Snake gall bulbus fritilariae dropping pill and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a snake gall bulbus fritilariae dropping pill and a preparation method thereof. The raw material prescription of the snake gall and bulbus fritillariae cirrhosae dropping pill provided by the invention comprises the following components in parts by weight: 2-6 parts of snake gall, 1-5 parts of bulbus fritillariae ussuriensis, 0.05-0.1 part of amygdronitrile, 50-80 parts of polyethylene glycol and 5-15 parts of a dispersion carrier, the dispersion carrier comprises at least one of glyceryl monostearate and stearyl palmitate. The snake gall and bulbus fritilariae dropping pill provided by the invention is convenient to take orally, does not contain preservatives, so that the snake gall and bulbus fritilariae dropping pill has very good safety, has very good stability based on material selection, can form a sustained-release dropping pill, can prolong the acting time of snake gall and bulbus fritilariae, can improve the bioavailability, can reduce the taking frequency, and can be used for preparing a sustained-release preparation for the snake gall and bulbus fritilariae dropping pill. The traditional Chinese medicine composition is also suitable for patients with diabetes and hyperglycemia.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a snake gall and fritillary bulb pill and a preparation method thereof. Background Art

[0002] Snake Gallbladder and Fritillaria Liquid is a commonly used Chinese medicine formula with good efficacy. Its functions and indications are: expectorant and cough relieving, expectorant and stagnation-dispersing. It is used for wind-heat cough, sputum and wheezing, chest tightness, coughing up sputum or long-term cough. It has a large market sales volume, and its quality directly affects the efficacy of medication for a large number of patients.

[0003] At present, the prescription of snake gall and Fritillaria cirrhosa liquid includes: snake gall, menthol, Fritillaria cirrhosa, sodium benzoate, sucrose, honey, and almond water. The snake gall and Fritillaria cirrhosa liquid is a syrup, which is prone to yellow flocculent suspension or white needle-shaped crystal precipitation during storage, thus affecting the appearance quality and stability of the preparation. In addition, the added sodium benzoate preservative is prone to adverse reactions. In particular, it cannot be used by patients with diabetes and hyperglycemia. Summary of the invention

[0004] The purpose of the present application is to provide a snake gall and fritillaria cirrhosa pill and a preparation method thereof, aiming to solve the technical problem of how to improve the stability and safety of snake gall and fritillaria cirrhosa preparations.

[0005] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0006] In a first aspect, the present application provides a snake gall bladder and fritillary bulb dripping pill, wherein the raw material prescription of the snake gall bladder and fritillary bulb dripping pill comprises the following components in parts by weight:

[0007] 2-6 parts of snake bile, 1-5 parts of Fritillaria cirrhosae, 0.05-0.1 parts of apricot nitrile, 50-80 parts of polyethylene glycol, and 5-15 parts of a dispersion carrier; the dispersion carrier comprises at least one of glyceryl monostearate and glyceryl stearate palmitate.

[0008] In a second aspect, the present application provides a method for preparing snake gall bladder and fritillary bulb pills, comprising:

[0009] Providing a raw material prescription for the Shedan Chuanbei pills of the first aspect of the present application;

[0010] The snake gall is soaked in alcohol, then incorporated into snake bile, and concentrated to obtain a snake bile concentrated paste;

[0011] Extracting and concentrating the Fritillaria thunbergii with alcohol to obtain a Fritillaria thunbergii extract;

[0012] The snake bile concentrated paste, the Fritillaria cirrhosa extract and the almond nitrile are mixed, and then mixed with the molten dispersion carrier and the molten polyethylene glycol to obtain a mixed material;

[0013] The mixture is dripped into a coolant for solidification to obtain Shedan Chuanbei dripping pills.

[0014] The snake gall and Fritillaria cirrhosa pills provided in the first aspect of the present application are solid preparations obtained by a raw material prescription of certain weight portions of snake bile, Fritillaria cirrhosa, apricot nitrile, polyethylene glycol, and a dispersion carrier (including at least one of monostearate glyceryl and palmitic stearyl glyceryl); compared with the snake gall and Fritillaria cirrhosa liquid preparation, the snake gall and Fritillaria cirrhosa pills of the present application are not only convenient for oral administration, but also do not contain added preservatives, thus having excellent safety. At the same time, based on polyethylene glycol as a matrix and at least one of monostearate glyceryl and palmitic stearyl glyceryl as a dispersion carrier, the snake gall and Fritillaria cirrhosa pills have excellent stability and can form a sustained-release pill, which can prolong the action time of snake gall and Fritillaria cirrhosa, improve bioavailability, reduce the number of doses, reduce the risk of adverse reactions, and can also be suitable for patients with diabetes and hyperglycemia.

[0015] The preparation method of the snake gall bladder and fritillaria pills provided in the second aspect of the present application is to soak snake gall in alcohol, incorporate snake bile, concentrate the obtained snake bile concentrated paste, extract and concentrate fritillaria brevis to obtain fritillaria brevis extract, and almond nitrile, dispersion carrier (including at least one of monostearate glyceryl and stearyl palmitate glyceryl) and polyethylene glycol as the mixed material components, and solidify and form by dropping into a coolant to obtain the snake gall bladder and fritillaria pills. In this process, the snake bile concentrated paste, fritillaria brevis extract and almond nitrile can be evenly dispersed in the dispersion carrier and polyethylene glycol in a molten state, and the pills are formed in a coolant, so that a snake gall bladder and fritillaria pill with good stability and sustained release effect can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0017] Figure 1 It is a cumulative release curve diagram of the Snake Gallbladder and Fritillaria cirrhosa pills prepared in the examples and comparative examples of the present application. DETAILED DESCRIPTION

[0018] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0019] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0020] In the present application, "at least one" means one or more, "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single or plural items.

[0021] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0022] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0023] The weight of the relevant components mentioned in the embodiment description of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the embodiment description of the present application, it is within the scope disclosed in the embodiment description of the present application. Specifically, the mass described in the embodiment description of the present application can be a mass unit known in the chemical industry such as μg, mg, g, kg, etc.

[0024] The terms "first" and "second" are used only for descriptive purposes to distinguish objects such as substances from each other, and should not be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the embodiments of the present application, the first XX may also be referred to as the second XX, and similarly, the second XX may also be referred to as the first XX. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features.

