CN112603934A

CN112603934A - Chinese angelica and ligusticum wallichii composition and preparation method thereof

Info

Publication number: CN112603934A
Application number: CN202011634554.9A
Authority: CN
Inventors: 宋更申; 孙艳玲; 陈向阳
Original assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Current assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2021-04-06

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a Chinese angelica and ligusticum wallichii composition and a preparation method thereof. The medicine intermediate raw materials comprise volatile oil and cyclodextrin, wherein the volatile oil is completely or basically completely included by the cyclodextrin; the volatile oil is prepared from radix Angelicae sinensis and rhizoma Ligustici Chuanxiong. The traditional Chinese medicine composition comprises the intermediate raw materials and the extract of the medicine; wherein the extract is prepared from angelica and ligusticum wallichii serving as raw materials. The intermediate raw materials of the medicine provided by the invention effectively improve the stability of the volatile oil prepared by taking angelica and ligusticum wallichii as raw materials. The invention also provides a traditional Chinese medicine preparation, which keeps the material basis of the original prescription of the fingered citron powder and can better play the functions of nourishing blood, promoting blood circulation, removing blood stasis and promoting tissue regeneration of the original prescription.

Description

Chinese angelica and ligusticum wallichii composition and preparation method thereof

Technical Field

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a Chinese angelica and ligusticum wallichii composition and a preparation method thereof.

Background

Fingered citron powder is from Song xu Wei 'general Ji Ben Fang' and is a main prescription for treating antenatal and postpartum diseases in ancient obstetrics and gynecology. For instance, it is called "Buddha powder" because it is a popular herb of Buddha's hand. It is described in the original text that the angelica (six two, wash) and the chuanxiong rhizome (four two, wash) are coarse powder, two coins are taken each time, a small cup of water is taken, the dried qiqi is decocted, a large cup of wine is added, the boiling is stopped, and the dregs are removed and taken warmly. "it can treat pregnancy five seven months with stubborn fetus due to construction or immobility in the abdomen, lochiorrhea and bleeding.

The prescription only consists of two traditional Chinese medicines of angelica and ligusticum wallichii, the compatibility of the two medicines is an ancient prescription and a famous pair of medicines, and the ancient and modern applications are based on the effects of nourishing blood, promoting blood circulation, removing blood stasis and promoting tissue regeneration. The prescription is widely applied to the fields of diseases related to dialectical symptoms, such as treatment of primary and adolescent dysmenorrhea, gynecological diseases such as induced abortion, postpartum blood stasis, bleeding and abdominal pain, cerebral neuropathy such as migraine and intractable pain, cardiovascular and cerebrovascular diseases, liver and gall diseases and the like, and has profound clinical development and application values.

The modern phytochemical separation and pharmacological research carries out systematic research on each extraction part and active ingredients of the phytochemical separation and pharmacological research, the main active substances of the phytochemical separation and pharmacological research are phthalides, organic phenolic acids, alkaloids, flavonoids and polysaccharide compounds, and the extraction parts are mainly concentrated in volatile oil, alcohol extract, water extraction and alcohol precipitation liquid and other parts. The volatile oil has high content and strong drug effect activity, is a main drug effect substance, is easy to volatilize and degrade, and has poor stability; when medium and high-polarity components are extracted by adopting a water and alcohol system, inactive components such as tannin, pigment, gum and the like are extracted together, and the phenomena of thick extract and high extract yield are caused during concentration, so that the feasibility of the preparation and the exertion of the drug effect are influenced. These are all the technical problems that the recipe is faced with to develop into the modern Chinese patent medicine preparation.

Disclosure of Invention

The invention firstly provides a medicine intermediate raw material, which effectively improves the stability of the volatile oil prepared by taking angelica and ligusticum wallichii as raw materials.

A pharmaceutical intermediate material comprises volatile oil and cyclodextrin, wherein the volatile oil is completely or substantially completely included by the cyclodextrin; the volatile oil is prepared from radix Angelicae sinensis and rhizoma Ligustici Chuanxiong.

According to an embodiment of the invention, the cyclodextrin is β -cyclodextrin.

According to the embodiment of the invention, the weight ratio of the volatile oil to the cyclodextrin is 1: 5-8.

Experiments prove that the volatile oil can be completely included or basically completely included by using the cyclodextrin in the proportion. The stability of the included volatile oil is obviously improved, and the content and the composition of the volatile oil in the intermediate raw materials of the medicine are not obviously changed.

In the invention, the complete inclusion means that all the included volatile oil components enter cavities of cyclodextrin, and the theoretical encapsulation rate is 100%.

