CN114377048B

CN114377048B - Qiyeshenan dripping pill for treating insomnia and preparation method thereof

Info

Publication number: CN114377048B
Application number: CN202210068373.7A
Authority: CN
Inventors: 张云生
Original assignee: Yunnan Jinqi Pharmaceuticals Co ltd
Current assignee: Yunnan Jinqi Pharmaceuticals Co ltd
Priority date: 2022-01-20
Filing date: 2022-01-20
Publication date: 2022-10-21
Anticipated expiration: 2042-01-20
Also published as: CN114377048A

Abstract

The invention provides a Qiyeshenan dripping pill for treating insomnia and a preparation method thereof, in particular provides a method for extracting a high-yield and high-content total saponins from panax notoginseng leaves, and relates to the field of extraction of active ingredients of medicaments. When the panax notoginseng leaves are extracted, the mixed solution of acetic acid and ethanol is used for leaching, so that the active ingredients in the panax notoginseng leaves can be effectively released, the dissolution rate of the total saponins in the panax notoginseng leaves is improved, and then the mixed solution of water, 1-butyl-3-methylimidazolium bromide and a surfactant is used for extracting the filter residue again, so that the yield of the total saponins in the panax notoginseng leaves is improved, the utilization rate of traditional Chinese medicines is improved, and the waste of traditional Chinese medicine resources is reduced; according to the invention, the D101 and AB-8 mixed large-aperture resin with the volume ratio of 1.

Description

Qiyeshenan dripping pill for treating insomnia and preparation method thereof

Technical Field

The invention relates to the field of extraction of active ingredients of medicaments, in particular to a dripping pill for treating insomnia and a preparation method thereof, and particularly relates to an extraction method of a panax notoginseng leaf total saponin raw material.

Background

Folium Notoginseng is leaf of Panax notoginseng (Burk.) F.H.Chen of Araliaceae, has effects of promoting blood circulation for removing blood stasis, relieving swelling and pain, and nourishing and strengthening body constitution. The main active component is total saponins of panax notoginseng leaves. Recent researches show that the main components in the folium Notoginseng are ginsenoside Rb1, ginsenoside Rb3, and Re, gypenoside, notoginsenoside Fa, fc, and Fe. Pharmacological research shows that the total saponins of panax notoginseng leaves have the effects of reducing blood fat, tranquilizing and allaying excitement, improving the organism immunity function of experimental animals, prolonging the life and the like; the analgesic has obvious analgesic effect on pain caused by thermal stimulation and chemical stimulation, the analgesic effect is generated by improving pain threshold and inhibiting central and peripheral pain-causing factors, the effect is quick, and the maintenance time is long; has contraction effect on cerebral vessels and inhibition effect on platelet aggregation.

The aescinate dripping pill is an improved preparation form of the aescinate dripping pill, has the main ingredient of total arasaponin, has pharmacological effects of easing pain, calming, improving sleep and the like, is clinically used for treating insomnia, neurasthenia, migraine and the like, and therefore, the total arasaponin is extracted efficiently, the medicament quality is favorably improved, and the waste of medicament resources is reduced.

At present, the extraction method for the total saponins of panax notoginseng leaves mainly comprises an ethanol extraction method, an ethanol extraction-large-aperture resin method or a water extraction and alcohol precipitation-large-aperture resin method.

For example, chinese patent application 201811645544.8 discloses a panax notoginseng leaf total saponin dropping pill, wherein it also discloses a method for extracting panax notoginseng leaf saponin comprising: decocting: mixing folium Notoginseng with water, decocting, and filtering for the first time to obtain filtrate; separation: adsorbing effective components in the filtrate with macroporous adsorbent resin, and eluting with 50-80% ethanol to obtain eluate rich in arasaponin.

For another example, chinese patent application 201611196949.9 discloses a preparation method of total saponins of folium Notoginseng as raw material of a preparation (QIYESHEN' AN tablet), which is prepared from ginsenoside Rb ₃ A method for preparing panax notoginseng leaf total saponins with the content as an evaluation index. The method comprises the following steps: 1) Coarsely crushing folium Notoginseng, and extracting with solvent selected from one of water and 70% ethanol to obtain folium Notoginseng extractive solution; 2) After the relative density of the obtained panax notoginseng leaf extract concentrated juice is 1.10-1.25 (60 ℃), adding ethanol to ensure that the alcohol content is 50% -70% or adding 3-7 times of water for water precipitation, standing and separating, and taking supernatant; 3) Decolorizing the supernatant with macroporous resin, eluting with water and low concentration ethanol, eluting with 70% ethanol, collecting eluate, recovering ethanol, concentrating, and drying. The folium Notoginseng total saponin obtained by the preparation method has high content, feasible production and stable process, and improves quality controllability of folium Notoginseng total saponin, thereby ensuring quality and effectiveness of the product, QIYESHEN' AN tablet, and facilitating standardized production of medicine.