[0025] Snake Gallbladder Fritillaria Liquid was included as a Chinese medicine formula in the 1983 "Jiangxi Provincial Drug Standards" and has been included in more than ten provincial drug standards. In these drug standards, the Fritillaria of "Snake Gallbladder Fritillaria Liquid" is specified to be Fritillaria cirrhosa. However, the prescription of Snake Gallbladder Fritillaria Liquid included in the 1994 edition of the "Drug Standards of the Ministry of Health of the People's Republic of China" (hereinafter referred to as the Ministry of Health Drug Standards) stipulates that it should be used with Fritillaria cirrhosa, standard number: WS 3 -B-1832-94. On November 5, 2011, the State Food and Drug Administration revised the national drug standard for "Snake Gallbladder and Fritillaria Liquid" and issued the National Drug Standard (Revised) Promulgation Document, standard number: WS 3 -B-1832-94-2011; On December 30, 2022, the State Food and Drug Administration revised the national drug standard of "Snake Gallbladder and Fritillaria Liquid" again and issued the National Drug Administration Drug Standard (Revised) Promulgation Document, Standard No.: WS 3 -B-1832-94-2022, this national drug standard is the current statutory standard for "Snake Gallbladder and Fritillaria Liquid".

[0026] In view of the fact that the snake gall and Fritillaria liquid is prone to produce yellow flocculent suspension or white needle-shaped crystal precipitation during storage, the appearance quality and stability of the preparation are affected; at the same time, the snake gall and Fritillaria liquid takes effect quickly, but the action time is short, and it needs to be taken frequently to control the symptoms of coughing, and the snake gall and Fritillaria liquid directly contacts the oral mucosa, causing the fishy smell of the snake gall to affect the taking of the medicine and reduce the compliance of taking the medicine. For this reason, the embodiment of the present application develops a snake gall and Fritillaria solid preparation, which not only does not use the preservatives or antibacterial agents commonly used in the preparation production process, but also uses polyethylene glycol as a matrix, monostearate glyceryl and stearyl palmitate glyceryl as a dispersion carrier, which can improve the stability of the snake gall and Fritillaria preparation, and has a sustained release effect, which is significantly better than the existing snake gall and Fritillaria liquid preparation. The specific technical scheme is as follows.

[0027] A first aspect of an embodiment of the present application provides a snake gall and fritillary pill, the raw material prescription of the snake gall and fritillary pill includes the following components in parts by weight: 2 to 6 parts of snake bile, 1 to 5 parts of Fritillaria cirrhosa, 0.05 to 0.1 parts of apricot nitrile, 50 to 80 parts of polyethylene glycol, and 5 to 15 parts of a dispersion carrier; wherein the dispersion carrier includes at least one of glyceryl monostearate and glyceryl stearate palmitate.

[0028] Snake bile is bile stored in the gallbladder of snakes. Snake bile is cool in nature, bitter and slightly sweet in taste; it has the effects of dispelling wind and dampness, cooling and improving eyesight, detoxifying and removing prickly heat; it can regulate and replenish the nervous system, endocrine system and immune system of human beings. All snake biles can be used as medicine, for example, it can be the bile from Bungarus bungarus, Bungarus bungarus, Chessboard snake, Cobra, King cobra, Five-step snake, Gray rat snake, Elaphe tricolor, Agkistrodon acutus, etc. In the specific embodiments of the present application, the bile from Cobra, Bungarus bungarus and Agkistrodon acutus is selected.

[0029] Fritillaria ussuriensis Maxim. is a heat-clearing and phlegm-resolving medicine, which is selected from the dried bulbs of Fritillaria ussuriensis Maxim., a plant of the Liliaceae family. It has the effects of clearing heat and moistening the lungs, resolving phlegm and relieving cough. It is used for lung heat and dry cough, dry cough with little phlegm, yin deficiency and fatigue cough, and cough with blood in sputum.

[0030] Mandelonitrile is also known as bitter almond nitrile and benzyl alcohol nitrile; mandelonitrile can exert a sedative effect by regulating the function of the central nervous system.

[0031] Polyethylene glycol is a general term for ethylene glycol polymers containing α,ω-dihydroxyl groups. It is a high molecular weight polymer with the chemical formula HOCH 2 (CH 2 OCH 2 ) m CH 2 OH, m is the degree of polymerization, polyethylene glycol has good water solubility, and in the examples of the present application, polyethylene glycol is selected as the matrix of the Shedan Chuanbei pills.

[0032] Glyceryl monostearate is also known as glyceryl monostearate or 1,2,3-propanetriol monooctadecanoate, with a molecular formula of C 21 H 42 O 4 ; Stearyl palmitin, also known as glyceryl palmitate / stearate, is a glyceride synthesized from palmitic acid (also known as hexadecanoic acid / palmitic acid), stearic acid (also known as octadecanoic acid) and glycerol (also known as glycerol triol), such as 1-palmitic acid-3-stearic acid glyceryl, 1,3-stearic acid-2-palmitic acid glyceryl or 1,2-stearic acid-3-palmitic acid glyceryl, etc. In the present application, monostearic acid glyceryl and / or stearyl palmitin are selected as the dispersion carrier.

[0033] The embodiment of the present application uses a raw material prescription of certain weight parts of snake bile, Fritillaria cirrhosa, apricot nitrile, polyethylene glycol, and a dispersion carrier (including at least one of monostearate glyceryl and stearyl palmitol) to obtain the snake gall and Fritillaria cirrhosa pills; compared with the snake gall and Fritillaria cirrhosa liquid preparation, the snake gall and Fritillaria cirrhosa pills of the present application are not only convenient for oral administration, but also do not contain preservatives, thus having excellent safety. At the same time, based on polyethylene glycol as a matrix and at least one of monostearate glyceryl and stearyl palmitol as a dispersion carrier, the snake gall and Fritillaria cirrhosa pills have excellent stability, can form a sustained-release pill, can prolong the action time of snake gall and Fritillaria cirrhosa, improve bioavailability, reduce the number of doses, reduce the probability and frequency of adverse reactions, reduce the severity of adverse reactions, and are also suitable for patients with diabetes and hyperglycemia.