In the invention, the meaning of the basically complete inclusion means that the color and the smell of the volatile oil can not be identified through senses after the volatile oil is included by cyclodextrin, and the determined encapsulation rate is not lower than 90%.

In the invention, the encapsulation rate refers to the mass percentage of the encapsulated volatile oil in the total volatile oil; the calculation and characterization are generally carried out according to the amount of the volatile oil in the inclusion compound, the adding amount of the volatile oil and the blank recovery rate of the volatile oil content measurement.

According to the embodiment of the invention, the encapsulation efficiency of the intermediate raw material of the medicine is more than or equal to 90.

According to the embodiment of the invention, in the raw materials for preparing the volatile oil, the weight ratio of the angelica and the ligusticum wallichii is 1-5:1-5, preferably 1-3:1-3, and more preferably 3: 2.

According to the embodiment of the invention, the volatile oil is prepared by using angelica and ligusticum wallichii as raw materials and adopting a steam distillation method. Generally, the water adding amount is 4-8 times of the weight of the angelica and the ligusticum wallichii; the distillation can be carried out after soaking for 6-24 h. The distillation time is generally from 2 to 6 h.

The invention also provides a preparation method of the intermediate raw material of the medicine, which comprises the following steps:

providing the volatile oil;

providing the cyclodextrin;

and performing inclusion on the cyclodextrin and the volatile oil.

According to the embodiment of the invention, the inclusion is carried out by adopting a grinding method, namely, the cyclodextrin and the volatile oil are subjected to grinding inclusion by a hand mill or a ball mill according to an optimized proportion until the color and the smell of the volatile oil are completely or basically completely included.

According to the embodiment of the invention, the cyclodextrin can be uniformly mixed and dispersed with water before inclusion. Typically, the cyclodextrin to water weight ratio is 1:1 to 5, such as 1:1.5 to 2.

According to the embodiment of the invention, the volatile oil can be diluted by absolute ethyl alcohol before inclusion. Generally, the weight ratio of the volatile oil to the absolute ethyl alcohol is 1: 1-2. The effective contact area of the volatile oil and the cyclodextrin can be increased by diluting with a proper amount of absolute ethyl alcohol, so that volatile oil molecules can enter cyclodextrin cavities, and the inclusion efficiency is improved.

According to the embodiment of the invention, the angelica and the ligusticum wallichii medicinal materials or decoction pieces are firstly crushed, and then the volatile oil is extracted. For example, it is usually broken to 5-15 mm.

In some embodiments of the invention, the method of preparing the essential oil comprises: crushing the medicinal materials or decoction pieces of angelica and ligusticum wallichii, soaking for 6-24h by using 4-8 times of water, extracting volatile oil by adopting a steam distillation method for 2-6h, and collecting the volatile oil. In some embodiments, the distillate may be further collected and used to prepare a Chinese medicinal composition, as described below.

In some embodiments of the present invention, the method for preparing the pharmaceutical intermediate material comprises:

dissolving and diluting the volatile oil with 1-2 times of anhydrous ethanol;

taking the cyclodextrin, and mixing and dispersing the cyclodextrin uniformly by using water with the weight of 1-5 times;

mixing the diluted volatile oil and cyclodextrin, preferably at a weight ratio of the volatile oil to cyclodextrin of 1:5-8, grinding until the color and odor of the volatile oil are completely or substantially completely included.

In some embodiments of the invention, the method further comprises the step of refrigerating the inclusion compound after inclusion; the temperature of the refrigeration treatment is preferably 0-5 ℃, and the refrigeration time is preferably 12-24 h.

In the research process, the clathrate compound is still in a dynamic unstable state after being formed and before being dried. For example, during the water removal process by suction filtration or centrifugation, a part of volatile oil molecules will migrate out of cyclodextrin cavities due to external force, and further migrate out during the subsequent heat drying process. The inventor finds that the inclusion rate can be improved by cold storage, for example, cold storage at 0-5 ℃ for 12-24 h. The analysis reason may be that the cold storage can enhance the complexing ability of the volatile oil molecules and the beta-cyclodextrin and improve the suction force of the volatile oil molecules generated by resisting suction filtration or centrifugation; meanwhile, the dissolution of cyclodextrin in water can be reduced through refrigeration, the loss of a part of inclusion compound caused by dissolution in water is reduced, and the yield of the inclusion compound is improved.

In some embodiments of the present invention, the method further comprises a step of performing a water removal treatment after the refrigeration treatment, i.e. removing water or a part of water in the clathrate. Water removal methods conventional in the art, such as centrifugal water removal, may be employed.

In some embodiments of the present invention, the method further comprises drying after the water removal treatment. Drying methods conventional in the art, such as drying under reduced pressure at 45 deg.C, may be used.

