A Huoxiang Zhengqi pharmaceutical preparation, its preparation method and application

Abstract

The present invention discloses a Huoxiang Zhengqi pharmaceutical preparation, its preparation method and application, belonging to the technical field of traditional Chinese medicine. Using the raw materials recorded in the Chinese Pharmacopoeia, after extracting each raw material, the extract is processed, including: the extract of Magnolia officinalis, the extract of Angelica dahurica, Pogostemon oil, Perilla leaf oil are included by beta-cyclodextrin, and the extracts of Atractylodes lancea, Citrus reticulata Blanco, Poria cocos, Areca peel, Pinellia ternata and Glycyrrhiza glabra extract are made into an extract; or the combined extract of Atractylodes lancea, Citrus reticulata Blanco and Angelica dahurica is included by beta-cyclodextrin, and the extracts of Poria cocos, Areca peel, Pinellia ternata and Glycyrrhiza glabra extract are made into an extract; the inclusion compound and the extract are mixed and made into a preparation. The present invention uses beta-cyclodextrin to include the ethanol extract and volatile oil of Magnolia officinalis (or Magnolia officinalis and Angelica dahurica) at the same time. The inclusion compound is insoluble in water and made into an oral solid preparation, which significantly improves the taste, enhances the stability of components such as volatile oil, and avoids the use of co-solvents such as Tween 80 and ethanol.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and specifically relates to a Huoxiang Zhengqi drug preparation, its preparation method and application. Background Art

[0002] Huoxiang Zhengqi water, oral liquid, tablets, soft capsules, dripping pills, etc. have been widely used clinically and are large varieties of traditional Chinese medicine with definite curative effects. The Chinese Pharmacopoeia (2020 Edition) includes Huoxiang Zhengqi water, oral liquid, dripping pills and soft capsules, which have the effects of relieving exterior syndrome and resolving dampness, regulating qi and harmonizing the middle, and are used for colds caused by exogenous wind-cold, internal injury by dampness stagnation or summer injury by dampness, with symptoms such as headache and dizziness, stuffiness and oppression in the chest diaphragm, abdominal distension and pain, vomiting and diarrhea; or those with the above syndromes in gastrointestinal colds. Although the raw material prescriptions of the above products are the same, their extraction solvents and processes are significantly different. For the Huoxiang Zhengqi products prepared by different extraction solvents and processes, there must be certain differences in their pharmacodynamic components, pharmacological effects and clinical curative effects, and there are also differences in the applicable populations (compliance) of different products. For example, in Huoxiang Zhengqi water, Atractylodes lancea, Citrus reticulata Blanco, Magnolia officinalis (processed with ginger), and Angelica dahurica are extracted by percolation with 60% ethanol. For the first three, 400 ml of the initial percolate is collected each, and for the latter, 500 ml of the initial percolate is collected and reserved; continue percolation, collect the subsequent percolate, concentrate it and incorporate it into the initial percolate, and then directly add it to the other components of Huoxiang Zhengqi water to form Huoxiang Zhengqi water. In Huoxiang Zhengqi oral liquid, Magnolia officinalis (processed with ginger) is extracted by heating under reflux with 60% ethanol, Atractylodes lancea, Citrus reticulata Blanco, and Angelica dahurica are distilled with water, the distillate and the aqueous solution after distillation are collected, and then after further treatment, they are added to the other components of Huoxiang Zhengqi oral liquid to form Huoxiang Zhengqi oral liquid. Thus, it can be seen that in the above two products, Huoxiang Zhengqi water contains the liposoluble components (ethanol extraction) of Angelica dahurica, Atractylodes lancea and Citrus reticulata Blanco, while the content of liposoluble components in Huoxiang Zhengqi oral liquid is less (water extraction). For example, the former contains more imperatorin and isoimperatorin (Angelica dahurica coumarin), and the latter contains less imperatorin and isoimperatorin. Our experimental results show that the difference between the two is about 5-10 times. In addition, the ethanol content in Huoxiang Zhengqi water is 40%-50%. Ethanol has a great irritation to the gastrointestinal tract. After taking it, people often feel uncomfortable and even vomit, with poor compliance. Those who are allergic to ethanol, or the elderly, children, and patients with gastrointestinal ulcers who are prohibited from drinking alcohol are not suitable to take it, which limits the scope of treatment objects; Huoxiang Zhengqi oral liquid does not contain ethanol, but contains a large amount of volatile oils (such as Pogostemon cablin oil, Perilla frutescens oil, and volatile oil components in the extracts of Atractylodes lancea, Citrus reticulata Blanco, and Angelica dahurica), and solubilizer Tween 80 is used, and the taste is also not good, especially for children (infants and young children) with poor compliance.