[0034] In some embodiments, the raw material prescription of snake gall and Fritillaria cirrhosa pills includes: 2 to 6 parts of snake bile, for example, including but not limited to 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, etc.; 1 to 5 parts of Fritillaria thunbergii, for example, including but not limited to 2 parts, 3 parts, 4 parts, 5 parts, etc.; 0.05 to 0.1 parts of apricot nitrile, for example, including but not limited to 0.05 parts, 0.07 parts, 0.08 parts, 0.09 parts, 0.1 parts, etc.; 50 to 80 parts of polyethylene glycol, for example, including but not limited to 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 76 parts, 80 parts, etc.; 5 to 15 parts of stearyl palmitin, for example, including but not limited to 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, etc.

[0035] In some embodiments, the raw material prescription of snake gall and Fritillaria cirrhosa pills includes the following components in parts by weight: 4 parts of snake bile, 3 parts of Fritillaria cirrhosa, 0.08 parts of apricot nitrile, 60 parts of polyethylene glycol, and 10 parts of a dispersion carrier (including at least one of glyceryl monostearate and glyceryl palmitostearate).

[0036] In some embodiments, the snake gall bladder Chuanbei dripping pill contains: snake gall bladder soaked in alcohol and then incorporated into snake bile, and concentrated to obtain a snake bile concentrated paste with a relative density of 1.25 to 1.30. The snake bile concentrated paste can increase the material concentration, reduce the amount of materials, and is easy to take. For example, the snake gall bladder soaked in ethanol can be taken out, the gallbladder coat can be cut off, the bile can be collected, the gallbladder coat can be rinsed with the ethanol soaked in the snake gallbladder, the rinse liquid can be incorporated into the ethanol soaked in the snake gallbladder, placed in a rotary evaporator, and concentrated to a snake bile concentrated paste with a relative density of 1.25 to 1.30 (60°C) under the conditions of vacuum degree -0.05 to -0.08MPa and temperature 55 to 60°C.

[0037] In some embodiments, the snake gall bladder and Chuanbei dripping pills contain: a relative density of 1.25 to 1.30 of the flat Fritillaria extract obtained by alcohol extraction and concentration. The flat Fritillaria extract can increase the material concentration, reduce the amount of materials, and is easy to take. For example, the flat Fritillaria is refluxed and extracted with ethanol at least three times, and then the combined extract is decompressed and ethanol is recovered under the conditions of a vacuum degree of -0.04MPa to -0.09MPa and a temperature of 60 to 65°C to obtain a flat Fritillaria extract with a relative density of 1.25 to 1.30 (60°C).

[0038] The relative density in the examples of the present application refers to the density relative to water at 60°C.

[0039] In some embodiments, the degree of polymerization of polyethylene glycol is 2000-6000. Exemplarily, the polyethylene glycol in the snake gall bladder and Fritillaria cirrhosa pills can be polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 2000, polyethylene glycol 3000, etc., and polyethylene glycol 4000 can be specifically selected. Polyethylene glycol has good chemical stability, is not conducive to microbial growth, is not easy to become rancid, and does not react with drugs. Polyethylene glycol 4000 is solid at room temperature (25°C), has a melting point not higher than 70°C, and can be sterilized by hot pressing, filtration sterilization or gamma ray sterilization.

[0040] In some embodiments, the dispersion carrier is selected from at least one of stearyl palmitin and monostearate glyceryl. Stearyl palmitin is further selected, which can retard drug release, slow down drug release rate, prolong drug action time, stabilize drug release rate, reduce drug peak concentration, reduce the severity of adverse drug reactions, and reduce the probability of adverse drug reactions.

[0041] In a second aspect, the present application provides a method for preparing a snake gall bladder and fritillary bulb pill, comprising:

[0042] S01: providing a raw material prescription of the Shedan Chuanbei pills according to the first aspect of the embodiment of the present application;

[0043] S02: soaking the snake gallbladder in alcohol, adding it into snake bile, and concentrating it to obtain a snake bile concentrated paste;

[0044] S03: extracting and concentrating the Fritillaria thunbergii with alcohol to obtain a Fritillaria thunbergii extract;

[0045] S04: mixing the snake bile concentrated paste, the Fritillaria cirrhosa extract and the almond nitrile, and then mixing with a molten dispersion carrier and molten polyethylene glycol to obtain a mixed material;

[0046] S05: dropping the mixture into a coolant for solidification to obtain snake gall and fritillary bulb dripping pills.

[0047] The preparation method of the snake gall and Fritillaria cirrhosa pill provided in the embodiment of the present application, first, alcohol soaking of snake gall and incorporation of snake bile, concentrated snake bile concentrated paste, alcohol extraction and concentration of Fritillaria cirrhosa to obtain Fritillaria cirrhosa extract, snake bile concentrated paste, Fritillaria cirrhosa extract, almond nitrile, dispersion carrier and polyethylene glycol as mixed material components, by dripping into a coolant for solidification, to obtain the snake gall and Fritillaria cirrhosa pill. In this process, the snake bile concentrated paste and the Fritillaria cirrhosa extract are dispersed in the dispersion carrier, so that the active ingredients in the snake bile and the Fritillaria cirrhosa are dispersed in the molten controlled release skeleton material, i.e., the dispersion carrier, in a molecular state, and dispersed in a molten polyethylene glycol matrix to prepare a sustained-release pill, which prolongs the drug action time, reduces the number of times of administration, improves bioavailability, reduces the probability and severity of adverse drug reactions, and is also suitable for patients with diabetes and hyperglycemia.

[0048] In step S01: the raw material preparation step of the provided Snake Gallbladder and Fritillaria Chuanxiong Pills.

[0049] In some embodiments, the raw materials include: 2 to 6 parts of snake bile, 1 to 5 parts of Fritillaria thunbergii, 0.05 to 0.1 parts of apricot nitrile, 50 to 80 parts of polyethylene glycol, and 5 to 15 parts of stearyl palmitin.

[0050] Step S02: Snake bile concentration step.

[0051] In some embodiments, the steps of soaking the snake bile in alcohol and then incorporating it into snake bile, and concentrating it to obtain a concentrated snake bile paste include: soaking the snake bile in ethanol and then incorporating it into snake bile, and then concentrating it under vacuum conditions of -0.05 to -0.08 MPa and a temperature of 55 to 60°C to obtain a concentrated snake bile paste with a relative density of 1.25 to 1.30.

