are significantly higher than those of Comparative Examples 1-3. The inventor believes that it may be that Comparative Example 1 does not contain esculetin, resulting in a decrease in the stability of risedronic acid, and there is slight degradation after the tablets are prepared; Comparative Example 2 does not contain monoethanolamine or the content of monoethanolamine is insufficient, and it cannot play the role of reducing related substances.

[0091] Figure 2:Dissolution comparison of accelerated tests for each example at 0, 1, 2, 3, and 6 months; Although Examples 1-3 and Comparative Examples 4-5 can all meet the requirements of the pharmacopoeia, it can be seen that the release degrees of Comparative Examples 3-5 at the end of 5 min are lower than those of Examples 1-3. The inventor believes that the use of different excipients may have an impact on the release degree of tablets, especially the filler has a greater impact. Lactose is also a commonly used excipient, but it has an impact on the release degree of risedronate. Lactose is a reducing sugar containing a free aldehyde group, which may react with the amino group in risedronate to form a Maillard reaction, generating a covalent complex, resulting in drug degradation or the formation of a poorly soluble complex, delaying the dissolution rate, and reducing the bioavailability.

[0092] Figure 3 :Comparison of related substances of each example in the accelerated test at 0, 1, 2, 3, and 6 months; It can be seen that the total impurities of Examples 1-3 are below 0.05, and the impurities of Comparative Examples 1-5 are above 0.1 (at the 6th month). The quality of the tablets of the present invention is significantly higher than that of the comparative examples.

[0093] Verification Example Two: Detection of Physical Properties

[0094] Table 1

[0095]

[0096] It can be seen that the physical properties of Examples 1-3 are good, with a smooth surface, uniform color, no mottles, and the friability and moisture absorption weight gain are within the controllable range.

Claims

1. A tablet containing risedronate sodium, characterized in that: The tablet is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol, a disintegrant and a lubricant; calculated by weight, specifically as follows: The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone; the lubricant is selected from talc, magnesium stearate, and sodium dodecyl sulfate.

2. The tablet according to claim 1, characterized in that The disintegrant is selected from sodium carboxymethyl starch; and the lubricant is selected from magnesium stearate.

3. The tablet according to claim 1, characterized in that The tablet is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol, a disintegrant and a lubricant; calculated by weight, specifically as follows:

4. The tablet according to claim 1, characterized in that The tablet preparation process is as follows: 1) dissolving monoethanolamine, esculetin and risedronate sodium in an organic solvent, stirring and mixing continuously, and rotary evaporating to dryness to obtain a mixture for later use; 2) The risedronate sodium mixture and chitosan are mixed evenly, and then sorbitol is added and mixed evenly, and finally a disintegrant and a lubricant are added and mixed evenly, and then tableting is performed.

5. The tablet according to claim 4, characterized in that The organic solvent is selected from one of glacial acetic acid, chloroform and chloroform, and preferably the organic solvent is selected from glacial acetic acid.

6. The tablet according to claim 1, characterized in that The tablet preparation process is as follows: 1) dissolving monoethanolamine, esculetin and risedronate sodium in glacial acetic acid, stirring and mixing continuously, and rotary evaporating to dryness to obtain a mixture for later use; 2) The risedronate sodium mixture and chitosan are mixed evenly, and then sorbitol is added and mixed evenly, and finally low-substituted hydroxypropyl cellulose and magnesium stearate are added and mixed evenly, and then tableting is performed.

7. The tablet according to claim 1, characterized in that The tablet is composed of the following raw materials in parts by weight:

8. The tablet according to claim 1, characterized in that The tablet is composed of risedronate sodium, esculetin, monoethanolamine, chitosan, sorbitol, a disintegrant and a lubricant; calculated by weight, specifically as follows: The tablet preparation process is as follows: 1) dissolving monoethanolamine, esculetin and risedronate sodium in an organic solvent, stirring and mixing continuously, and rotary evaporating to dryness to obtain a mixture for later use; 2) The risedronate sodium mixture and chitosan are mixed evenly, and then sorbitol is added and mixed evenly, and finally a disintegrant and a lubricant are added and mixed evenly, and then tableting is performed.

9. The tablet according to claim 1, characterized in that The tablet is composed of the following raw materials in parts by weight: The tablet preparation process is as follows: 1) dissolving monoethanolamine, esculetin and risedronate sodium in glacial acetic acid, stirring and mixing continuously, and rotary evaporating to dryness to obtain a mixture for later use; 2) The risedronate sodium mixture and chitosan are mixed evenly, and then sorbitol is added and mixed evenly, and finally low-substituted hydroxypropyl cellulose and magnesium stearate are added and mixed evenly, and then tableting is performed.

10. Use of the tablet according to any one of claims 1 to 9 in the preparation of a medicament for treating postmenopausal osteoporosis.

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