However, the content of the panax notoginseng leaf total saponins obtained by the existing preparation method is lower, and the requirement cannot be better met, so that a preparation method of the panax notoginseng leaf tranquilizing dripping pill needs to be provided, and particularly, an extraction method capable of better improving the yield and the content of the panax notoginseng leaf total saponins needs to be developed.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a dripping pill for treating insomnia and a preparation method thereof, in particular to an extraction method of a total saponins of panax notoginseng leaf raw material with high yield and high content.

In order to achieve the purpose, the technical scheme of the invention is as follows:

on one hand, the invention provides a preparation method of a Qiyeshenan dripping pill for treating insomnia, which comprises the following steps:

mixing folium Notoginseng total saponin and polyethylene glycol, melting, making into dripping pill, cooling, and removing coolant attached on the dripping pill to obtain QIYESHEN dripping pill.

The method for extracting the panax notoginseng leaf total saponins raw material comprises the following steps:

(1) Pulverizing folium Notoginseng, extracting with solvent 1, and filtering to obtain residue 1 and filtrate 1;

(2) Adding a solvent 2 into the filter residue 1 obtained in the step (1), performing ultrasonic extraction, filtering to obtain a filter residue 2 and a filtrate 2, discarding the filter residue 2, combining the filtrate 1 and the filtrate 2, and concentrating until no alcohol smell exists to obtain a concentrated solution of the panax notoginseng leaf total saponin extract;

(3) And (3) adding 3 times of water into the concentrated solution of the panax notoginseng leaf total saponin extract obtained in the step (2) to dissolve, passing through a large-aperture resin, eluting, concentrating and drying to obtain a panax notoginseng leaf total saponin raw material.

Wherein, the solvent 1 in the step (1) is an ethanol-acetic acid mixed solution, the volume ratio of ethanol to acetic acid is 3-5;

the concentration of the ethanol is 70-80%, and the concentration of the acetic acid is 50-60%;

preferably, the concentration of the ethanol is 70 percent, and the concentration of the acetic acid is 60 percent;

the concentration of the ethanol is 80 percent, and the concentration of the acetic acid is 50 percent.

The feed-liquid ratio of the step (1) is 1; preferably 1.

As a preferred embodiment, the leaching in step (1) above further comprises a quick-freezing and instant-dissolving step, i.e. after the crushed leaves of panax notoginseng are soaked in the solvent 1, the leaves of panax notoginseng are quickly freeze-dried and then melted at room temperature, and the soaking time is 10-20min.

The solvent 2 in the step (2) is a mixed solution of water, 1-butyl-3-methylimidazolium bromide and a surfactant;

the concentration of the 1-butyl-3-methylimidazole bromine salt is 0.5g/mL, and the preparation method comprises the following steps: 5g of 1-butyl-3-methylimidazole bromine salt is dissolved in 10mL of water to prepare the compound.

In the implementation process, the concentration of the surfactant is unexpectedly found to obviously influence the content of the panax notoginseng leaf total saponins, the yield of the panax notoginseng leaf total saponins is reduced due to too low concentration, and the resource waste can be caused due to too high concentration, so that the extraction amount of the panax notoginseng leaf total saponins can not be increased;

in the implementation process, the invention unexpectedly discovers that the volume ratio of the water to the 1-butyl-3-methylimidazolium bromide to the surfactant is controlled to be 60-80 to 10-15, so that the extraction efficiency of the panax notoginseng leaf total saponins can be obviously improved, and the content of the panax notoginseng leaf total saponins is obviously improved.

Preferably, the volume ratio of the water to the 1-butyl-3-methylimidazolium bromide salt to the surfactant is 80.

Wherein the surfactant is a mixture of lauryl glucoside and cocoyl propyl betaine.

The volume ratio of the dodecyl glucoside to the cocoyl propyl betaine is 2-4;

preferably, the volume ratio of the dodecyl glucoside to the cocoyl propyl betaine is 3-4;

still more preferably, the volume ratio of lauryl glucoside to cocoyl propyl betaine is 3.

The mass volume ratio of the filter residue 1 to the solvent 2 is 1; preferably 1.