[0003] The aforementioned Huoxiang Zhengqi products are all for adult use (adult medicines). There are currently no Huoxiang Zhengqi products for pediatric use (children). The main reason is that Huoxiang Zhengqi liquid and oral solution have poor taste and poor compliance, making them difficult for children to accept. In addition, solid dosage forms such as tablets, soft capsules, and pills are inconvenient for children (infants). Generally speaking, the preferred dosage forms for pediatric use (children) are liquid preparations (oral liquids, syrups, and mixtures), or suspensions (dry suspensions), powders, and granules (suspended granules), which are dispersed or suspended in water before administration. However, there are currently no Huoxiang Zhengqi suspensions (dry suspensions), powders, or suspended granules on the market.

[0004] The applicant conducted oral tastings on the extracts from each step of the preparation of Huoxiang Zhengqi Water and its oral liquid. They found that Magnolia officinalis (processed with ginger) and Angelica dahurica, extracted with 60% ethanol and after ethanol recovery, had a very strong bitter, numbing, and astringent taste, mainly from magnolol and honokiol in Magnolia officinalis, and coumarin components in Angelica dahurica. Furthermore, patchouli oil and perilla leaf oil had a strong pungent and irritating taste, resulting in a poor taste, unpleasant patient experience, and poor compliance, especially for children and infants. Existing technologies use inclusion complexation to reduce the bitterness or irritation of drugs, thereby improving drug compliance. Encapsulation of volatile oils with cyclodextrin is the most common method, primarily aimed at increasing the stability of volatile oils, preventing volatilization loss, and reducing the bitterness or irritation of the drug. Cyclodextrins are classified into water-soluble cyclodextrins (hydroxypropyl cyclodextrin, sulfonic acid cyclodextrin, etc.) and water-poorly soluble cyclodextrins (such as beta-cyclodextrin).

[0005] Some drug dosage forms require increased solubility of encapsulated components such as volatile oils in water. In such cases, water-soluble cyclodextrins are generally used to encapsulate the volatile oils because these encapsulated components are readily soluble in water. However, beta-cyclodextrin is poorly soluble in water. Therefore, the applicant argues that encapsulating volatile oils and other fat-soluble components in Huoxiang Zhengqi liquid preparations with beta-cyclodextrin generally fails to achieve ideal solubilization. However, beta-cyclodextrin is used to encapsulate volatile oils in some granule formulations because the granules are taken with a relatively large amount of warm water (approximately 200ml each time), which helps dissolve the encapsulated components. Oral liquids are typically 10ml in volume; using beta-cyclodextrin to encapsulate volatile oils in oral liquids would result in poor dissolution of the encapsulated components.

[0006] To address the poor taste of Huoxiang Zhengqi oral liquid, 117257883A describes the use of water-soluble cyclodextrin to encapsulate patchouli oil, perilla leaf oil, and volatile oils, thus improving the taste of the oral liquid. Further research by the applicant revealed that water-soluble cyclodextrins (such as hydroxypropyl cyclodextrin or sulfonic acid cyclodextrin) can indeed encapsulate the solubilizing volatile oil components, allowing patchouli oil, perilla leaf oil, and volatile oils to fully dissolve in the oral liquid. However, the improvement in taste is still very limited and insufficient to meet the taste requirements of pediatricians (children) for Huoxiang Zhengqi products.