The cyclodextrin is a cyclic oligosaccharide, is nontoxic and edible, has a hollow annular structure with hydrophilic outer edge and hydrophobic inner cavity in a slightly conical shape, and the inner space of the ring can just contain volatile oil molecules, and the volatile oil molecules enter the cyclodextrin cavity to form an inclusion compound under a certain condition, and under the protection of the cyclodextrin cavity, the volatile oil components can effectively avoid the oxidation of oxygen in the air and the decomposition and volatilization after exposure to light. After the volatile oil is included by the beta-cyclodextrin, the stability of the volatile oil is obviously improved compared with the mixture of the volatile oil and the cyclodextrin.

The invention also comprises the intermediate raw materials of the medicine prepared by the method.

Herein, the intermediate raw materials of the medicine are sometimes also referred to as volatile oil inclusion compounds.

The intermediate raw materials of the medicine can be used as raw materials for preparing traditional Chinese medicine compositions or pharmaceutical preparations.

The invention also provides a traditional Chinese medicine composition, which comprises the main components of the intermediate raw materials of the medicine and also comprises an extract; wherein the extract is prepared from angelica and ligusticum wallichii serving as raw materials.

According to an embodiment of the invention, the extract is also meant to include liquid extracts, such as extraction solutions.

According to an embodiment of the invention, the extract does not include the essential oils mentioned above.

According to the embodiment of the invention, the weight ratio of angelica and ligusticum wallichii in the raw materials for preparing the extract is 1-5:1-5, preferably 1-3:1-3, and more preferably 3: 2.

According to an embodiment of the present invention, the preparation method of the extract comprises:

1) crushing Chinese angelica and ligusticum wallichii medicinal materials or decoction pieces, extracting volatile oil by adopting a steam distillation method, and collecting the volatile oil and distillate;

2) adding ethanol into the material subjected to volatile oil extraction in the step 1) and continuously extracting to obtain an ethanol extract;

3) standing the alcohol extract obtained in the step 2) at a low temperature, centrifuging, and concentrating the obtained supernatant in a decompression manner to obtain a concentrated solution;

4) mixing the distillate obtained in the step 1) and the concentrated solution obtained in the step 3), clarifying, centrifuging, and removing the solvent from the obtained supernatant by adopting a reduced pressure mode to obtain the extract.

Further, the specific method in step 1) can be referred to the preparation method of the volatile oil.

Further, the concentration of ethanol used in step 2) is 50-100%, optionally 85-95%, e.g. 85% or 90%. Typically, the extraction with ethanol may be performed 1-3 times, e.g., 1, 2 or 3 times. The amount of ethanol used in each time is 4-10 times of the weight of radix Angelicae sinensis and rhizoma Ligustici Chuanxiong. The liquid medicine is boiled once and then stands for 6-12h for each extraction. That is, the liquid medicine is boiled in each extraction, and then is kept still for 6-12h for further extraction. Researches show that the stability of the active ingredient ferulic acid can be ensured by adopting the extraction mode of stopping heating after boiling once and discharging liquid medicine after standing to room temperature. In step 2), a large amount of white flocculent floating substances (impurities) are generated in the water extracting solution at the moment of adding the ethanol, the floating substances can be intercepted by the medicine residues, and the extraction process is accompanied with impurity removal.

Further, in step 3), the alcoholic extract obtained in step 2) may be first allowed to stand at a low temperature, typically 0-10 ℃, for a period of time, for example 8-24 hours, and then centrifuged. White flocculent impurities can be separated out by standing, so that the aim of removing impurities is fulfilled.

Further, in step 3), the concentration may be carried out by a reduced pressure method, for example, the solvent may be recovered under reduced pressure at 40 to 60 ℃ and concentrated to a concentrated solution containing 0.2 to 1.0g of the crude drug per 1ml of the drug solution.

Further, in step 4), a chitosan solution is added to the combined solution for clarification, wherein the addition amount of the chitosan is 8-15%, such as 10%, of the total mass of the combined solution. The concentration of the chitosan solution is 0.2-2%, e.g., 1%. Adding chitosan solution, stirring, standing, and centrifuging to further remove flocculent impurities.

Further, in step 4), the solvent is removed from the supernatant under reduced pressure, for example, the solvent is recovered under reduced pressure at 40-55 deg.C, and concentrated to a concentrated solution containing 3.5-5.5g crude drug per 1ml of the medicinal solution.