The ultrasonic frequency is 40-60Hz, and the ultrasonic time is 5-10min; the ultrasonic frequency is 2-3 times.

The step (2) further comprises a step of removing the solvent, and the specific operations are as follows: and mixing the filtrate 1 and the filtrate 2, performing vacuum filtration on the mixed solution, and recovering the solvent.

The large-aperture resin in the step (3) is selected from one or more of D101, AB-8 and X-5;

preferably, the large-aperture resin is D101 or/and AB-8.

In some preferred embodiments, the large pore size resins are D101 and AB-8 in a volume ratio of 1.

The elution is washing by water and ethanol respectively; the specific elution steps are as follows: eluting with water, 30-40% ethanol, and 70% ethanol, and collecting eluate when the color of eluate changes from colorless to brown.

The washing dosage is 4-6BV; the using amount of the 30-40% ethanol is 4-6BV; the using amount of the 70 percent ethanol is 4-6BV.

As some preferred technical schemes, the method for extracting the total saponins of panax notoginseng leaves in the tranquilizing notoginseng drop pills comprises the following steps:

(1) Pulverizing folium Notoginseng, adding mixed solvent of 70-80% ethanol and 50-60% acetic acid at volume ratio of 3-5:1, leaching for 10-20min, rapidly lyophilizing the leaching solution, melting at room temperature, repeating for 1-2 times, and filtering to obtain residue 1 and filtrate 1;

(2) Adding the filter residue 1 obtained in the step (1) into a mixed solution of water, 1-butyl-3-methylimidazole bromine salt and a surfactant in a volume ratio of 60-80; performing ultrasonic treatment for 2-3 times, filtering to obtain residue 2 and filtrate 2, discarding residue 2, mixing filtrate 1 and filtrate 2, and concentrating until there is no alcohol smell to obtain folium Notoginseng total saponin extract concentrate;

(3) Adding 3 times of water into the concentrated solution of the panax notoginseng leaf total saponin extract obtained in the step (2) to dissolve, then passing through D101 and AB-8 with the volume ratio of 1.

As a preferred embodiment, the method for extracting total saponins of panax notoginseng leaves from the dripping pill comprises the following steps:

(1) Pulverizing folium Notoginseng, adding mixed solvent of 80% ethanol and 60% acetic acid at volume ratio of 4:1, extracting for 15min, rapidly lyophilizing the extract, melting at room temperature, repeating for 2 times, and filtering to obtain residue 1 and filtrate 1;

(2) Adding the filter residue 1 obtained in the step (1) into a mixed solution of water, 1-butyl-3-methylimidazole bromine salt and a surfactant in a volume ratio of 80; performing ultrasonic treatment for 2 times, filtering to obtain residue 2 and filtrate 2, discarding residue 2, mixing filtrate 1 and filtrate 2, and concentrating until there is no alcohol smell to obtain folium Notoginseng total saponin extract concentrate;

(3) Adding 3 times of water into the concentrated solution of the panax notoginseng leaf total saponin extract obtained in the step (2) to dissolve, then passing the concentrated solution through D101 and AB-8 with the volume ratio of 1.

The surfactant is dodecyl glucoside and cocoyl propyl betaine in a volume ratio of 3.

On the other hand, the panax notoginseng leaf total saponins raw material obtained by the extraction method provided by the invention is applied to preparing the panax notoginseng leaf tranquilizing dripping pill.

On the other hand, the invention also provides the aescinate tranquilizing dripping pill prepared by using the panax notoginseng leaf total saponins as raw materials.

Compared with the prior art, the invention has the beneficial effects that:

(1) The extraction method provided by the invention can better extract the panax notoginseng leaf saponins in the panax notoginseng leaves, improves the dissolution rate of the panax notoginseng leaf saponins, reduces the waste of medicine resources and improves the extraction efficiency;

(2) When the panax notoginseng leaf is extracted, firstly, an acetic acid-ethanol mixed solution is used for leaching, and a quick-freezing and instant dissolving mode is adopted, so that the effective components in the panax notoginseng leaf can be effectively released, the dissolution rate of the panax notoginseng leaf total saponins is improved, then, the filter residue is extracted by using a mixed solution of water, 1-butyl-3-methylimidazolium bromide and a surfactant with the volume ratio of 60-80.

(3) According to the invention, in the purification process, D101 and AB-8 mixed large-aperture resin with the volume ratio of 1.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the detailed description and specific examples, while indicating the scope of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

The reagents used in the practice of the invention are all commercially available reagents.