[0007] Meanwhile, we conducted market research and analysis on Huoxiang Zhengqi products. Most people believe that Huoxiang Zhengqi water has better curative effects than Huoxiang Zhengqi oral liquid, but its taste is poor, the patient experience is not good, and the compliance is poor. Summary of the Invention

[0008] In view of the above situation, the object of the present invention is to provide a Huoxiang Zhengqi pharmaceutical preparation without ethanol and Tween, with good taste, and its preparation method on the basis of the extraction processes of Huoxiang Zhengqi water and Huoxiang Zhengqi oral liquid recorded in the Chinese Pharmacopoeia, without changing the composition of raw materials and the dosage ratio stipulated in the Pharmacopoeia. It is especially suitable for children (infants and young children) to take, significantly improves compliance, and at the same time the product quality is more stable.

[0009] Huoxiang Zhengqi medicine contains a large amount of volatile oils, and the contents of magnolol, honokiol and angelicin in the ethanol extracts of Magnolia officinalis and Angelica dahurica are relatively high, with a strong bitter, astringent and pungent taste, and poor taste. It is not suitable to be made into liquid oral preparations (such as oral liquid, syrup, mixture, etc.), nor should water-soluble cyclodextrin inclusion be used (which will increase the solubility of fat-soluble components such as volatile oils in water and cannot well solve the problem of poor taste). The present invention uses water-insoluble inclusion complex beta-cyclodextrin to simultaneously include the ethanol extracts and volatile oils of Magnolia officinalis (or Magnolia officinalis and Angelica dahurica). The inclusion complex is insoluble in water (reducing the solubility and concentration of the bitter, astringent and pungent components of Magnolia officinalis and Angelica dahurica and the pungent and irritating components of volatile oils in water), and is made into oral solid preparations, preferably dry suspension, powder, suspension granules, and dispersed or suspended with water before use. It is especially suitable for children (infants and young children) to take, and well solves the problem of poor taste of Huoxiang Zhengqi water and oral liquid, filling the market gaps of Huoxiang Zhengqi dry suspension, powder and suspension granules.

[0010] To achieve the above object, the present invention provides a preparation method of a Huoxiang Zhengqi pharmaceutical preparation, including the following steps:

[0011] (1) Prepare raw materials, including: Atractylodes lancea, Citrus reticulata Blanco, Angelica dahurica, Magnolia officinalis, Poria cocos, Areca peel, Pinellia ternata, Glycyrrhiza glabra extract, Pogostemon cablin oil, Perilla frutescens oil;

[0012] (2) Extract the raw materials, including:

[0013] Use an alcohol solution as a solvent to extract Magnolia officinalis to obtain a Magnolia officinalis extract;

[0014] Use a solvent to extract Atractylodes lancea, Citrus reticulata Blanco, and Angelica dahurica separately or in combination to obtain separate extracts or a combined extract;

[0015] Use a solvent to extract Poria cocos, Areca peel, and Pinellia ternata to obtain an extract;

[0016] (3) Treat the extract, including:

[0017] Inclusion complexes were obtained by encapsulating Magnolia officinalis extract, Patchouli oil, and Perilla frutescens leaf oil separately or together with beta-cyclodextrin.

[0018] An inclusion complex is obtained by encapsulating the extract of Angelica dahurica. An extract is prepared by combining the extracts of Atractylodes lancea and Citrus reticulata, the extracts of Poria cocos, Areca catechu, and Pinellia ternata, and the licorice extract. Alternatively, an inclusion complex is obtained by encapsulating the combined extracts of Atractylodes lancea, Citrus reticulata, and Angelica dahurica with beta-cyclodextrin. An extract is prepared by combining the extracts of Poria cocos, Areca catechu, and Pinellia ternata with the licorice extract.

[0019] (4) Mix the inclusion complex obtained in step (3) with the extract.

[0020] In step (2), there is no restriction on the order of extraction of each raw material. In step (3), there is no restriction on the order of inclusion of the extract and preparation of the extract. If multiple extracts are combined during inclusion, the order of inclusion of each component in the process can be adjusted, so that Magnolia officinalis extract, patchouli oil, and Perilla frutescens leaf oil are all included. In addition, if Angelica dahurica is extracted separately, it can also be included or combined with other included components.

