Preparation method and application of salvia tablets

Abstract

The invention relates to the field of traditional Chinese medicine preparation, and discloses a preparation method of salvia miltiorrhiza tablets, which comprises the following steps: 1) mixing salvia miltiorrhiza, lauryl sodium sulfate and / or hydroxypropyl methyl-beta-cyclodextrin and water, and boiling for 0.5-2 hours to obtain an extracting solution; 2) concentrating the extracting solution to obtain an extract; 3) filtering the extract to obtain a liquid medicine; 4) performing spray drying on the liquid medicine to obtain salvia miltiorrhiza spray powder; 5) granulating and sieving the salvia miltiorrhiza spray powder to obtain salvia miltiorrhiza granules; and (6) mixing the salvia miltiorrhiza granules with magnesium stearate, and tabletting to obtain the salvia miltiorrhiza tablets. By changing the extraction method of the salvia miltiorrhiza tablets, the content of salvianolic acid B is increased by 30%, and the content of tanshinone IIA is increased by about 3 times, so that the extraction rate of effective components in the salvia miltiorrhiza tablets can be remarkably increased by the method, and the medicine effect of the product is favorably improved. The weight of the salvia miltiorrhiza tablets prepared by the method is reduced by 30%, the disintegration time is shortened by 50%, and the salvia miltiorrhiza tablets are helpful to take effect quickly.

Description

Technical Field

[0001] This specification relates to the field of traditional Chinese medicine preparation, and particularly to a preparation method and application of danshen tablets. Background Art

[0002] Danshen is the dried root and rhizome of the plant Salvia miltiorrhiza Bunge of the Labiatae family. It is bitter and slightly cold in nature, and belongs to the heart and liver meridians. It is a commonly used drug for promoting blood circulation and removing blood stasis in clinical practice. It was first recorded in "Shennong's Herbal Classic" in the Qin and Han dynasties, and it was recorded that it has the effects of "treating pathogenic factors in the heart and abdomen, gurgling bowel sounds like running water, cold and heat accumulation; breaking masses and removing accumulations, relieving vexation and fullness, and tonifying qi". Wang Qingren's "Corrections of Medical Errors" written in the Qing Dynasty pointed out that "lumps in the abdomen and abdomen must be caused by the blood in the form", which more clearly expounded the relationship between pathological "blood stasis" and the formation of abdominal "abdominal masses" and "accumulations" (equivalent to modern tumors). Some scholars have clearly shown through network pharmacology research that danshen can be used for the treatment of gastric cancer. Zhang Wenshan used the traditional Chinese medicine injection danshen combined with astragalus to treat advanced gastric cancer. The research results showed that danshen has definite clinical efficacy, can inhibit tumor growth, reduce the toxic and side effects of drugs, prolong the survival time of patients, and improve the clinical efficacy. Fan Shumei used the traditional Chinese medicine injection danshen for patients after gastric cancer surgery and found that danshen improved the hypercoagulable state of patients' blood and reduced the risk of lower extremity deep vein thrombosis. Modern pharmacological research has found that danshen contains up to 15 liposoluble active tanshinone compounds, including tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, and isocryptotanshinone, etc. Zhong Xiongdong's research found that tanshinone I can initiate the generation of reactive oxygen species in gastric cancer cells, thereby inducing oxidative stress and apoptosis. Ge Yuqing's research found that dihydrotanshinone can inhibit the activity of the Hedgehog pathway, thereby inhibiting the migration and invasion ability of SGC7901 gastric cancer cells.

[0003] In the extraction of the active ingredients of current danshen preparations, water extraction or alcohol extraction is used, but there is a problem of low extraction rate. The main reason is that during the process of concentrating the extraction solution, the liposoluble components are unstable, resulting in large batch-to-batch differences in the liposoluble components in the products made from the concentrated solution. Summary of the Invention

[0004] In order to solve the above technical problems, this application provides a process method for improving the active ingredients of danshen tablets, shortening the drug disintegration and onset time. The content of salvianolic acid B is increased by 30%, the content of tanshinone IIA is increased by about 3 times, and the disintegration time of danshen tablets is shortened by 50%, which helps the rapid dissolution and absorption of the active ingredients and enables the product to take effect quickly.

