Tablet containing risedronate sodium and total flavonoids of rhizoma sparganii and application of tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tablet containing risedronate sodium and total flavonoids of rhizoma sparganii and application of the tablet. The tablet is composed of risedronate sodium, total flavonoids of rhizoma sparganii, L-cysteine, a filler, a disintegrating agent and a lubricant, and compared with single use of risedronate sodium, the prepared tablet can significantly increase the content of estradiol (Plt; 0.05), the dissolution effect is relatively good, the quality of the tablet is relatively high, and the tablet is suitable for further clinical application.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tablet containing risedronate sodium and total flavonoids of trifoliate spatholobi and uses thereof. Background Art

[0002] With the acceleration of the aging process of society, the medical care of the elderly is increasingly attracting people's attention. At present, osteoporosis has become one of the most common diseases that endanger the health of the elderly. Statistics from the International Osteoporosis Foundation show that osteoporosis currently endangers about one-third of women over the age of one-fifth of men over the age of one-fifth of the world. With the increase in the world's population and the increase in average life expectancy, the incidence of osteoporosis is bound to rise rapidly, and the pathological fractures caused by it will also increase accordingly, seriously affecting the life and quality of life of patients. The prevention and treatment of osteoporosis is of great significance to protecting human health and quality of life.

[0003] Risedronate sodium is a third-generation bisphosphonate drug developed by Procter & Gamble in the United States. It is used to prevent and treat osteoporosis in postmenopausal women. Its chemical name is: 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid monosodium salt, and its structural formula is Formula I:

[0004]

[0005] Chinese invention patent CN 116712568B discloses a sodium risedronate inclusion compound, preparation and use thereof. The invention uses a certain proportion of sodium carboxymethyl starch and peach gum to participate in the preparation of the sodium risedronate inclusion compound, thereby increasing the drug loading and encapsulation rate of the sodium risedronate inclusion compound, greatly improving the quality of the sodium risedronate inclusion compound, and using the sodium risedronate inclusion compound to prepare the sodium risedronate preparation, thereby overcoming the defect that sodium risedronate is sensitive to temperature and light, solving the problem that related substances are easily generated under high temperature and light conditions, and improving the stability of the sodium risedronate preparation.

[0006] Chinese invention patent CN101601661A is a sodium risedronate tablet and its preparation method. The present invention provides a sodium risedronate tablet, which is prepared by a powder direct tabletting 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%. The present invention also provides a preparation method of the tablet. The sodium risedronate tablet provided by the present invention reduces the high temperature and high humidity drying step, avoids the introduction of impurities, improves the stability of the drug, and can also save energy, save raw materials, and reduce production costs.

[0007] Chinese invention patent CN104721165B discloses a sodium risedronate coated tablet composition and its preparation method. The sodium risedronate coated tablet of the present invention contains excipients such as chitosan, hypromellose, polyethylene glycol, microcrystalline cellulose, etc., and has the advantages of low content of related substances, less adverse reactions in the digestive tract, and high safety of medication.

[0008] In the prior art, there is no report of preparing risedronate sodium and total flavonoids of Trigonella ternata into a pharmaceutical composition for use, and even less of preparing the two into tablets for use in related efficacy verification experiments. Summary of the invention

[0009] Based on the deficiencies of the prior art, a tablet containing risedronate sodium and total flavonoids of trifoliate is provided, which solves the problem of low solubility of risedronate sodium caused by poor water solubility and makes up for the defect of high related substances of risedronate sodium.

[0010] Specifically, the inventors solved the problem through the following technical solutions:

[0011] The first object of the present invention is to provide a tablet comprising risedronate sodium and total flavonoids from Tripterygium wilfordii, wherein the tablet is composed of risedronate sodium, total flavonoids from Tripterygium wilfordii, L-cysteine, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows:

[0012]

[0013] Furthermore, the filler is selected from any one of microcrystalline cellulose PH101, sorbitol, starch, and lactose, or a combination of two or more thereof; the disintegrant is selected from one of sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sodium polyacrylate, and cross-linked polyvinyl pyrrolidone; and the lubricant is selected from one of colloidal silicon dioxide, calcium stearate, magnesium stearate, and sodium lauryl sulfate.