[0052] For example, take a prescribed amount of snake bile, soak it in 60 ml of 90% to 95% ethanol solution by volume, cut open the bile coating, take out the snake bile, then use the ethanol solution used to soak the snake bile to wash off the bile on the bile coating three times and add the bile into the snake bile, place it in a rotary evaporator, and concentrate it to a concentrated paste with a relative density of 1.25 to 1.30 (60°C) under vacuum conditions of -0.05 to -0.08 MPa and a temperature of 55 to 60°C.

[0053] Step S03: alcohol extraction step of Fritillaria thunbergii.

[0054] In some embodiments, the step of extracting Fritillaria dahurica with alcohol to obtain Fritillaria dahurica extract includes: refluxing the Fritillaria dahurica with ethanol for at least three times, and then reducing the combined extract to recover ethanol under the conditions of a vacuum degree of -0.04MPa to -0.09MPa and a temperature of 60 to 65°C to obtain a Fritillaria dahurica extract with a relative density of 1.25 to 1.30.

[0055] For example, a prescribed amount of Fritillaria brevis is placed in an extractor, an ethanol solution with a volume percentage of 80% to 85% is added, the solution is heated to a slight boil, and refluxed for extraction three times, each time 3.0 to 4.0 times the amount of ethanol solution is added for reflux extraction for 1 to 2 hours, the extracts are filtered, the extracts are combined, and the ethanol is recovered under reduced pressure at -0.04 MPa to -0.09 MPa and 60 to 65° C., and the extract is concentrated to a Fritillaria brevis extract with a relative density of 1.25 to 1.30 (65° C.).

[0056] Step S04: the step of preparing the mixed materials before the pellets are formed.

[0057] In some embodiments, the step of mixing snake bile concentrated paste, Fritillaria thunbergii extract and almond nitrile, and then mixing with a molten dispersion carrier and molten polyethylene glycol includes: mixing the snake bile concentrated paste, Fritillaria thunbergii extract and almond nitrile for 10 to 30 minutes, then adding them to the molten dispersion carrier and keeping them warm and homogenizing at a speed of 8000 to 10000 rpm for 1 to 2 minutes, and then adding them to the molten polyethylene glycol and stirring them at 80 to 100 rpm for 10 to 30 minutes.

[0058] For example, place the extract of Fritillaria dahurica in a stainless steel container, add snake bile concentrate and almond nitrile, and stir to obtain material C; take the prescribed amount of dispersion carrier such as stearyl palmitin and place it in a homogenizer, heat it to 70-76°C until the stearyl palmitin is completely melted into a liquid, add material C under heat preservation conditions, and homogenize at a speed of 8000-10000rpm to obtain material D; this can make the above-mentioned drugs dispersed in the dispersion medium in a molecular state. Take the prescribed amount of polyethylene glycol and place it in the batching cylinder of the drop pill machine, heat it to 70-76°C until the polyethylene glycol is completely melted into a liquid, add material D, and stir at 80-100rpm to obtain the final mixture, and keep the temperature of the mixture controlled at 70-76°C for the subsequent drop pill forming step.

[0059] Step S05: pill forming step.

[0060] In some embodiments, in the step of dripping the mixed material into a coolant for solidification: the temperature of the mixed material and the dripping is 70-76°C, and the temperature of the coolant is 4-10°C.

[0061] In some embodiments, the sedimentation distance of the mixed material dripped into the coolant is 15 to 20 cm. The sedimentation distance is the dripping distance, which is a fixed distance of the dripping pill machine, and the dripping temperature can be adjusted according to the dripping distance.

[0062] For example, 1.8 L of coolant is added to the cooling cylinder, and chilled brine is passed through the cooling pipe to ensure that the coolant in the cooling cylinder is cooled and maintained at 4-10°C, the compressed air is turned on, the above-mentioned mixture is input into the liquid storage barrel, and the mixture is dripped into the coolant under the insulation condition of 70-76°C, the dripping temperature is 70-76°C, the sedimentation distance is 15-20 cm, the dripping rate is 20 drops / minute, each drop weighs 50 mg, the solidified pills are collected, and the residual coolant on the surface of the pills is wiped off with filter paper to obtain the final snake gall and Fritillaria cirrhosa pills.

[0063] The temperature of the coolant is controlled at 4-10°C. Under this cooling temperature condition, the polyethylene glycol can solidify and form after the tail is retracted into the pill, so that the pills are complete and round, with good roundness, and the pill weight difference is controlled within a small range. The temperature of the mixed material and the dripping temperature are controlled at 70-76°C. The dripping at this temperature can ensure that the liquid state is maintained under the dripping distance conditions, and can also ensure that the coolant depth (under the above-mentioned sedimentation distance conditions, it can be well solidified and can form spherical pills with sufficient roundness).

[0064] In some embodiments, the coolant includes at least one of dimethyl silicone oil, liquid paraffin, kerosene, and vegetable oil. The above coolants are poor thermal conductors with low heat transfer rates. After cooling to a specified temperature, the original temperature can be maintained to a large extent, which can save cooling sources. In particular, the relative density of these coolants is more suitable, which can better control the sedimentation rate of the pellets, so that they are fully cooled and formed, and are easy to clean and remove.

[0065] In some embodiments, the coolant includes dimethicone and liquid paraffin in a mass ratio of (1-2):1. Dimethicone and liquid paraffin are inert liquids and are difficult to volatilize. Dimethicone and liquid paraffin are mixed together in the above mass ratio, which can control the sedimentation speed of the droplets so that they will not be too fast and cause tailing, and can also make the formed tails collected in the pills, so that the droplets return to their original state. Therefore, the tails formed by the droplets in the process of falling after dripping enter the coolant before solidification, and the sedimentation rate is slowed down under the action of the above coolant, and the tails are fully recovered to form round droplets with good roundness.

[0066] The following describes the invention in conjunction with specific embodiments.

[0067] Example 1

[0068] A snake gall and fritillary bulb pill and a preparation method thereof.