A dripping pill for treating insomnia, and its preparation method

The method comprises the following steps:

mixing and melting the panax notoginseng leaf total saponins and the polyethylene glycol according to the weight ratio of 1.

Embodiment 1 a method for extracting total saponins from folium Notoginseng in QIYESHEN dripping pill for treating insomnia comprises the following steps:

(1) 1Kg of pseudo-ginseng leaves are crushed, added with a mixed solvent of 70 percent ethanol (6L) and 60 percent acetic acid (2L) (the material-liquid ratio is 1;

(2) Adding water (3336 mL), 1-butyl-3-methylimidazole bromine salt (556 mL) and a surfactant (55.6 mL) into the filter residue 1 (986.9 g) obtained in the step (1) (the material-liquid ratio is 1;

The surfactant in the step (2) is dodecyl glucoside and cocoyl propyl betaine in a volume ratio of 4.

Embodiment 2 a method for extracting total saponins from folium Notoginseng in QIYESHEN dripping pill for treating insomnia comprises the following steps:

(1) Pulverizing 1Kg of folium Notoginseng, adding mixed solvent of 80% ethanol (8.3L) and 50% acetic acid (1.7L) (ratio of material to liquid is 1;

(2) Adding water (4896 mL), 1-butyl-3-methylimidazolium bromide (918 mL) and a mixed solution of a surfactant (61.2 mL) into the filter residue 1 (979.2 g) obtained in the step (1) (the material-liquid ratio is 1;

The surfactant in the step (2) is dodecyl glucoside and cocoyl propyl betaine in a volume ratio of 2.

Embodiment 3 a method for extracting total saponins from folium Notoginseng in dripping pill for treating insomnia comprises the following steps:

(1) 1Kg of pseudo-ginseng leaves are crushed, mixed solvent (the material-liquid ratio is 1;

(2) Adding water (4320 mL), 1-butyl-3-methylimidazolium bromide (540 mL) and a mixed solution of a surfactant (54 mL) into the filter residue 1 (982.8 g) obtained in the step (1) (the feed-liquid ratio is 1; performing ultrasonic treatment for 2 times, filtering to obtain residue 2 and filtrate 2, discarding residue 2, mixing filtrate 1 and filtrate 2, and concentrating until there is no alcohol smell to obtain folium Notoginseng total saponin extract concentrate;

(3) And (3) adding 3 times of water into the concentrated solution of the panax notoginseng leaf total saponin extract obtained in the step (2) to dissolve, then, passing through D101 and AB-8 with the volume ratio of 1.

The surfactant in the step (2) is dodecyl glucoside and cocoyl propyl betaine in a volume ratio of 3.

Comparative example 1

The difference from example 3 is that: the leaching was performed using only 80% ethanol in the step (1), and other operations and steps were the same as in example 3.

Comparative example 2

The difference from example 3 is that: the leaching was performed using only 60% acetic acid in the step (1), and other operations and steps were the same as in example 3.

Comparative example 3

The difference from example 3 is that: in step (2), only the mixed solution of water and surfactant, i.e., water (4860 mL) and surfactant (54 mL), was added, and the other operations and steps were the same as in example 3.

Comparative example 4

The difference from example 3 is that: in step (2), only a mixed solution of water and 1-butyl-3-methylimidazolium bromide salt was added, that is, water (4374 mL) and 1-butyl-3-methylimidazolium bromide salt (540 mL) were added, and the operation and procedure were otherwise the same as in example 3.

Comparative example 5

The difference from example 3 is that: the surfactant was replaced with tween-20 in step (2), and the other operations and steps were the same as in example 3.

Comparative example 6

The difference from example 3 is that: in the step (2), the mass ratio of the surfactant lauryl glucoside to the surfactant cocoyl propyl betaine was 1.

Comparative example 7

The difference from example 3 is that: only the D101 large pore resin was used in step (3), and the other operations and steps were the same as in example 3.

Comparative example 8

The difference from example 3 is that: the volume ratio of D101 to AB-8 in step (3) was 3, and the other operations and steps were the same as in example 3.

Comparative example 9

A method for preparing total saponins of folium Notoginseng is disclosed in Chinese patent application 201611196949.9.

Effect verification

The results of the determination of the yield and purity of the total saponins of panax notoginseng leaf raw material obtained in the above examples 1 to 3 and comparative examples 1 to 9 are shown in table 1 below.

The purity detection method comprises the following steps: measuring by high performance liquid chromatography (general rule 0512 of Chinese pharmacopoeia).

Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile is taken as a mobile phase A, 0.2 percent phosphoric acid solution is taken as a mobile phase B, and gradient elution is carried out according to the specification in the following table; the detection wavelength was 203nm. The number of theoretical plates is not less than 6000 calculated according to the peak of ginsenoside Rb 3.

Preparation of control solutions: taking appropriate amount of ginsenoside Rb3 reference substance, precisely weighing, and adding ethanol to obtain solution containing 0.5mg per 1 ml.

Preparation of a test solution: weighing 50mg of the product, accurately weighing, placing in a 10ml measuring flask, dissolving with ethanol, diluting to scale, shaking, filtering, and collecting the filtrate.

The determination method comprises precisely sucking 10 μ L of each of the reference solution and the sample solution, injecting into liquid chromatograph, and determining.

The gradient elution conditions were:

time (minutes)	Mobile phase A (%)	Mobile phase B (%)
			0-19	30→35	70→65
19-21	35→50	65→50
			21-26	50	50

TABLE 1

According to the detection data in table 1 above, it can be seen that the yield and purity of the total saponins of panax notoginseng leaf obtained by the extraction method provided in embodiments 1-3 of the present invention are both high, and especially the yield of the total saponins of panax notoginseng leaf obtained in embodiment 3 is 9.12%, and the purity is 18.61%, which is obviously superior to the existing level. Comparative examples 1-2 changing the solvent of the first extraction, using only ethanol or only acetic acid, may affect the yield of total saponins of panax notoginseng leaves to some extent, but has little effect on purity. Comparative examples 3-4 change the kind of solvent for the second extraction, which also affects the yield of total saponins in panax notoginseng leaves to a certain extent, but has little effect on the purity. Comparative examples 5-6 change the kind or ratio of the surfactant, have a large influence on the yield of the total saponins of panax notoginseng leaf, and have no obvious influence on the purity. Comparative examples 7 to 8 change the types or volume ratios of the large-aperture resins in the purification process, have little influence on the yield of the panax notoginseng leaf total saponins, but obviously influence the purity of the panax notoginseng leaf total saponins, so that the purity is obviously reduced compared with examples 1 to 3. Comparative example 9 the yield and purity of total saponins from leaves of panax notoginseng obtained by extraction using the extraction methods disclosed in the prior art are significantly lower than those provided in examples 1-3 of the present application.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a dripping pill for treating insomnia comprises the following steps: mixing folium Notoginseng total saponin and polyethylene glycol, melting, making into dripping pill, cooling, and removing coolant attached on the dripping pill to obtain QIYESHEN dripping pill; the method is characterized in that: the panax notoginseng leaf total saponins are extracted by the following method, and the method comprises the following steps:

(1) Pulverizing folium Notoginseng, adding solvent 1, extracting, and filtering to obtain residue 1 and filtrate 1;

(3) Dissolving the concentrated solution of the panax notoginseng leaf total saponin extract obtained in the step (2) in 3 times of water, passing through a large-aperture resin, eluting with water, then eluting with 30-40% ethanol, finally eluting with 70% ethanol, concentrating and drying to obtain a panax notoginseng leaf total saponin raw material;

the solvent 1 in the step (1) is a mixed solution of 70-80% ethanol and 50-60% acetic acid in a volume ratio of 3-5;

the solvent 2 in the step (2) is a mixed solution of water, 1-butyl-3-methylimidazolium bromide and a surfactant in a volume ratio of 60-80; the surfactant is a mixture of dodecyl glucoside and cocoyl propyl betaine in a volume ratio of 2-4;

the large-aperture resin in the step (3) comprises D101 and AB-8 in a volume ratio of 1.

2. The method of claim 1, wherein: the volume ratio of ethanol to acetic acid was 4.

3. The method for producing according to claim 1, characterized in that: the concentration of the ethanol is 70 percent, and the concentration of the acetic acid is 60 percent.

4. The method for producing according to claim 1, characterized in that: the feed-liquid ratio of the step (1) is 1.

5. The production method according to claim 1, characterized in that: the volume ratio of the water to the 1-butyl-3-methylimidazole bromine salt to the surfactant is 80.

6. The method of claim 1, wherein: the mass volume ratio of the filter residue 1 to the solvent 2 is 1.

7. The production method according to claim 1, characterized in that: the panax notoginseng leaf total saponins are extracted by the following method, and specifically comprise the following steps:

8. A dripping pill for treating insomnia is characterized in that: prepared by the preparation method of any one of claims 1 to 7.