[0014] Furthermore, the filler is selected from microcrystalline cellulose PH101 and sorbitol; the disintegrant is selected from cross-linked polyvinyl pyrrolidone; and the lubricant is selected from magnesium stearate.

[0015] Further, in a preferred embodiment of the present invention, the tablet is composed of risedronate sodium, total flavonoids of trifoliate, L-cysteine, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows:

[0016]

[0017] The second object of the present invention is to provide a tablet preparation process, which is as follows:

[0018] 1) dissolving the disintegrant in the citric acid-sodium citrate buffer solution of risedronate sodium, stirring continuously, and mixing well;

[0019] 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing and heating to a molten state;

[0020] 3) The filler is uniformly added to the mixed solution of step 2), stirred to dry, granulated, lubricant is added, and tableting is performed.

[0021] Furthermore, in a preferred embodiment of the present invention, the pH value of the citric acid buffer is 5.5-6.5.

[0022] Furthermore, the tablet preparation process is:

[0023] 1) dissolving cross-linked polyvinyl pyrrolidone in a citric acid-sodium citrate solution of risedronate sodium with a pH value of 6.0, stirring continuously to mix well;

[0024] 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing well, and heating in a water bath at 80° C. until molten;

[0025] 3) adding 101 microcrystalline cellulose and sorbitol uniformly to the mixed solution of step 2), stirring for 1-2 hours; drying, granulating into 16 mesh, adding magnesium stearate, and tableting.

[0026] The third object of the present invention is to provide the use of the risedronate sodium tablets in the preparation of drugs for treating postmenopausal osteoporosis.

[0027] The third object of the present invention is to provide a combination of total flavonoids from Tripterygium wilfordii and risedronate sodium and their pharmacological effects. Figure 1 It can be seen that the risk of fracture of castrated rats increases by 2.6 times for every standard deviation reduction in femoral bone density (BMO). The experimental results show that the femoral bone density of castrated rats in the model group is lower than that in the normal group, indicating that the femoral bone density of castrated rats after ovarian removal is reduced and the risk of fracture is increased; the femoral bone density of castrated rats after treatment with the tablet of the present invention is significantly higher than that of the model group. The therapeutic effect of the comparative example 1 group is similar to that of the western medicine group, indicating that the tablets prepared by the present invention can be used normally. The femoral bone density of castrated rats in the embodiment 1 group is higher than that of the other groups, indicating that the combination of total flavonoids of Sanleng and risedronate sodium has played an unexpected technical effect in improving the femoral bone density of castrated rats in rats. At the same time, the inventor found that the tablets prepared by total flavonoids of Sanleng and risedronate sodium can increase the content of estradiol in serum and increase the bone mass of the waist, hip, forearm, etc.

[0028] The fourth object of the present invention is to provide a tablet of total flavonoids from Tripterygium wilfordii and risedronate sodium. The dissolution of risedronate sodium tablets in different systems can meet the pharmacopoeia standards. Accelerated experiments have shown that the risedronate sodium in Examples 1-3 of the present invention is significantly degraded. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 :BMD (g / m 2 ), where ## indicates that there is a significant difference between Example 1 and the normal group (P<0.01); @@ indicates that there is a significant difference between the model group and the normal group (P<0.01); ** indicates that there is a significant difference between Example 1 and the comparative example 1 group and the western medicine group (P<0.01).

[0030] Figure 2 : The results of serum E2 (mg / L) content detection in each relevant embodiment, wherein ## indicates that there is a significant difference between Example 1 and the normal group (P<0.01); @@ indicates that there is a significant difference between Example 1 and the comparative example 1 group and the western medicine group (P<0.01).

[0031] Figure 3 : The dissolution rates of Examples 1-3 and Comparative Examples 6-7 in water at 0, 1, 2, 3, and 6 months.

[0032] Figure 4 : The dissolution rates of Examples 1-3 and Comparative Examples 6-7 in 0.1 mol / L hydrochloric acid at 0, 1, 2, 3, and 6 months.

[0033] Figure 5 : The dissolution of Examples 1-3 and Comparative Examples 6-7 in pH 6.8 buffered saline at 0, 1, 2, 3, and 6 months.

[0034] Figure 6 : The contents of related substances in Examples 1-3 and Comparative Examples 1-7 at 0, 1, 2, 3, and 6 months.