[0005] The present application provides a method for preparing danshen tablets, comprising the following steps: 1) Mix danshen, sodium dodecyl sulfate and / or hydroxypropyl methyl-β-cyclodextrin with water and boil for 0.5 to 2 hours to obtain an extract; 2) Concentrate the extract to obtain an extract paste; 3) Filter the extract paste to obtain a medicinal liquid; 4) Spray-dry the medicinal liquid to obtain danshen spray powder; 5) Granulate the danshen spray powder and sieve it to obtain danshen granules; 6) Mix the danshen granules with magnesium stearate and press them into tablets to obtain danshen tablets.

[0006] The present application also provides danshen tablets prepared by the above preparation method. In the danshen tablets, the content of salvianolic acid B is 41.762 mg / g, and the content of tanshinone IIA is 1.568 mg / g.

[0007] The present application also provides the application of the above preparation method in the preparation of danshen tablets.

[0008] The beneficial effects brought by the examples of the specification of the present application include but are not limited to: (1) To increase the content of lipophilic components in danshen tablets, the present application introduces new excipients such as β-cyclodextrin or hydroxypropyl β-cyclodextrin. The cavity size of β-cyclodextrin or hydroxypropyl β-cyclodextrin is moderate and the inclusion ability is strong. β-cyclodextrin or hydroxypropyl β-cyclodextrin can form cyclodextrin inclusion complexes with the lipophilic components of danshen. Sodium dodecyl sulfate or polysorbate 80, etc. have amphiphilic structures of hydrophilic and lipophilic, which helps the active ingredients of danshen dissolve in water. The combination of the two can increase the dissolution of the active ingredients of danshen and improve the content of the active ingredients in danshen tablets; (2) The combination of solubilizers, cosolvents and danshen extract paste can accelerate the disintegration / dissolution rate of this product and shorten the disintegration onset time of this product. Detailed implementation mode

[0009] As shown in this specification and the claims, unless the context clearly indicates otherwise, words such as "a", "an", "one" and / or "the" are not specifically singular and may also include plural. Generally speaking, the terms "comprising" and "including" only indicate the inclusion of the steps and elements that have been clearly identified, and these steps and elements do not constitute an exclusive list. The method or device may also include other steps or elements.

[0010] The present application provides a method for preparing danshen tablets, comprising the following steps: 1) Mix danshen, sodium dodecyl sulfate and / or hydroxypropyl methyl-β-cyclodextrin with water and boil for 0.5 to 2 hours to obtain an extract; 2) Concentrate the extract to obtain an extract paste; 3) Filter the extract paste to obtain a medicinal liquid; 4) Spray-dry the medicinal liquid to obtain danshen spray powder; 5) Granulate the danshen spray powder and sieve it to obtain danshen granules; 6) Mix the danshen granules with magnesium stearate and press them into tablets to obtain danshen tablets.

[0011] In some embodiments, in step 1), the mass ratio of danshen (Salvia miltiorrhiza), sodium dodecyl sulfate, hydroxypropyl methyl-β-cyclodextrin, and water can be 200:1:2:2400.

[0012] In some embodiments, in step 1), the boiling time can be 1 to 1.5 hours. In some embodiments, preferably, in step 1), the boiling time can be 1.5 hours.

[0013] In some embodiments, in step 1), after boiling, it needs to be filtered through an 80-120 mesh sieve. In some embodiments, in step 1), after boiling, it needs to be filtered through a 90-110 mesh sieve. In some embodiments, in step 1), after boiling, it needs to be filtered through a 100-110 mesh sieve. In some embodiments, in step 1), preferably, after boiling, it needs to be filtered through a 100 mesh sieve.

[0014] In some embodiments, in step 2), the concentration can be by reduced pressure vacuum concentration. In some embodiments, preferably, the concentration conditions can be 65 - 75°C, 0.04 - 0.08 Mpa.

[0015] In some embodiments, in step 2), the relative density of the extract can be 1.10 - 1.16.

[0016] In some embodiments, in step 3), it can be filtered through an 80 - 100 mesh sieve.