[0069] 1.1 Prescription

[0070] The raw material prescription of Shedan Chuanbei Pills is shown in Table 1 below.

[0071] Table 1

[0072] Raw material name Weight Raw material name Weight Raw material name Weight Snake bile 100g Fritillaria 750g Almond nitrile 2g Polyethylene glycol 4000 600g Glyceryl Palmitate 100g —— ——

[0073] 1.2 Preparation method

[0074] 1.2.1 Preparation of Fritillaria cirrhosa extract

[0075] A prescription amount of Fritillaria brevis is placed in a traditional Chinese medicine extraction tank, and an ethanol solution with a volume fraction of 80% is added for extraction three times: the first time, 4.0 times the weight (relative to the weight of Fritillaria brevis) of the ethanol solution is added for reflux extraction for 2 hours, the second time, 3.5 times the weight of the ethanol solution is added for reflux extraction for 1.5 hours, and the third time, 3.0 times the weight of the ethanol solution is added for reflux extraction for 1 hour; the extracts extracted three times are filtered, combined, and concentrated into an extract (about 150g) with a relative density of about 1.30 (under 60°C) by a multifunctional alcohol concentrator under vacuum degree of -0.04MPa to -0.09MPa and 60 to 65°C, filtered for standby use, and material A is obtained.

[0076] 1.2.2 Preparation of snake gallbladder concentrated paste

[0077] Take a snake gall containing a prescribed amount of snake bile, soak it in 60 ml of a 95% volume fraction ethanol solution, take it out and cut off the gallbladder coating, collect the bile, rinse the gallbladder coating three times with the 95% ethanol solution used to soak the snake bile, add the washing liquid into the ethanol used to soak the snake bile, place it in a rotary evaporator, and concentrate it to a concentrated paste with a relative density of 1.30 (under 60°C) under a vacuum degree of -0.05 to -0.08 MPa and a temperature of 55 to 60°C to obtain material B for standby use.

[0078] 1.2.3 Place the Fritillaria thunbergii extract (i.e., material A) in a stainless steel container, add the prescribed amount of snake bile concentrate (i.e., material B) and almond nitrile, stir for 30 minutes to obtain material C, which is set aside.

[0079] 1.2.4 Place the prescribed amount of stearyl palmitin in a homogenizer and heat to 73°C until the stearyl palmitin is completely melted into a liquid. Then add material C to the molten stearyl palmitin and homogenize at 10,000 rpm for 90 seconds to obtain material D.

[0080] 1.2.5 Place the prescribed amount of polyethylene glycol 4000 in the batching cylinder of the pill machine, heat to 73°C until the polyethylene glycol 4000 is completely melted into liquid, add material D, stir at 80 rpm for 30 minutes to obtain material E, and keep the material temperature controlled at 73°C.

[0081] 1.2.6 Mix 1.8 L of coolant dimethyl silicone oil-liquid paraffin (mass ratio of 2:1) evenly and add it to the cooling cylinder, and pass frozen brine into the cooling pipe to ensure that the dimethyl silicone oil-liquid paraffin in the cooling cylinder is cooled and maintained at 7°C. Turn on the compressed air, input material E into the liquid storage barrel, and drip material E into the above coolant under the condition of 73°C insulation. The dripping temperature is 73°C, the sedimentation distance is 15 cm, the dripping rate is 20 drops / min, and each drop weighs 50 mg. Collect the solidified pills and wipe off the coolant on the surface of the pills with filter paper to obtain Snake Gallbladder and Fritillaria cirrhosa pills.

[0082] Example 2

[0083] A snake gall and fritillary bulb pill and a preparation method thereof.

[0084] The difference from Example 1 is that the matrix polyethylene glycol 4000 in Example 1 is replaced with polyethylene glycol 3000; the other prescriptions and preparation processes are the same as those in Example 1.

[0085] Example 3

[0086] A snake gall and fritillary bulb pill and a preparation method thereof.

[0087] The difference from Example 1 is that the matrix polyethylene glycol 4000 in Example 1 is replaced with polyethylene glycol 6000; the other prescriptions and preparation processes are the same as those in Example 1.

[0088] Example 4

[0089] A snake gall and fritillary bulb pill and a preparation method thereof.

[0090] The difference from Example 1 is that the dispersing carrier palmitic acid glyceryl stearate in Example 1 is replaced with monostearate glyceryl; the other formulas and preparation processes are the same as those in Example 1.

[0091] Example 5

[0092] A snake gall and fritillary bulb pill and a preparation method thereof.

[0093] The difference from Example 1 is that the dripping temperature of 73° C. in Example 1 is adjusted to 71° C.; the other prescriptions and preparation processes are the same as those in Example 1.

[0094] Example 6

[0095] A snake gall and fritillary bulb pill and a preparation method thereof.

[0096] The difference from Example 1 is that the dripping temperature of 73° C. in Example 1 is adjusted to 75° C.; the other prescriptions and preparation processes are the same as those in Example 1.

[0097] Example 7

[0098] A snake gall and fritillary bulb pill and a preparation method thereof.

[0099] The difference from Example 1 is that the coolant temperature of 7°C in Example 1 is adjusted to 5°C; other prescriptions and preparation processes are the same as those in Example 1.

[0100] Implementation 8

[0101] A snake gall and fritillary bulb pill and a preparation method thereof.

[0102] The difference from Example 1 is that the coolant temperature of 7° C. in Example 1 is adjusted to 9° C.; other prescriptions and preparation processes are the same as those in Example 1.

[0103] Implementation 9

[0104] A snake gall and fritillary bulb pill and a preparation method thereof.

[0105] The difference from Example 1 is that the coolant in Example 1 is replaced by dimethyl silicone oil; other prescriptions and preparation processes are the same as those in Example 1.

[0106] Example 10

[0107] A snake gall and fritillary bulb pill and a preparation method thereof.

[0108] The difference from Example 1 is that the coolant in Example 1 is replaced by liquid paraffin; the other prescriptions and preparation processes are the same as those in Example 1.

[0109] Embodiment 11

[0110] A snake gall and fritillary bulb pill and a preparation method thereof.

[0111] The difference from Example 1 is that the coolant in Example 1 is replaced by corn oil; the other prescriptions and preparation processes are the same as those in Example 1.