[0035] Specific embodiment

[0036] The present invention discloses a tablet containing risedronate sodium and total flavonoids of trifoliate and its use. Those skilled in the art can refer to the content of this article and appropriately change the process parameters. It should be particularly pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through more embodiments, and relevant personnel can obviously modify or appropriately change and combine 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 risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0038] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 1.7 L-Cysteine 2.8 Microcrystalline Cellulose 101 200 Sorbitol 78 Cross-linked polyvinyl pyrrolidone 16 Magnesium Stearate 3.2

[0039] The preparation method is as follows:

[0040] 1) dissolving cross-linked polyvinyl pyrrolidone in a citric acid-sodium citrate solution of risedronate sodium with a pH value of 6.0, stirring continuously to mix well;

[0041] 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing well, and heating in a water bath at 80° C. until molten;

[0042] 3) adding 101 microcrystalline cellulose and sorbitol uniformly to the mixed solution of step 2), stirring for 1-2 hours; drying, granulating into 16 mesh, adding magnesium stearate, and tableting.

[0043] Example 2: A tablet containing risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0044]

[0045]

[0046] The preparation method is as follows: wherein cross-linked polyvinyl pyrrolidone is dissolved in a citric acid-sodium citrate solution of risedronate sodium with a pH value of 5.5, and the mixture is stirred continuously to mix well;

[0047] The other steps are the same as in Example 1.

[0048] Example 3: A tablet containing risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0049] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 2.5 L-Cysteine 3.5 Microcrystalline Cellulose 101 360 Sorbitol 23 Cross-linked polyvinyl pyrrolidone 5 Magnesium Stearate 5

[0050] The preparation method is as follows:

[0051] 1) dissolving cross-linked polyvinyl pyrrolidone in a citric acid-sodium citrate solution of risedronate sodium with a pH value of 6.5, stirring continuously to mix well;

[0052] The other steps are the same as in Example 1.

[0053] Comparative Example 1: A tablet containing risedronate sodium and total flavonoids of Tripterygium wilfordii and a preparation method thereof, as follows

[0054]

[0055]

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

[0057] Comparative Example 2: A tablet containing risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0058] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 1.7 Microcrystalline Cellulose 101 200 Sorbitol 78 Cross-linked polyvinyl pyrrolidone 16 Magnesium Stearate 3.2

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

[0060] Comparative Example 3: A tablet containing risedronate sodium and total flavonoids of Tripterygium wilfordii and a preparation method thereof, as follows

[0061] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 1.7 Sodium Lauryl Sulfate 2.8 Microcrystalline Cellulose 101 200 Sorbitol 78 Cross-linked polyvinyl pyrrolidone 16 Magnesium Stearate 3.2

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

[0063] Comparative Example 4: A tablet containing risedronate sodium and total flavonoids of Tripterygium wilfordii and a preparation method thereof, as follows

[0064]

[0065]

[0066] The preparation method is the same as Example 1.

[0067] Comparative Example 5: A tablet containing risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0068] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 1.7 L-Cysteine 2.8 Microcrystalline Cellulose 101 200 Sorbitol 78 Cross-linked polyvinyl pyrrolidone 16 Magnesium Stearate 3.2

[0069] The preparation method is as follows:

[0070] 1) dissolving cross-linked polyvinyl pyrrolidone in a phosphate buffer solution of risedronate sodium with a pH value of 6.0, stirring continuously to mix well;

[0071] 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing well, and heating in a water bath at 80° C. until molten;

[0072] 3) adding 101 microcrystalline cellulose and sorbitol uniformly to the mixed solution of step 2), stirring for 1-2 hours; drying, granulating into 16 mesh, adding magnesium stearate, and tableting.

[0073] Comparative Example 6: A tablet containing risedronate sodium and total flavonoids of Tripterygium wilfordii and a preparation method thereof, as follows

[0074]

[0075]

[0076] The preparation method is the same as Example 1.

[0077] Comparative Example 7: A tablet containing risedronate sodium and total flavonoids from Tripterygium wilfordii and a preparation method thereof, as follows

[0078] Material Name Weight(g) Risedronate 5 Total flavonoids from Tripterygium wilfordii 1.7 Sodium phenylpropionate 2.8 sucrose 200 β-Cyclodextrin 78 Sodium Hydroxypropyl Starch 16 Sodium Lauryl Sulfate 3.2

[0079] The preparation method is the same as Example 1.