[0021] The 2020 edition of the Chinese Pharmacopoeia lists the same raw material formulations used in Huoxiang Zhengqi Water and Oral Liquid as in step (1) above. The preparation method of Huoxiang Zhengqi drug preparations provided by this invention is applicable to the corresponding formulations recorded in the 2020 edition of the Chinese Pharmacopoeia. In addition, adding other raw materials is also acceptable to the method of this invention, because the main purpose of this invention is to specially treat the bitter and irritating components in the effective ingredients of Huoxiang Zhengqi products to improve product compliance and make the products suitable for children (infants). The ratio of raw materials can be formulated according to the 2020 edition of the Chinese Pharmacopoeia, or it can be adjusted based on it.

[0022] This invention uses an alcohol solution as a solvent to extract Magnolia officinalis to obtain Magnolia officinalis extract. The alcohol solution refers to an ethanol-water solution.

[0023] The extraction solvents for Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica can be either water or alcohol solutions. In addition, other extraction solvents described in the prior art are also acceptable. The effective components extracted when using water as a solvent and alcohol solution as a solvent are different. As mentioned in the background art, there are significant differences in the fat-soluble and water-soluble components in the extracts obtained by different solvents. Therefore, the subsequent process, such as step (3), will vary due to the different extraction solvents and methods. Extracting Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica separately with solvents to obtain separate extracts means extracting Atractylodes lancea with solvent to obtain Atractylodes lancea extract, extracting Citrus reticulata peel with solvent to obtain Citrus reticulata peel extract, and extracting Angelica dahurica with solvent to obtain Angelica dahurica extract. The extracts of the three raw materials are obtained through three separate extractions. Extracting Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica together with solvents to obtain a combined extract means mixing the three raw materials together and extracting them together with a solvent. The resulting extract contains the combined effective components of Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica.

[0024] Extracting Poria cocos, Areca peel, and raw Pinellia ternata with solvents to obtain extracts refers to: extracting Poria cocos with solvents to obtain Poria cocos extract, extracting Areca peel with solvents to obtain Areca peel extract, and extracting raw Pinellia ternata with solvents to obtain raw Pinellia ternata extract, thus obtaining extracts of the three raw materials through three separate extractions; or extracting a mixture of Poria cocos, Areca peel, and raw Pinellia ternata with solvents. There are many existing extraction methods for Poria cocos, Areca peel, and raw Pinellia ternata. Currently, it is more beneficial to obtain the effective components in each raw material by using different process conditions to extract the three raw materials separately.

[0025] The inclusion of Magnolia officinalis extract, patchouli oil, and perilla leaf oil with beta-cyclodextrin, either separately or together, means that beta-cyclodextrin can be used to include Magnolia officinalis extract, patchouli oil, and perilla leaf oil separately, and the resulting inclusion compounds can be mixed and used in Huoxiang Zhengqi products. Alternatively, beta-cyclodextrin can be used to include two of the three extracts, while the remaining one is included separately. Or, beta-cyclodextrin can be used to include Magnolia officinalis extract, patchouli oil, and perilla leaf oil together.

[0026] When Angelica dahurica is extracted alone, an extract can be obtained. This extract can then be used to form inclusion complexes. Angelica dahurica extract, Magnolia officinalis extract, Patchouli oil, and Perilla frutescens leaf oil are all inclusion targets; therefore, they can be extracted separately or together, and this method is not limited to this. When Atractylodes lancea and Citrus reticulata peel are extracted alone, separate extracts of Atractylodes lancea and Citrus reticulata peel can be obtained. These extracts can then be combined with extracts of Poria cocos, Areca catechu peel, Pinellia ternata, and the aforementioned licorice extract to form an extract.

[0027] When Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica are extracted together, the resulting extract is a combination of Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica, and it is not possible to obtain Angelica dahurica extract alone. Therefore, the combined extract of Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica is encapsulated with beta-cyclodextrin to obtain an inclusion complex. The extracts of Poria cocos, Areca catechu peel, and Pinellia ternata are then combined with the licorice extract to form an extract.

[0028] After the active ingredients of the raw drug are made into extracts or inclusion complexes, they are mixed to obtain the Huoxiang Zhengqi drug preparation. Further processing of this preparation can produce different dosage forms.