[0017] In some embodiments, in step 4), the specific conditions for spray drying are: the liquid medicine is kept at 60 - 80°C, the inlet air temperature is 180 - 200°C; the outlet air temperature is 90 - 105°C, the rotation speed of the atomizer is 10000 - 12000 revolutions per minute, and the pressure inside the tower is 195 - 205 Pa.

[0018] In some embodiments, in step 5), the danshen spray powder is put into a fluidized bed granulator, and water is used as a wetting agent for granulation, followed by screening and sizing.

[0019] In some embodiments, in step 6), the mass ratio of danshen granules to magnesium stearate can be 100:1.

[0020] In some embodiments, in step 6), the mixing can be carried out at room temperature in a V-type mixer for 15 minutes.

[0021] This application also provides danshen tablets prepared by the above preparation method. In the danshen tablets, the content of salvianolic acid B is 41.762 mg / g, and the content of tanshinone IIA is 1.568 mg / g.

[0022] Tanshinone IIA (TSA) is one of the fat-soluble active ingredients in Salvia miltiorrhiza, which contains an orthoquinone structure and can participate in various biochemical reactions in the body. In recent years, a large number of clinical and experimental studies have proved that TSA has significant pharmacological effects such as anti-lung, anti-myocardial, and anti-renal fibrosis, and can also inhibit the infiltration of inflammatory cells and the expression of inflammatory cytokines, have antioxidant effects, and improve microcirculation, etc.

[0023] Salvianolic acid B (SAB) is the water-soluble ingredient with the highest content in Salvia miltiorrhiza, which is formed by the condensation of three molecules of danshensu and one molecule of caffeic acid. Research shows that SAB has anti-inflammatory, antioxidant, free radical scavenging effects, etc., especially has significant therapeutic effects on fibrotic diseases of organs such as the heart and lungs. Therefore, SAB shows great potential in the treatment of skin fibrotic diseases.

[0024] This application also provides the use of the above preparation method in the preparation of Salvia tablets.

[0025] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all obtained from regular biochemical reagent companies unless otherwise specified. In the following examples, all quantitative tests are set with three repeated experiments, and the results are averaged.

[0026] Example 1

[0027] Combined with the production process and prescription of Salvia tablets, 1% hydroxypropyl methyl-β-cyclodextrin is added to test the retention of active ingredients in the finished Salvia tablets.

[0028] The extraction method of the active ingredients of Salvia in this example includes the following steps:

[0029] An extraction method of the active ingredients of Salvia includes the following steps:

[0030] (1) Water extraction: 1 kg of Salvia miltiorrhiza medicinal materials, add 10 g of hydroxypropyl methyl-β-cyclodextrin, add 8 kg of water, decoct once, start timing from boiling, decoct the juice for 1 hour, and pass the medicinal liquid through a 100-mesh sieve to obtain the water extract for standby.

[0031] (2) Concentration: The extract is concentrated under reduced pressure and vacuum (65 - 75 °C, 0.04 - 0.08 MPa) to a relative density of 1.10 - 1.16 (65 - 75 °C), and the extract is reserved for standby;

[0032] (3) Drying: 600 g of the extract, stir evenly, pass through an 80 - 100-mesh sieve, keep the medicinal liquid at 60 - 80 °C, control the inlet air temperature at about 180 - 200 °C; control the outlet air temperature between 90 - 105 °C, control the rotation speed of the atomizer between 10000 - 12000 revolutions per minute, and the pressure in the tower is about 195 - 205 Pa for spray drying;

[0033] (4) Granulation: Put 200 g of Danshen spray powder into a fluidized bed granulator, use water as the wetting agent for granulation, sieve and size the granules, and reserve the granules.

[0034] (5) Total mixing: Add 2 g of magnesium stearate to 200 g of granules, mix in a V-type mixer at room temperature for 15 minutes, and reserve.

[0035] (6) Tabletting: Tablettize the total mixed granules and reserve.

[0036] Example 2

[0037] Combined with the production process and prescription of Danshen tablets, add 5‰ sodium dodecyl sulfate, and test the retention of active ingredients in the finished Danshen tablets.