In some embodiments of the invention, the extract is prepared by a method comprising:

1) crushing medicinal materials or decoction pieces of radix Angelicae sinensis and rhizoma Ligustici Chuanxiong, soaking in 4-8 times of water for 6-24 hr, extracting volatile oil by steam distillation for 2-6 hr, and collecting volatile oil and distillate;

2) adding 4-8 times of 50-100% ethanol into the material (medicinal liquid of residue) obtained in step 1), heating to boil, stopping heating, standing to room temperature, and separating to obtain extractive solution; adding 6-10 times of 50-100% ethanol, heating until the liquid medicine is boiling, stopping heating, cooling the liquid medicine to room temperature, collecting extractive solution, and mixing the two liquid medicines to obtain ethanol extractive solution;

3) standing the alcohol extract prepared in step 2) at low temperature (0-10 deg.C) for 8-24h, centrifuging, removing precipitate, and concentrating the supernatant at 40-60 deg.C under reduced pressure to obtain crude drug containing 0.2-1.0g per 1ml of medicinal liquid to obtain alcohol extract concentrate;

4) mixing the distillate obtained in step 1) and the concentrated solution of the alcohol extract obtained in step 3), adding chitosan solution with concentration of 0.2-2% and total mass of 8-15%, stirring uniformly, standing at room temperature for 8-24h, centrifuging, recovering solvent under reduced pressure at 40-55 deg.C, and concentrating to obtain concentrated solution containing 3.5-5.5g crude drug per 1ml of liquid medicine to obtain the extract.

In some more specific embodiments of the present invention, the extract is prepared by a method comprising:

1) crushing medicinal materials or decoction pieces of radix Angelicae sinensis and rhizoma Ligustici Chuanxiong, soaking in 6 times of water for 12 hr, extracting volatile oil by steam distillation for 5 hr, and collecting volatile oil and distillate;

2) adding 90% ethanol with 8 times of weight concentration into the material extracted from the volatile oil in the step 1), heating to boil, stopping heating, standing to room temperature, and separating out an extracting solution; adding 90% ethanol 8 times the weight of the medicinal liquid again, heating until the medicinal liquid is boiling, stopping heating, cooling the medicinal liquid to room temperature, collecting extractive solution, and mixing the two medicinal liquids to obtain ethanol extractive solution;

3) standing the alcohol extract prepared in step 2) at low temperature (0-5 deg.C) for 24h, centrifuging, removing precipitate, and concentrating the supernatant at 45-55 deg.C under reduced pressure to obtain crude drug containing 0.2-1.0g per 1ml of medicinal liquid to obtain alcohol extract concentrate;

4) mixing the distillate obtained in step 1) and the concentrated alcohol extract obtained in step 3), adding 1% chitosan solution with a total mass of 10%, stirring, standing at room temperature for 24h, centrifuging, and recovering under reduced pressure at 45-50 deg.C.

The extract prepared by the method has high purity, low impurity content and non-sticky paste, and is beneficial to drying and production of subsequent preparations. According to the preparation method of the original formula of the fingered citron powder, the total extract is prepared by adopting a water extraction and alcohol extraction mode, ethanol is added into medicine residue liquid to continue extraction on the basis of extracting volatile oil by a steam distillation method, and the unexpected discovery shows that a large amount of white floccule floaters are generated after the ethanol is added, the floccule floaters can be effectively intercepted by medicine residues, namely, impurities are removed in the extraction process, and the impurity content of the collected extracting solution is greatly reduced.

The invention also provides a traditional Chinese medicine preparation which contains the traditional Chinese medicine composition or further contains pharmaceutically acceptable auxiliary materials.

According to the embodiment of the invention, the traditional Chinese medicine preparation can be prepared from the traditional Chinese medicine composition independently; or further mixing with pharmaceutically acceptable adjuvants.

According to the embodiment of the invention, the auxiliary material can be one or more selected from starch, dextrin, sugar powder, microcrystalline cellulose, lactose, mannitol, menthol, vitamin C, citric acid, silicon dioxide, tocopherol, maltitol, sucrose fatty acid ester, aspartame, magnesium stearate, croscarmellose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, povidone, polyacrylic resin IV and polyethylene glycol.

According to the embodiment of the invention, the traditional Chinese medicine preparation is prepared from the intermediate raw materials (volatile oil inclusion compound) of the medicines and dry paste powder of the extracts.

According to the embodiment of the invention, the traditional Chinese medicine preparation is prepared from the intermediate raw materials (volatile oil inclusion compound) of the medicine and the extract or the concentrated solution of the extract. Specifically, for example, the intermediate raw material (volatile oil inclusion compound) is added to the concentrated solution of the extract, or the intermediate raw material (volatile oil inclusion compound) and the auxiliary material are mixed or granulated with the concentrated solution of the extract. The advantages are that not only uniform mixing of all components is achieved, but also the drying step of the extract is omitted.