[0112] Example 12

[0113] A snake gall and fritillary bulb pill and a preparation method thereof.

[0114] The difference from Example 1 is that the coolant in Example 1 is replaced by kerosene; other prescriptions and preparation processes are the same as those in Example 1.

[0115] Comparative Example 1

[0116] A snake gall and fritillary bulb pill and a preparation method thereof.

[0117] The difference from Example 1 is that stearyl palmitin in Table 1 of Example 1 is replaced with 18-cetyl alcohol; the other formulas and preparation processes are the same as those of Example 1.

[0118] Comparative Example 2

[0119] A snake gall and fritillary bulb pill and a preparation method thereof.

[0120] The difference from Example 1 is that the polyethylene glycol 4000 and stearyl palmitin in Table 1 of Example 1 are deleted together and replaced with glyceryl monostearate, i.e. the total weight of glyceryl monostearate is 700g.

[0121] The preparation method comprises:

[0122] The preparation of Fritillaria thunbergii extract is the same as that in Example 1.

[0123] The preparation of snake gallbladder concentrated paste is the same as that in Example 1.

[0124] Place the Fritillaria thunbergii extract in a stainless steel container, add the prescribed amount of snake bile concentrate and almond nitrile, stir for 30 minutes, and obtain material C for later use.

[0125] Place the prescribed amount of glyceryl monostearate in the batching cylinder of the pill machine, heat to 73°C until glyceryl monostearate is completely melted into liquid, add material C, stir at 80 rpm for 30 minutes to obtain material D, and keep the material temperature controlled at 73°C.

[0126] Mix 1.8 L of coolant dimethyl silicone oil-liquid paraffin (mass ratio of 2:1) evenly and add it to the cooling cylinder, and pass frozen brine into the cooling pipe to ensure that the dimethyl silicone oil-liquid paraffin in the cooling cylinder is cooled and maintained at 7°C. Turn on the compressed air, input material D into the liquid storage barrel, and drop material D into the above coolant under 73°C insulation conditions. The dropping temperature is 73°C, the sedimentation distance is 15 cm, the dropping rate is 20 drops / minute, and each drop weighs 50 mg. Collect the solidified pills, wipe off the coolant on the surface of the pills with filter paper, and the Snake Gallbladder and Fritillaria Drop Pills are obtained.

[0127] Comparative Example 3

[0128] A snake gall and fritillary bulb pill and a preparation method thereof.

[0129] The difference from Example 1 is that the polyethylene glycol 4000 in Table 1 of Example 1 is replaced with stearyl palmitin, that is, the total weight of stearyl palmitin is 700 g.

[0130] The preparation method comprises:

[0131] The preparation of Fritillaria extract is the same as that in Example 1.

[0132] The preparation of snake gallbladder concentrated paste is the same as that in Example 1.

[0133] Place the Fritillaria thunbergii extract in a stainless steel container, add the prescribed amount of snake bile concentrate and almond nitrile, stir for 30 minutes, and obtain material C for later use.

[0134] Place the prescribed amount of stearyl palmitin in the batching cylinder of the pill machine, heat to 73°C until the stearyl palmitin is completely melted into liquid, add material C, stir at 80rpm for 30 minutes to obtain material D, and keep the material temperature controlled at 73°C.

[0135] Mix 1.8 L of coolant dimethyl silicone oil-liquid paraffin (mass ratio of 2:1) evenly and add it to the cooling cylinder, and pass frozen brine into the cooling pipe to ensure that the dimethyl silicone oil-liquid paraffin in the cooling cylinder is cooled and maintained at 7°C. Turn on the compressed air, input material D into the liquid storage barrel, and drop material D into the above coolant under 73°C insulation conditions. The dropping temperature is 73°C, the sedimentation distance is 15 cm, the dropping rate is 20 drops / minute, and each drop weighs 50 mg. Collect the solidified pills, wipe off the coolant on the surface of the pills with filter paper, and the Snake Gallbladder and Fritillaria Drop Pills are obtained.

[0136] Comparative Example 4

[0137] A snake gall and fritillary bulb pill and a preparation method thereof.

[0138] The difference from Example 1 is that the stearyl palmitin in Table 1 of Example 1 is replaced with polyethylene glycol 4000, that is, the total weight of polyethylene glycol 4000 is 700 g.

[0139] The preparation method comprises:

[0140] The preparation of Fritillaria extract is the same as that in Example 1.

[0141] The preparation of snake gallbladder concentrated paste is the same as that in Example 1.

[0142] Place the Fritillaria thunbergii extract in a stainless steel container, add the prescribed amount of snake bile concentrate and almond nitrile, stir for 30 minutes, and obtain material C for later use.

[0143] Place the prescribed amount of polyethylene glycol 4000 in the batching cylinder of the pill machine, heat to 73°C until the polyethylene glycol 4000 is completely melted into liquid, add material C, stir at 80 rpm for 30 minutes to obtain material D, and keep the material temperature controlled at 73°C.

[0144] Mix 1.8 L of coolant dimethyl silicone oil-liquid paraffin (mass ratio of 2:1) evenly and add it to the cooling cylinder, and pass frozen brine into the cooling pipe to ensure that the dimethyl silicone oil-liquid paraffin in the cooling cylinder is cooled and maintained at 7°C. Turn on the compressed air, input material D into the liquid storage barrel, and drop material D into the above coolant under 73°C insulation conditions. The dropping temperature is 73°C, the sedimentation distance is 15 cm, the dropping rate is 20 drops / minute, and each drop weighs 50 mg. Collect the solidified pills, wipe off the coolant on the surface of the pills with filter paper, and the Snake Gallbladder and Fritillaria Drop Pills are obtained.

[0145] Comparative Example 5

[0146] A snake gall and fritillary bulb pill and a preparation method thereof.

[0147] The difference from Example 1 is that stearyl palmitin in Table 1 of Example 1 is replaced with octadecyl alcohol; the other formulas and preparation processes are the same as those of Example 1.

[0148] Effect test

[0149] (1) Determination of taurocholic acid content in snake bile:

[0150] Determined according to the high performance liquid chromatography method (0512) in the fourth part of the 2020 edition of the Chinese Pharmacopoeia.