[0038] In this example, the extraction method of the active ingredients of Danshen includes the following steps:

[0039] An extraction method of the active ingredients of Danshen includes the following steps:

[0040] (1) Water extraction: Add 5 g of sodium dodecyl sulfate to 1 kg of Danshen medicinal materials, add 8 kg of water, decoct once, start timing from boiling, decoct for 1 hour, sieve the decoction with a 100-mesh sieve to obtain the water extract, and reserve.

[0041] (2) Concentration: Concentrate the extract under reduced pressure and vacuum (65 - 75 °C, 0.04 - 0.08 MPa) to a relative density of 1.10 - 1.16 (65 - 75 °C), and reserve the extract.

[0042] (3) Drying: 600 g of the extract, sieve through an 80 - 100-mesh sieve, keep the decoction at 60 - 80 °C, control the inlet air temperature at about 180 - 200 °C; control the outlet air temperature between 90 - 105 °C, control the rotational speed of the atomizer between 10000 - 12000 revolutions per minute, and the pressure in the tower is about 195 - 205 Pa, and spray dry.

[0043] (4) Granulation: Put 200 g of Danshen spray powder into a fluidized bed granulator, use water as the wetting agent for granulation, sieve and size the granules, and reserve the granules.

[0044] (5) Total mixing: Add 2 g of magnesium stearate to 200 g of granules, mix in a V-type mixer at room temperature for 15 minutes, and reserve.

[0045] (6) Tabletting: Tablettize the total mixed granules and reserve.

[0046] Example 3

[0047] Combined with the production process and prescription of Danshen tablets, add 5‰ sodium dodecyl sulfate and 1% hydroxypropyl methyl-β-cyclodextrin, and test the retention of active ingredients in the finished Danshen tablets.

[0048] The method for extracting the effective components of Salvia miltiorrhiza in this example comprises the following steps:

[0049] A method for extracting effective components of Salvia miltiorrhiza comprises the following steps:

[0050] (1) Extraction: Take 1 kg of Salvia miltiorrhiza, 5 g of sodium dodecyl sulfate, and 10 g of hydroxypropylmethyl-β-cyclodextrin, add 12 kg of water, extract once, start timing from boiling, the time is 1.5 hours, pass the liquid through a 100-mesh sieve, and obtain a water extract for later use;

[0051] (2) The extract is concentrated under reduced pressure and vacuum (65-75°C, 0.04-0.08MPa) to a relative density of 1.10-1.16 (65-75°C), and the extract is used for later use;

[0052] (3) Drying: 600 g of extract was stirred evenly, passed through a 80-100 mesh sieve, the liquid was kept at 60-80°C, and spray dried;

[0053] (4) Granulation: Put 200 g of Danshen spray powder into a boiling granulator, use water as a wetting agent to granulate, sieve the granules, and set aside;

[0054] (5) Total mixing: Add 200 g of the granules to 2 g of magnesium stearate, mix for 15 minutes, and set aside.

[0055] (6) Tableting: Press the total mixed granules into tablets for later use.

[0056] Comparative Example 1

[0057] A method for extracting effective components of Salvia miltiorrhiza comprises the following steps:

[0058] (1) Ethanol extraction: 1 kg of Salvia miltiorrhiza was placed in a round-bottom flask, and 3 kg of 90% ethanol was added. Reflux extraction was performed once, and the time was counted from the boiling point, and the time was 1.5 hours. The medicinal solution was passed through a 100-mesh sieve to obtain an ethanol extract, which was set aside;

[0059] (2) Water extraction: Add 5 kg of water to the residue after alcohol extraction of Danshen, boil once, start timing from boiling, boil for 1 hour, pass the liquid through a 100-mesh sieve, and obtain the water extract for later use;

[0060] (3) Concentration: The alcohol extract is filtered through a 100-mesh sieve, and the filtrate is concentrated under reduced pressure and vacuum (65-75° C., 0.04-0.08 MPa), and the ethanol is recovered until there is no alcohol taste, and the ethanol is combined with the water extract, and concentrated under reduced pressure and vacuum (65-75° C., 0.04-0.08 MPa) to a relative density of 1.10-1.16 (65-75° C.), and about 800 g of the extract is prepared for use;