According to the embodiment of the invention, the traditional Chinese medicine preparation comprises capsules, granules, capsules and tablets.

The preparation of the intermediate raw materials of the medicine adopts a grinding method for inclusion, the physical kneading is realized, the inclusion rate is high, the composition of the volatile oil before and after inclusion is not changed, the operation is simple and convenient, the environmental pollution is avoided, the industrial production is easy, and the popularization and the application are easy. The extract provided by the invention adopts a physical method to remove impurities from the water-soluble extract, so that the problems of high impurity content, thick paste and difficulty in drying of the traditional Chinese medicine water-soluble extract and production of subsequent preparations are solved. The traditional Chinese medicine preparation provided by the invention maintains the material basis of the original prescription of the fingered citron powder, provides an oral solid preparation, can better exert the functions of nourishing blood and activating blood circulation, removing blood stasis and promoting tissue regeneration of the original prescription, and has better clinical application value and market popularization value.

Drawings

FIG. 1 is a gas phase diagram of a sample of Experimental example 1 left at a high temperature of 60 ℃ for 10 days.

FIG. 2 is a gas phase diagram of a sample of Experimental example 1 placed under illumination of 4500 lx. + -. 500lx for 10 days.

FIG. 3 is a gas phase spectrum of a sample of Experimental example 2.

In fig. 1 to 3, PA in the ordinate represents the response value, and FID1B represents the hydrogen flame ion detector.

FIG. 4 is a TLC spectrum of a sample of Experimental example 3 using n-hexane-ethyl acetate (9:1) as a developing system.

FIG. 5 is a TLC spectrum of a sample of Experimental example 3 using cyclohexane-dichloromethane-ethyl acetate-formic acid (4:1:1:0.1) as a developing system.

FIG. 6 is a TLC spectrum of a sample of Experimental example 3 using n-butanol-glacial acetic acid-water (4:1:1) as a developing system.

Detailed Description

The technical solutions of the present invention are described in detail below by way of examples, which should not be construed as limiting the scope of the present invention.

EXAMPLE 1 preparation of the essential oils

Crushing the angelica and the ligusticum wallichii into coarse particles with the particle size of 5-15mm, feeding the angelica and the ligusticum wallichii according to the weight ratio of 3:2, adding 6 times of water, soaking for 24 hours, extracting volatile oil by steam distillation for 5 hours, and respectively collecting the volatile oil and distillate. The yield of the volatile oil is 0.52% (ml/g).

Example 2 preparation of extract

Adding 90% ethanol 8 times the weight of the material (decoction dregs) obtained in the extraction of volatile oil in example 1, heating until the decoction is boiling, stopping heating, cooling to room temperature, and slowly collecting the extractive solution from the bottom of the extraction tank. Adding 90% ethanol 8 times the weight of the residue, heating until the decoction is boiling, stopping heating, cooling to room temperature, slowly collecting the extractive solution from the bottom of the extraction tank, and mixing the two extractive solutions to obtain ethanol extractive solution; standing at 0-5 deg.C for 24 hr, and centrifuging to obtain supernatant; recovering solvent at 45-50 deg.C under reduced pressure, and concentrating to 0.4g crude drug/ml medicinal liquid to obtain ethanol extract concentrate; mixing the ethanol extract concentrate with the distillate obtained in example 1, adding 1% chitosan solution with total mass of 10%, stirring, standing at room temperature for 24 hr, centrifuging, recovering solvent at 45-50 deg.C under reduced pressure, and concentrating to obtain concentrated solution containing 2.5g crude drug per 1ml medicinal liquid.

EXAMPLE 3 preparation of clathrate of volatile oil

And (3) adding 2 times of anhydrous ethanol into the volatile oil prepared in the embodiment 1 to dissolve and dilute the volatile oil to obtain an ethanol solution of the volatile oil for later use.

Weighing beta-cyclodextrin which is 8 times of the volatile oil prepared in the embodiment 1 by weight, putting the beta-cyclodextrin and water into a ball mill according to the weight ratio of 1:2, and grinding until the mixture is homogeneous; adding the volatile oil ethanol solution into a ball mill, starting the ball mill to perform inclusion until the volatile oil color and smell are eliminated and the material is in a sticky paste; discharging, and refrigerating at 0-5 deg.C for 24 hr; centrifuging at low speed to remove water; drying the clathrate at 45 deg.C under reduced pressure to obtain volatile oil clathrate.

The volatile oil inclusion compound prepared by the embodiment can be used as an intermediate raw material of a medicament and further used for preparing a medicinal preparation.