[0029] The inclusion process between inclusion compounds and their constituents is a routine procedure in pharmaceutical formulation. Specific inclusion methods include: saturated aqueous solution method, colloid milling method, and ultrasonic method. For detailed references, please see: 1. Li Hailiang et al., Regularity exploration of preparation of β-cyclodextrin inclusion complexes of volatile oils of four kinds of Chinese medicines by two methods, Chinese Journal of Traditional Chinese Medicine, 2012, 37(7): 908-912; 2. Liu Lili et al., Process study on inclusion of mixed volatile oils of perilla leaf and schizonepeta by colloid milling, World Science and Technology - Modernization of Traditional Chinese Medicine, 2016, 18(4): 632-639; 3. Fu Liang et al., Extraction and inclusion process of volatile oils from Si Ni effervescent tablets, Chinese Journal of Experimental Traditional Medical Formulae, 2012, 18(4): 5-9; 4. Gu Sihao et al., Optimization of inclusion process of β-cyclodextrin of volatile components in Jiawei Linggui Zhugan Decoction, Chinese Patent Medicine, 2019, 41(9): 2039-2043.

[0030] Based on the above-mentioned preparation method of Huoxiang Zhengqi medicine preparation, the present invention further provides a solution that is more convenient for industrial application:

[0031] Step (2) involves extracting Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica using solvents. The extraction method for Angelica dahurica is as follows: extract Angelica dahurica using an alcoholic solution as the solvent to obtain the Angelica dahurica extract. The extraction methods for Atractylodes lancea and Citrus reticulata peel are as follows: extract Atractylodes lancea and Citrus reticulata peel separately using an alcoholic solution as the solvent to obtain Atractylodes lancea extract and Citrus reticulata peel extract, or extract Atractylodes lancea and Citrus reticulata peel separately using an alcoholic solution as the solvent to obtain Atractylodes lancea extract and Citrus reticulata peel extract. The extracts are then combined, the ethanol is removed, and the extract is concentrated into a clear paste. The Atractylodes lancea extract and Citrus reticulata peel extract can be directly used in subsequent processes to produce the extract, or they can be made into a clear paste before being used in subsequent processes to produce the extract.

[0032] Step (3) involves encapsulating the Magnolia officinalis extract and the Angelica dahurica extract separately or in combination with beta-cyclodextrin. The method is as follows: add beta-cyclodextrin to the Magnolia officinalis extract and the Angelica dahurica extract, recover and remove the ethanol, encapsulate, and filter to obtain inclusion complex ① and filtrate ①; or recover and remove the ethanol from the Magnolia officinalis extract and the Angelica dahurica extract, add beta-cyclodextrin, encapsulate, and filter to obtain inclusion complex ① and filtrate ①. There are two methods for encapsulating the Magnolia officinalis extract and the Angelica dahurica extract: one is to add beta-cyclodextrin first and then recover and remove the ethanol; the other is to recover and remove the ethanol first and then add beta-cyclodextrin. The first method is more conducive to the encapsulation of beta-cyclodextrin.

[0033] The preparation method of the extract in step (3) is as follows: the filtrate ① and the extracts of Poria cocos, Areca peel and raw Pinellia ternata are combined, concentrated, the licorice extract is added, ethanol solution is added to remove the precipitate by alcohol precipitation, the Atractylodes lancea extract and Citrus reticulata extract are added, the ethanol is recovered, concentrated, and dried to obtain the extract; or the filtrate ① and the extracts of Poria cocos, Areca peel and raw Pinellia ternata are combined, concentrated, the licorice extract is added, the clear extract is added, concentrated, and dried to obtain the extract.

[0034] The patchouli oil and perilla leaf oil were combined and then encapsulated to obtain inclusion compound ②.

[0035] The inclusion complex ①, inclusion complex ② and the extract are pulverized, mixed, and pharmaceutically acceptable excipients are added to prepare a formulation.

[0036] Preferably, the ratio of beta-cyclodextrin added to the Magnolia officinalis extract and the Angelica dahurica extract is as follows: based on the weight ratio of the raw herbs used to prepare the Magnolia officinalis extract and the Angelica dahurica extract, the weight ratio of Magnolia officinalis raw herbs to beta-cyclodextrin is 10:(0.5-5), and the weight ratio of Angelica dahurica raw herbs to beta-cyclodextrin is 10:(0.5-5).