[0061] (4) Drying: The extract (800 g) is mixed with 17 g of dextrin and water to prepare a liquid medicine with a relative density of 1.08 - 1.10 (50 - 60 °C). After stirring evenly, it is sieved through an 80 - 100 mesh sieve. The liquid medicine is kept at a temperature of 60 - 80 °C, the inlet air temperature is controlled at about 180 - 200 °C, the outlet air temperature is controlled between 90 - 105 °C, the rotation speed of the atomizer is controlled between 10,000 - 12,000 revolutions per minute, and the pressure inside the tower is about 195 - 205 Pa for spray drying;

[0062] (5) Granulation: 200 g of Danshen spray powder, 11 g of microcrystalline cellulose, 50 g of starch, and 13 g of calcium sulfate are put into a fluidized bed granulator. Take 2 g of starch, add boiling water to 100 g to prepare a 2% starch paste as a wetting agent for granulation. After sieving and sizing, the granules are reserved;

[0063] (6) Total mixing: 2.76 g of magnesium stearate is added to 276 g of the granules, and they are mixed in a V - type mixer at room temperature for 15 minutes and reserved.

[0064] (7) Tabletting: The total - mixed granules are tabletted and reserved.

[0065] Test Example

[0066] 1. Content determination

[0067] Take the tablets prepared in the preparation example and refer to the determination method of Compound Danshen Tablets on page 1307 of the first part of the Chinese Pharmacopoeia (2020 edition). Select tanshinone IIA and cryptotanshinone, the fat - soluble characteristic components in Danshen, as the index components to further understand the extraction situation of related components in Danshen.

[0068] The test conditions are as follows:

[0069] Chromatographic column: Agilent Zorbax SB C18 (4.6 * 250 mm, 5 μm)

[0070] Mobile phase: Methanol: Water (75:25)

[0071] Detection wavelength: 270 nm

[0072] Test conditions for tanshinone IIA, tR = 35.862 min

[0073] Test conditions for cryptotanshinone: tR = 22.022 min

[0074] Column temperature: 25 °C

[0075] Injection volume: 10 μL

[0076] Experimental sample treatment. Grind the prepared Danshen tablets finely, take an appropriate amount, dissolve it in 75% methanol, filter through a membrane filter, collect 1.5 mL of the continued filtrate for liquid - phase testing. The test results are shown in Table 1 below.

[0077] Cryptotanshinone reference solution, 20.02 μg / mL

[0078] Tanshinone IIA reference solution, 19.22 μg / mL.

[0079] Table 1 Determination of active components in Salvia miltiorrhiza

[0080] Preparation method Salvianolic acid B (mg / g) Tanshinone IIA (mg / g) Comparative example 32.305 0.356 Example 1 34.567 0.654 Example 2 36.883 0.836 Example 3 41.762 1.568

[0081] Result analysis: By changing the extraction method of Salvia miltiorrhiza tablets, the content of salvianolic acid B increased by 30%, and the content of tanshinone IIA increased by about 3 times; it can be seen that this method can significantly improve the extraction rate of active components in Salvia miltiorrhiza tablets, which helps to improve the efficacy of the product.

[0082] 2. Disintegration time limit

[0083] Referring to the disintegration time limit determination method under the general rules of tablets in the fourth part of the Chinese Pharmacopoeia (2020 Edition), the disintegration time of tablets in several preparation methods was detected, and the results are shown in Table 2 below.

[0084] Table 2 Results table of disintegration time limit

[0085] Preparation method Disintegration time (minutes) Comparative example 20 Example 1 15 Example 2 18 Example 3 10

[0086] Result analysis: By changing the excipients in Salvia miltiorrhiza tablets, the disintegration time of Salvia miltiorrhiza tablets was shortened by 50%, which helps the rapid dissolution and absorption of active components, and makes the product take effect quickly.

[0087] The basic concepts have been described above. Obviously, for those skilled in the art, the above detailed disclosure is only an example and does not constitute a limitation to this specification. Although not explicitly stated here, those skilled in the art may make various modifications, improvements, and corrections to this specification. Such modifications, improvements, and corrections are suggested in this specification, so such modifications, improvements, and corrections still fall within the spirit and scope of the exemplary embodiments of this specification.