Taking the dried volatile oil inclusion compound prepared in the embodiment, leaching and leaching the volatile oil inclusion compound for 3 times by absolute ethyl alcohol, drying the volatile oil inclusion compound at 45 ℃ under reduced pressure to obtain a washed inclusion compound, measuring the content of the volatile oil in the washed inclusion compound and the blank recovery rate according to < volatile oil content measuring method-B method > in the fourth part of 2020 edition of Chinese pharmacopoeia, and calculating the encapsulation rate to be 95.7%.

EXAMPLE 4 Capsule preparation

Taking the volatile oil inclusion compound prepared in the example 3 and the extract prepared in the example 2 for standby;

concentrating the extract at 45-50 deg.C under reduced pressure to obtain 3.5g crude drug/ml medicinal liquid, and further drying at 50-55 deg.C under reduced pressure to obtain extract dry extract powder.

Taking the extract dry paste powder, crushing, sieving, uniformly mixing with the volatile oil inclusion compound prepared in the embodiment 3 and a proper amount of silicon dioxide, and filling capsules to obtain capsules.

EXAMPLE 5 preparation of granules

Essential oils, extracts and inclusion compounds of essential oils were prepared in the same manner as in examples 1 to 3.

Concentrating the extract at 45-50 deg.C under reduced pressure to obtain 3.5g crude drug/ml medicinal liquid to obtain concentrated solution of extract;

mixing the volatile oil clathrate with appropriate amount of citric acid, maltitol, sugar powder and dextrin, adding into the concentrated solution of the extractive solution, mixing, and drying under reduced pressure at 50 deg.C to obtain intermediate granule;

sieving the intermediate granule, grading, adding appropriate amount of silicon dioxide, and mixing to obtain granule.

EXAMPLE 6 tablet preparation

Concentrating the extract at 45-50 deg.C under reduced pressure to obtain 4.5-5.0g crude drug/ml medicinal liquid, and concentrating to obtain concentrated extract;

sequentially adding microcrystalline cellulose, pregelatinized starch, the volatile oil clathrate, vitamin C, sucrose fatty acid ester and croscarmellose sodium into a wet mixing granulator, and mixing; adding the concentrated extract, granulating at low speed, and drying wet granules at 50-60 deg.C under reduced pressure to obtain intermediate granules; granulating the intermediate granule with 16 mesh circular sieve, adding appropriate amount of magnesium stearate, mixing, tabletting, and coating with film coat.

Experimental example 1 stability examination of volatile oils after Inclusion with Cyclodextrin

Test samples: a clathrate of volatile oil prepared in example 3.

Control sample: the volatile oil was prepared in the same manner as in example 1; dissolving and diluting the volatile oil with 2 times of absolute ethyl alcohol by weight to obtain a volatile oil ethanol solution; adding beta-cyclodextrin 8 times the weight of the volatile oil, mixing, and drying under reduced pressure at 40 deg.C.

The test method comprises the following steps: the samples are respectively placed under the conditions of high temperature of 60 ℃ and illumination of 4500lx +/-500 for 10 days, and the content change of the volatile oil is inspected.

The detection method comprises the following steps: volatile oil content determination-referring to 2020 edition of Chinese pharmacopoeia, the four parts of volatile oil determination-method B > volatile oil composition determination-gas chromatography, (5% -phenyl) -methyl polysiloxane capillary column, FID detector, carrier gas: nitrogen, carrier gas flow: 1.5 ml/min. Temperature programming: the initial temperature was 90 ℃, the temperature was raised to 120 ℃ at a rate of 10 ℃ per minute for 70 minutes, and the temperature was raised to 250 ℃ at a rate of 5 ℃ per minute for 10 minutes. The temperature of a sample inlet is 250 ℃, the temperature of a detector is 260 ℃, and the split ratio is 10: 1.

sample treatment: and (4) ultrasonically extracting the test sample and the control sample by using absolute ethyl alcohol, filtering and determining a gas phase map.

And (3) test results:

(1) standing at 60 deg.C for 10 days

The results are shown in table 1 below and fig. 1. FIG. 1 is a gas phase (GC) spectrum of the volatile oil (sample A, see example 1), a control sample (60 ℃, standing for 10 days, sample B), a test sample (60 ℃, standing for 10 days, sample C).

TABLE 1 determination of volatile oil content under high temperature conditions

As can be seen from Table 1, under the condition of high temperature of 60 ℃, the loss of the volatile oil in the control sample is serious, the content is reduced by about 85 percent, and as can be seen from a GC (gas chromatography) spectrum, the relative content of a main peak of the control sample is obviously reduced, and a large number of additional impurity peaks are added, which shows that the volatile oil component is degraded and volatilized at a continuous high temperature; after the inclusion compound is formed, the content of the volatile oil is reduced by 15%, the volatile oil is slightly degraded by a GC (gas chromatography) spectrum, but the integral composition is not obviously changed, and the stability is obviously improved compared with a control sample.