[0151] 1.1 Chromatographic conditions and system suitability

[0152] Octadecylsilane bonded silica gel is used as filler; methanol-0.029 mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid) (65:35) is used as mobile phase; the detection wavelength is 203 nm. The theoretical plate number is not less than 4000 calculated based on the taurocholic acid peak.

[0153] 1.2 Preparation of reference solution

[0154] Take an appropriate amount of sodium taurocholate reference substance, weigh it accurately, and dissolve it in methanol to prepare a solution containing 0.35 mg of taurocholic acid per 1 ml, that is, (taurocholic acid weight = sodium taurocholate / 1.0426).

[0155] 1.3 Preparation of test solution

[0156] Take 50 pills of Snake Gall and Fritillaria Dropping Pills under the weight difference item, grind them in a mortar, add 40ml of 95% ethanol solution, ultrasonic wash four times, 10ml each time for 30 minutes, filter, combine the filtrate, dilute to 50ml with ethanol solution, accurately measure 20ml, pass through a D101 macroporous adsorption resin column (inner diameter 1.5cm, column height 10cm), elute with 200ml of water, discard the water, and then elute with 60ml of ethanol, collect the filtrate, evaporate to dryness, dissolve the residue with methanol and transfer it to a 10ml volumetric flask, add methanol to the scale, shake well, filter, and take the filtrate.

[0157] 1.4 Determination method

[0158] Accurately pipette 10μl of reference solution and 10-20μl of test solution respectively, inject into liquid chromatograph, measure, and calculate the content of each pill.

[0159] (2) Release determination:

[0160] The cumulative release rate was measured for the implementation examples of different dispersion carriers and matrices that were evaluated to have a significant impact on the release rate during use in this application.

[0161] Referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, First Method Basket Method), 600 ml of 0.1 mol / L hydrochloric acid solution was measured and placed in each dissolution cup. The deviation between the actual measured volume and the specified volume should be within ±1%. The Shedan Chuanbei Pills samples were placed in 6 dry rotating baskets respectively, and the rotating baskets were lowered into the dissolution cups at a speed of 100 r / min. After starting, an appropriate amount of dissolution solution was drawn at the specified sampling point at the specified time and filtered. The sampling to filtration should be completed within 30 seconds. The sampling time is: 0, 30mim, 60min, 90min, 120min, 180min, 240min, 480min, 720min, 1080min, 1440min. Accurately take 5 ml of the solution, add 0.1 mol hydrochloric acid to dilute to 25 ml, pass through a D101 macroporous adsorption resin column (inner diameter 1.5 cm, column height 10 cm), elute with 200 ml of water, discard the water, and then elute with 60 ml of ethanol, collect the filtrate, evaporate to dryness, dissolve the residue in methanol and transfer to a 10 ml volumetric flask, add methanol to the scale, shake well, filter, take the filtrate, and determine the taurocholic acid content of snake bile according to the above-mentioned snake bile taurocholic acid content determination method to calculate the cumulative release.

[0162] (3) Accelerated stability test:

[0163] The determination was carried out in accordance with the General Chapter 9001 of Part IV of the 2020 edition of the Chinese Pharmacopoeia for Stability Experiments of Active Pharmaceutical Ingredients and Preparations.

[0164] Take 10 pills of Snake Gall and Fritillaria cirrhosa pills and put them into a weighing bottle without covering it, put it into a constant temperature and humidity chamber, set the temperature to 40℃±2℃, and the humidity to 75%±5%. Observe for 6 months, take samples in October, March, and June, observe the appearance, and then determine the snake bile taurocholic acid content using the above-mentioned snake bile taurocholic acid content determination method.

[0165] (4) Test results:

[0166] Release data are shown in Table 2 and Figure 1 ; The results of the appearance inspection are shown in Table 3.

[0167] Table 2

[0168]

[0169] Table 3

[0170]

[0171]

[0172] Result analysis:

[0173] In Example 1, stearyl palmitin is used as a water-insoluble dispersion carrier. The drug component is dispersed in the water-insoluble dispersion carrier in a molecular state by high-speed homogenization, and then mixed with the polyethylene glycol 4000 matrix and dripped into the immiscible coolant dimethicone-liquid paraffin (2:1), so that it shrinks into a round pill under the action of its own surface tension and the coolant, and solidifies into a smooth and round drop pill during the sedimentation process in the coolant, thereby reducing the release rate of the drug component. The smoothness, roundness, and solidification of the drop pill are the best among all the embodiments and comparative examples. Example 2 uses polyethylene glycol 3000 as the matrix, and the release rate is slightly lower than that of Example 1. Except for the roundness of the appearance, it is slightly worse than that of Example 1. Other indicators are the same as those of Example 1. Example 3 uses polyethylene glycol 6000 as the matrix, and its release rate is faster than that of Example 1, but the final cumulative release is significantly lower than that of Example 1. The appearance finish is the same as that of Example 1, but its roundness and coagulation are inferior to those of Example 1, and there is a little tailing; Example 4 uses glyceryl monostearate as a water-insoluble dispersion carrier, and its release rate is higher than that of Example 2, but slightly lower than that of Example 1. Example 1, its appearance smoothness, roundness, tailing, solidification, adhesion and other conditions are as ideal as those in Example 1; Example 5 adopts a dripping temperature of 71°C, which causes the tail to be unable to be completely retracted during the dripping process, premature solidification, resulting in tailing, and other appearance conditions are the same as Example 1; Example 6 adopts a dripping temperature of 75°C, which is slightly higher than the temperature, causing it to be unable to be completely solidified and there is adhesion, and other appearance conditions are similar to Example 1; Example 7 adopts a cooling temperature of 5°C, which causes it to cool and solidify prematurely, the surface is slightly rough, the smoothness is slightly poor, the roundness is out of tolerance, and there is tailing, The other appearances are similar to those of Example 1; Example 8 uses a cooling temperature of 9°C, which results in insufficient cooling and incomplete solidification of the pellets, and the other appearances are similar to those of Example 1; Example 9 uses dimethyl silicone oil as a coolant, and the relative density of the coolant is relatively high. The pellets are slightly deformed during the cooling and settling process, and the surface finish is slightly poor. The other appearances are similar to those of Example 1. Example 10 uses liquid paraffin as a coolant, and because of its relatively low relative density, the settling speed is too fast, the pellets are not completely solidified, and there are slight deformations. The other appearances are similar to those of Example 1. Example 11 uses corn oil as a coolant, and Example 12 uses kerosene as a coolant. There is no significant difference in the solidification conditions compared with Example 1, and the roundness is good and the surface finish is relatively ideal.