[0080] Verification Example 1: Effect of the tablet of the present invention on the postmenopausal osteoporosis model in rats

[0081] 1.1 Experimental animals and modeling

[0082] Forty healthy female SD rats aged 8 months with a body weight of (180-270) g (provided by Shandong Provincial Hospital, animal license number: SYXK(Lu)20230014) were raised for one week before the experiment.

[0083] Modeling: 32 healthy female SD rats were randomly divided into 5 groups: normal group, model group, western medicine group, Example 1 group and Comparative Example 1 group, 8 rats in each group. The rats in each group were numbered separately. Except for the normal group, the rats in other groups were subjected to ovariectomy to make castrated rat models. 20 g / L sodium pentobarbital was injected intraperitoneally at 40 mg / kg for anesthesia. The rats were fixed on a rat splint in the prone position and routinely disinfected. The skin and muscle layer were cut layer by layer at about 1 cm beside the lumbar vertebra on one side of the back, and the abdominal cavity was entered to remove the ovaries. The incisions were sutured layer by layer, and the contralateral side was treated in the same way. The wound was rubbed with penicillin powder.

[0084] 1.2 Experimental drugs and dosage

[0085] The tablets prepared in Example 1 and Comparative Example 1 were used once a day at a dosage of 31.5 mg / kg / time, and were prepared into 50 mg / L for oral administration.

[0086] Western medicine group: Nylestradiol tablets 0.1 mg / tablet (Batch number: National Medicine Standard H11020123; Langfang Gaobo Jingbang Pharmaceutical Co., Ltd.); intragastric administration, once a day.

[0087] The normal group and the model group were gavaged with an equal amount of saline every day, 5 mL / d for each rat.

[0088] During this period, the animals in each group had a normal diet and free access to water. After 8 weeks of drug administration, the eyeballs were removed and blood was collected from the left femur.

[0089] 1.3 Statistical analysis

[0090] The experimental data were statistically processed using GraphPadPrism 9.0 biostatistics software: the data were expressed as Mean±SD, and one-way analysis of variance was used for comparison among groups.

[0091] 1.4 Experimental Results Analysis

[0092] Figure 1 :BMD (g / m 2), where ## indicates that there is a significant difference between Example 1 and the normal group (P<0.01); @@ indicates that there is a significant difference between the model group and the normal group (P<0.01); ** indicates that there is a significant difference between Example 1 and the comparative example 1 group and the western medicine group (P<0.01).

[0093] Figure 2 : The results of serum E2 (mg / L) content detection in each relevant embodiment, wherein ## indicates that there is a significant difference between Example 1 and the normal group (P<0.01); @@ indicates that there is a significant difference between Example 1 and the comparative example 1 group and the western medicine group (P<0.01).

[0094] Verification Example 2: Dissolution of tablets of the present invention and content of related substances

[0095] 2.1 Dissolution Determination of Risedronate Sodium Tablets

[0096] Strictly follow the "Establishment of the Dissolution Determination Method for Risedronate Sodium Tablets" published by Li Pengmei et al. Specifically: High performance liquid chromatography was used to determine the concentration and calculate the cumulative dissolution. The chromatographic column was Shiseido C 18 The mobile phase was a mixed buffer solution (pH 7.2)-methanol (75:25, V / V), the flow rate was 1.0 mL / min, and the detection wavelength was 262 nm. The paddle method was used to screen the media (water, 0.1 mol / L hydrochloric acid, pH 6.8 buffered saline solution) and the rotation speed (50, 75, 100 r / min) based on the cumulative dissolution index, and the dissolution of the relevant examples was detected at the 5th minute.

[0097] Accelerated test conditions: According to commercial packaging, after accelerated testing (temperature 40±2°C, relative humidity 75%±5%), samples were taken at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month of the test to test the above dissolution rate.

[0098] 2.1.2 Result detection

[0099] Figure 3 : The dissolution rates of Examples 1-3 and Comparative Examples 6-7 in water at 0, 1, 2, 3, and 6 months.

[0100] Figure 4 : The dissolution rates of Examples 1-3 and Comparative Examples 6-7 in 0.1 mol / L hydrochloric acid at 0, 1, 2, 3, and 6 months.