(2) Standing under the condition of illumination of 4500lx +/-500 lx for 10 days

The results are shown in Table 2 below and FIG. 2. FIG. 2 is a gas phase spectrum of the volatile oil (sample A, see example 1), control sample (4500 lx. + -. 500lx, standing for 10 days, sample B), test sample (4500 lx. + -. 500lx, standing for 10 days, sample C).

TABLE 2 measurement of volatile oil content under light conditions

Table 2 shows that after the inclusion compound is placed for 10 days under the condition of 4500lx, the content of the volatile oil in the control sample is obviously changed, the content is reduced by 26 percent, and the content of the volatile oil in the inclusion compound is hardly changed; meanwhile, as can be seen from a gas phase spectrum (GC spectrum), the composition of the volatile oil of the control sample also changes remarkably, and the composition of the volatile oil in the inclusion compound does not change remarkably and is basically consistent with that of the crude oil which is not included. The volatile oil is coated by cyclodextrin, so that the light stability is obviously improved.

The results show that the volatile oil is successfully included, the capabilities of the inclusion compound for resisting illumination and high temperature are obviously improved, and the problem of poor stability of the effective components of the volatile oil is effectively solved.

Experimental example 2 determination of volatile oils in compositions

Volatile oil determination is performed on the preparation provided by the invention by adopting gas chromatography.

Test samples: example 4 the resulting capsule was prepared (sample a);

example 5 the resulting granules (sample B) were prepared;

example 6 the resulting tablet (sample C) was prepared.

Control sample: example 1 the resulting volatile oil (sample D) was prepared.

The experimental method comprises the following steps: gas chromatography, the parameters were the same as in experimental example 1.

Sample treatment: dissolving the volatile oil in anhydrous ethanol, and diluting.

The capsule is prepared by ultrasonically extracting the content with anhydrous ethanol, and filtering.

The granule is obtained by ultrasonic extraction with anhydrous ethanol and filtering.

Grinding the tablet into fine powder, ultrasonically extracting with anhydrous ethanol, and filtering.

The test results are shown in FIG. 3. FIG. 3 is a gas phase spectrum (GC spectrum) of the above sample.

As can be seen from figure 3, the composition of the volatile oil in the capsules, granules and tablets provided by the invention is basically consistent with that of the volatile oil which is not included. The invention shows that the composition of the volatile oil is not changed in the process of further preparing the preparation after the volatile oil is included, and an effective solution is provided for the clinical application of the active ingredients of the volatile oil.

Experimental example 3 comparative analysis of chemical components of the extract of the invention and the decoction of the Fingered citron powder

Control sample: preparing a decoction according to the original formula preparation method of the fingered citron powder, specifically, crushing angelica and ligusticum wallichii into coarse powder which is sieved by a 20-mesh sieve, mixing the coarse powder according to the proportion of 3:2, adding 5 times of water into an electromagnetic oven for decoction, adding 8 times of 90% ethanol until the liquid level of the liquid medicine is reduced to expose dregs, boiling the liquid medicine again, stopping heating, and filtering the dregs when the liquid medicine is reduced to room temperature to obtain an extract, namely the fingered citron powder decoction.

Component comparison: ferulic acid (ferulic acid is a marker component for the pharmacodynamic activity of the Chinese angelica and Szechuan lovage rhizome, so that the ferulic acid is used as a reference to analyze a decoction and an extract.)

Test samples: the volatile oil from example 1; example 2 the extract obtained.

The test method comprises the following steps: thin layer chromatography, adopting different development systems to carry out chromatography investigation on each component of the sample

And (3) test results:

(1) the analysis of the small polar components was carried out using n-hexane-ethyl acetate (volume ratio 9:1) as the development system, and the results are shown in FIG. 4. In FIG. 4, sample 1 is a control sample (Fingered citron decoct), sample 2 is the volatile oil prepared in example 1, and sample 3 is the extract prepared in example 2.

FIG. 4 is a TLC pattern obtained under a developing system for identifying small polar components of volatile oils. As shown in figure 4, the compositions of the volatile oil and the extract prepared by the invention are different due to sectional extraction of spots, but the compositions of the volatile oil and the extract are basically consistent with the main spots of the fingered citron decoct. The volatile oil in FIG. 4 shows more spot information due to the higher concentration and purity of the spot size.

(2) The medium and high polarity components were analyzed by using cyclohexane-dichloromethane-ethyl acetate-formic acid (volume ratio 4:1:1:0.1) as the development system, and the results are shown in FIG. 5.