[0174] Comparative Example 1 uses 1860 alcohol as a water-insoluble dispersion carrier, Comparative Example 2 uses glyceryl monostearate as a matrix, and Comparative Example 3 uses glyceryl palmitate as a matrix. The release rates and final cumulative releases of the three comparative examples are very different from those of Example 1, especially Comparative Example 2. However, the changes in the dispersion carriers and matrices of the three comparative examples do not affect the appearance of the drop pills. Comparative Example 4 is a non-sustained release drop pill, and its release rate is significantly faster than that of Example 1. Comparative Example 5 uses 1860 alcohol as a water-insoluble dispersion carrier, and its release rate is significantly higher than that of Example 1, but its final cumulative release is slightly lower than that of Example 1.

[0175] In summary, the snake gall and Fritillaria sustained-release drop pills prepared in the examples of the present application have obvious advantages over other comparative examples, and effectively solve the shortcomings of the snake gall and Fritillaria liquid preparations prepared in the prior art, which are directly released after taking and lead to a short action time, among which Example 1 has the best effect. Because the existing snake gall and Fritillaria liquid preparations are liquid preparations, they are directly absorbed through the gastrointestinal mucosa without release after taking, and the present application is a drop pill, and a controlled release dispersion is added, the release rate is significantly reduced compared with the general drop pill, and is much lower than that of comparative example 4 without the addition of a controlled release dispersion carrier. In this way, the snake gall and Fritillaria drop pills in the examples of the present application can reduce the number of times the drug is taken while maintaining the same dosage and provide an application prospect for expectorant and cough relieving / expectorant and dispersing drugs for patients with diabetes and hyperglycemia.

[0176] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A snake gall bladder and fritillary bulb pill, characterized in that: The raw material prescription of the Shedan Chuanbei pills includes the following components in parts by weight: 2-6 parts of snake bile, 1-5 parts of Fritillaria cirrhosae, 0.05-0.1 parts of apricot nitrile, 50-80 parts of polyethylene glycol, and 5-15 parts of a dispersion carrier; the dispersion carrier comprises at least one of glyceryl monostearate and glyceryl stearate palmitate.

2. The Snake Gallbladder and Fritillaria Chuanbei Drop Pills according to claim 1, characterized in that: The snake gall and fritillary bulb pills contain: snake gall that is soaked in alcohol and then incorporated into snake bile, which is concentrated to obtain a snake bile concentrated paste with a relative density of 1.25 to 1.

30.

3. The Snake Gallbladder and Fritillaria Chuanbei Drop Pills according to claim 1, characterized in that: The snake gall and Fritillaria cirrhosa pills contain: a Fritillaria cirrhosa extract with a relative density of 1.25 to 1.30 obtained by alcohol extraction and concentration of the Fritillaria cirrhosa.

4. The Snake Gallbladder and Fritillaria Chuanbei Drop Pills according to any one of claims 1 to 3, characterized in that: The polymerization degree of the polyethylene glycol is 2000-6000.

5. A method for preparing snake gall bladder and Fritillaria cirrhosa pills, characterized in that: include: Providing a raw material prescription for the Shedan Chuanbei pills according to any one of claims 1 to 4; The snake gall is soaked in alcohol, then incorporated into snake bile, and concentrated to obtain a snake bile concentrated paste; Extracting and concentrating the Fritillaria thunbergii with alcohol to obtain a Fritillaria thunbergii extract; The snake bile concentrated paste, the Fritillaria cirrhosa extract and the almond nitrile are mixed, and then mixed with the molten dispersion carrier and the molten polyethylene glycol to obtain a mixed material; The mixture is dripped into a coolant for solidification to obtain Shedan Chuanbei dripping pills.

6. The preparation method according to claim 5, characterized in that: In the step of dripping the mixed material into a coolant for solidification: the temperature of the mixed material is 70-76° C., and the temperature of the coolant is 4-10° C.; And / or, the sedimentation distance of the mixed material dripping into the coolant is 15 to 20 cm.

7. The preparation method according to claim 5, characterized in that: The coolant includes at least one of dimethyl silicone oil, liquid paraffin, kerosene and vegetable oil.

8. The preparation method according to claim 7, characterized in that: The coolant includes dimethyl silicone oil and liquid paraffin in a mass ratio of (1-2):

1.

9. The preparation method according to any one of claims 5 to 8, characterized in that: The step of soaking the snake gall in alcohol, incorporating it into snake bile, and concentrating it to obtain a concentrated snake bile paste comprises: soaking the snake gall in ethanol, washing the chopped bile skin with the ethanol obtained after soaking, and then incorporating it into the collected snake bile, and then concentrating it under the conditions of a vacuum degree of -0.05 to -0.08 MPa and a temperature of 55 to 60° C. to obtain a concentrated snake bile paste with a relative density of 1.25 to 1.30; And / or, the step of extracting and concentrating the Fritillaria dahurica with alcohol to obtain the Fritillaria dahurica extract comprises: refluxing the Fritillaria dahurica with ethanol for at least three times, then concentrating the combined extract under reduced pressure at a vacuum degree of -0.04MPa to -0.09MPa and a temperature of 60 to 65°C, recovering ethanol, and obtaining the Fritillaria dahurica extract with a relative density of 1.25 to 1.

30.

10. The preparation method according to any one of claims 5 to 8, characterized in that: The steps of mixing the snake bile concentrated paste, the Fritillaria balsamina extract and the almond nitrile, and then mixing with the molten dispersion carrier and the molten polyethylene glycol include: The snake bile concentrate paste, the Fritillaria thunbergii extract and the almond nitrile are mixed and stirred for 10 to 30 minutes, then added to the molten dispersion carrier and kept warm and homogenized at 8000 to 10000 rpm for 1 to 2 minutes, and then added to the molten polyethylene glycol and stirred at 80 to 100 rpm for 10 to 30 minutes.

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