[0101] Figure 5 : The dissolution of Examples 1-3 and Comparative Examples 6-7 in pH 6.8 buffered saline at 0, 1, 2, 3, and 6 months.

[0102] It can be seen that the risedronate sodium in the tablets was tested at 0th month, 1st month, 2nd month, 3rd month and 6th month, and it was found that the dissolution effect of Examples 1-3 was better than that of Comparative Examples 6-7. The inventors believe that the type and proportion of excipients may affect the dissolution of risedronate sodium.

[0103] 2.2 Determination of related substances in risedronate sodium tablets

[0104] Chromatographic conditions: Thermo BDS Hypersil C column 18 The column was 250 mm × 4.6 mm, 5 μm. The mobile phase was methanol-water (containing 5 mmol / L ammonium dihydrogen phosphate, 2 mmol / L tetrabutylammonium bromide, and 1.5 mmol / L disodium ethylenediaminetetraacetate) (25:75, v / v). The mobile phase was filtered through a 0.45 μm microporous filter membrane and ultrasonically degassed before use.

[0105] Preparation of reference substance: Take an appropriate amount of risedronate sodium bulk drug, add mobile phase to prepare a reference substance solution of about 1 mg / mL, and adjust the pH to 7.9 with 1 mol / L sodium hydroxide solution.

[0106] Preparation of test sample: Take the tablets of Examples 1-3 and Comparative Examples 1-6 and Comparative Example 7, grind them, add 80 mL of water, and then make the volume to 1000 mL, take 10 mL and add the mobile phase to prepare a test solution of about 1 mg / mL.

[0107] The flow rate was 0.8 mL / min, the column temperature was 30 °C, and the detection wavelength was 262 nm.

[0108] 2.2.2 Result detection

[0109] Figure 6 The risedronate sodium tablets of the present invention have stable content, low content of related substances and high stability under accelerated conditions. The content of related substances in Examples 1-3 is below 0.15%. The related substances are mainly 3-pyridineacetic acid hydrochloride.

Claims

1. A tablet comprising risedronate sodium and total flavonoids from Tripterygium wilfordii, characterized in that: The tablets are composed of risedronate sodium, total flavonoids of trifoliate, L-cysteine, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows: The filler is selected from any one of microcrystalline cellulose PH101, sorbitol, starch, and lactose, or a combination of two or more thereof; the disintegrant is selected from one of sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sodium polyacrylate, and cross-linked polyvinyl pyrrolidone; and the lubricant is selected from one of colloidal silicon dioxide, calcium stearate, magnesium stearate, and sodium lauryl sulfate.

2. The tablet containing risedronate sodium according to claim 1, characterized in that: The filler is selected from microcrystalline cellulose PH101 and sorbitol; the disintegrant is selected from cross-linked polyvinyl pyrrolidone; and the lubricant is selected from magnesium stearate.

3. The tablet containing risedronate sodium according to claim 1, characterized in that: The tablets are composed of risedronate sodium, total flavonoids of trifoliate, L-cysteine, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows:

4. The tablet containing risedronate sodium according to claim 1, characterized in that: The tablet preparation process is as follows: 1) dissolve the disintegrant in the risedronate sodium citric acid solution, stirring continuously to mix well; 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing and heating to a molten state; 3) The filler is uniformly added to the mixed solution of step 2), stirred to dry, granulated, lubricant is added, and tableting is performed.

5. The tablet containing risedronate sodium according to claim 4, characterized in that: The pH value of the citric acid buffer is 5.5-6.

5.

6. The tablet containing risedronate sodium according to claim 2, characterized in that: The tablet preparation process is as follows: 1) dissolving cross-linked polyvinyl pyrrolidone in a risedronate sodium citric acid-citric acid solution with a pH value of 6.0, stirring continuously to mix well; 2) adding L-cysteine ​​and total flavonoids from Tripterygium wilfordii to step 1), mixing well, and heating in a water bath at 80° C. until molten; 3) adding 101 microcrystalline cellulose and sorbitol uniformly to the mixed solution of step 2), stirring for 1-2 hours; drying, granulating into 16 mesh, adding magnesium stearate, and tableting.

7. Use of the tablet according to any one of claims 1 to 6 in the preparation of a medicament for treating postmenopausal osteoporosis.

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