In FIG. 5, sample 1 is a control sample (Fingered citron decoct), sample 2 is ferulic acid, and sample 3 is the extract prepared in example 2.

FIG. 5 is a TLC chromatogram obtained by chromatography of developing solvent for identifying characteristic component ferulic acid, and it can be seen from FIG. 5 that the fructus Citri Sarcodactylis decoction and the extract of the invention both contain ferulic acid, and the TLC spot composition of the two is not different.

(3) The analysis of the high-polar components was performed using n-butanol-glacial acetic acid-water (volume ratio 4:1:1) as the development system, and the results are shown in fig. 6. In FIG. 6, sample 1 is a control sample (Fingered citron decoct), sample 2 is ferulic acid, and sample 3 is the extract prepared in example 2. As can be seen from FIG. 6, the control sample fructus Citri Sarcodactylis decoction was consistent with the inventive high-polarity TLC spot.

Fig. 4, fig. 5 and fig. 6 show that the composition prepared by the invention has basically the same component composition as the finger citron powder decoction.

Although the invention has been described in detail hereinabove with respect to specific embodiments thereof, it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the scope of the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A pharmaceutical intermediate raw material is characterized by comprising volatile oil and cyclodextrin, wherein the volatile oil is completely or substantially completely included by the cyclodextrin; the volatile oil is prepared from radix Angelicae sinensis and rhizoma Ligustici Chuanxiong.

2. The pharmaceutical intermediate starting material of claim 1, wherein the cyclodextrin is β -cyclodextrin; and/or the presence of a gas in the gas,

the weight ratio of the volatile oil to the cyclodextrin is 1: 5-8; and/or the presence of a gas in the gas,

in the raw materials for preparing the volatile oil, the weight ratio of the angelica and the ligusticum wallichii is 1-5:1-5, preferably 1-3:1-3, and more preferably 3: 2.

3. A process for preparing a pharmaceutical intermediate material as claimed in claim 1 or 2, which comprises:

providing the volatile oil;

providing the cyclodextrin;

and performing inclusion on the cyclodextrin and the volatile oil.

4. The method according to claim 3, wherein the inclusion is carried out by a milling method; preferably, the cyclodextrin and the volatile oil are mixed and then ground until the color and odor of the volatile oil are completely or substantially completely included; and/or the presence of a gas in the gas,

preferably, the volatile oil is diluted by absolute ethyl alcohol before inclusion; and/or the presence of a gas in the gas,

preferably, the cyclodextrin is mixed with water and uniformly dispersed before inclusion.

5. A Chinese medicinal composition, comprising the pharmaceutical intermediate material of claim 1 or 2 or the pharmaceutical intermediate material prepared by the method of claim 3 or 4, and further comprising an extract; wherein the extract is prepared from angelica and ligusticum wallichii serving as raw materials.

6. The Chinese medicinal composition according to claim 5, wherein the weight ratio of the angelica and the ligusticum wallichii in the raw materials for preparing the extract is 1-5:1-5, preferably 1-3:1-3, and more preferably 3: 2.

7. The Chinese medicinal composition according to claim 5 or 6, wherein the preparation method of the extract comprises:

8. The Chinese medicinal composition according to claim 7, wherein in the preparation method of the extract,

the concentration of the ethanol used in the step 2) is 50-100%, and 85-95% can be selected; and/or the presence of a gas in the gas,

step 2) boiling the liquid medicine in each extraction, standing for 6-12h, and then extracting; and/or the presence of a gas in the gas,

in the step 3), the alcohol extract obtained in the step 2) can be firstly kept stand at a low temperature and then centrifuged; and/or the presence of a gas in the gas,

in the step 4), adding a chitosan solution into the combined solution for clarification.

9. The Chinese medicinal composition according to claim 5 or 6, wherein the preparation method of the extract comprises:

2) adding 50-100% ethanol with 4-8 times weight concentration into the material extracted from the step 1), heating to boil, stopping heating, standing to room temperature, and separating to obtain extractive solution; adding 6-10 times of 50-100% ethanol, heating until the liquid medicine is boiling, stopping heating, cooling the liquid medicine to room temperature, collecting extractive solution, and mixing the two liquid medicines to obtain ethanol extractive solution;

3) standing the alcohol extract prepared in step 2) at low temperature for 8-24h, centrifuging, removing precipitate, and concentrating the supernatant at 40-60 deg.C under reduced pressure to obtain crude drug containing 0.2-1.0g per 1ml of medicinal liquid to obtain alcohol extract concentrate;

10. A Chinese medicinal preparation, which is characterized by comprising the Chinese medicinal composition of any one of claims 5 to 9; or further comprises pharmaceutically acceptable auxiliary materials.