[0088] At the same time, this specification uses specific terms to describe the embodiments of this specification. Such as "one embodiment", "an embodiment", and / or "some embodiments" mean a certain feature, structure, or characteristic related to at least one embodiment of this specification. Therefore, it should be emphasized and noted that the "one embodiment" or "an embodiment" or "an alternative embodiment" mentioned twice or more at different positions in this specification does not necessarily refer to the same embodiment. In addition, certain features, structures, or characteristics in one or more embodiments of this specification can be combined appropriately.

[0089] In some embodiments, numbers are used to describe components and the quantity of attributes. It should be understood that such numbers used in the description of embodiments are modified by the modifiers "about", "approximately" or "substantially" in some examples. Unless otherwise stated, "about", "approximately" or "substantially" indicate that the stated number allows a variation of ±20%. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximate values, which may vary according to the characteristics required by individual embodiments. In some embodiments, the numerical parameters should consider the specified significant digits and adopt the method of retaining the general number of digits. Although the numerical ranges and parameters used in some embodiments of this specification to confirm the breadth of their scope are approximate values, in specific embodiments, such numerical settings are made as precise as possible within the feasible range.

[0090] Finally, it should be understood that the embodiments described in this specification are only used to illustrate the principles of the embodiments of this specification. Other variations may also fall within the scope of this specification. Therefore, by way of example and not limitation, alternative configurations of the embodiments of this specification may be regarded as consistent with the teachings of this specification. Accordingly, the embodiments of this specification are not limited to the embodiments explicitly introduced and described in this specification.

Claims

1. A preparation method of danshen tablets, comprising the following steps: 1) Mix danshen, sodium lauryl sulfate and / or hydroxypropyl methyl-β-cyclodextrin, and water, and boil for 0.5 - 2 hours to obtain an extract; 2) Concentrate the said extract to obtain an extract paste; 3) Filter the extract paste to obtain a medicinal liquid; 4) Spray-dry the medicinal liquid to obtain danshen spray powder; 5) Granulate the danshen spray powder and sieve to obtain danshen granules; 6) Mix the danshen granules with magnesium stearate and press tablets to obtain danshen tablets.

2. The preparation method according to claim 1, wherein the following features are included in step 1): the mass ratio of danshen, sodium lauryl sulfate, hydroxypropyl methyl-β-cyclodextrin, and water is 200:1:2:2400; the boiling time is 1.5 hours; after boiling, it is necessary to filter with an 80 - 120 mesh sieve. Preferably, after boiling, it is necessary to filter with a 100 mesh sieve.

3. The preparation method according to claim 1, wherein in step 2), the concentration is by reduced-pressure vacuum concentration. Preferably, the concentration conditions are 65 - 75°C, 0.04 - 0.08 Mpa.

4. The preparation method according to claim 1, wherein in step 2), the relative density of the extract paste is 1.10 - 1.

16.

5. The preparation method according to claim 1, wherein in step 3), an 80 - 100 mesh sieve is used for filtering.

6. The preparation method according to claim 1, wherein in step 4), the specific conditions for spray drying are: the medicinal liquid is kept at 60 - 80°C, the inlet air temperature is 180 - 200°C; the outlet air temperature is 90 - 105°C, the rotational speed of the atomizer is 10000 - 12000 revolutions per minute, and the pressure inside the tower is 195 - 205 Pa.

7. The preparation method according to claim 1, wherein in step 5), the danshen spray powder is put into a fluidized bed granulator, and water is used as a wetting agent for granulation and sieving for sizing.

8. The preparation method according to claim 1, wherein in step 6), the mass ratio of danshen granules to magnesium stearate is 100:1; and / or, in step 6), the mixing is carried out at room temperature in a V-type mixer for 15 minutes.

9. Danshen tablets prepared by the preparation method according to any one of claims 1 - 8, wherein in the danshen tablets, the content of salvianolic acid B is 41.762 mg / g, and the content of tanshinone IIA is 1.568 mg / g.

10. The application of the preparation method according to any one of claims 1 - 8 in the preparation of danshen tablets.