[0037] Based on the above-mentioned preparation method of Huoxiang Zhengqi medicine preparation, the present invention further provides a second solution that is more convenient for industrial application:

[0038] Step (2) involves solvent extraction of Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica. The method is as follows: after combining the Angelica dahurica, Atractylodes lancea, and Citrus reticulata peel, water is added and distilled to collect the volatile oil and / or distillate. The aqueous solution after distillation is filtered, and the filtrate ② is collected. During the water distillation process, the distillate is volatile oil and / or distillate, which contains a large number of volatile components that are then encapsulated in subsequent processes. The remaining water and the mixture of Angelica dahurica, Atractylodes lancea, and Citrus reticulata peel residue are filtered to remove the residue. During the distillation process, some water-soluble components are also present in the aqueous solution, which are collected and used as filtrate. In subsequent processes, it can be used to make an extract.

[0039] Step (3) involves (single) inclusion of the Magnolia officinalis extract with beta-cyclodextrin: Beta-cyclodextrin is added to the Magnolia officinalis extract, ethanol is recovered and removed, inclusion is performed, and the mixture is filtered to obtain inclusion compound ③ and filtrate ③; or ethanol is recovered from the Magnolia officinalis extract, beta-cyclodextrin is added, inclusion is performed, and the mixture is filtered to obtain inclusion compound ③ and filtrate ③. There are two methods for inclusion of the Magnolia officinalis extract: one is to add beta-cyclodextrin first and then recover and remove ethanol, and the other is to recover and remove ethanol first and then add beta-cyclodextrin. The first method is more conducive to the inclusion of beta-cyclodextrin.

[0040] The filtrates ② and ③, along with the extracts of Poria cocos, Areca peel, and raw Pinellia ternata, are combined, concentrated, and then the licorice extract is added. The mixture is then concentrated and dried to obtain an extract. Alternatively, the filtrates ② and ③, along with the extracts of Poria cocos, Areca peel, and raw Pinellia ternata, are combined, concentrated, and then the licorice extract is added. An ethanol solution is added to remove the precipitate through alcohol precipitation. The ethanol is recovered, and the mixture is then concentrated and dried to obtain an extract.

[0041] The patchouli oil and perilla leaf oil were combined with the volatile oil and / or distillate collected during the extraction of angelica, atractylodes, and tangerine peel, and then encapsulated to obtain inclusion compound ④.

[0042] The inclusion complex ③, inclusion complex ④ and the extract are pulverized, mixed, and pharmaceutically acceptable excipients are added to prepare a formulation.

[0043] Preferably, the proportion of beta-cyclodextrin added to the Magnolia officinalis extract is: based on the weight ratio of the raw medicinal material used to prepare the Magnolia officinalis extract, the weight ratio of Magnolia officinalis raw material to beta-cyclodextrin is 10:(0.5-5).

[0044] Both Scheme 1 and Scheme 2 involve encapsulating the Magnolia officinalis extract (or Magnolia officinalis extract and Angelica dahurica extract) with beta-cyclodextrin to mitigate the adverse effects of the alcohol extract on the taste of the Huoxiang Zhengqi product. Preferably, the Magnolia officinalis extract (or Magnolia officinalis extract and Angelica dahurica extract) is encapsulated separately from the volatile oil components (Paeonia lactiflora oil and Perilla frutescens leaf oil) in the formula. This allows for better control of the performance of the encapsulated products and further reduces the adverse effects of the extracts or volatile oils on the taste of the Huoxiang Zhengqi product.

[0045] In Scheme 1 and Scheme 2, optionally, the alcohol solution used when extracting any one or more of Angelica dahurica, Magnolia officinalis, Atractylodes lancea, and Citrus reticulata is an ethanol solution with a volume fraction of 50%-80%.

[0046] In Scheme 1 and Scheme 2, optionally, the ethanol solution added for alcohol precipitation is an ethanol solution with a volume fraction of 80% to 95%, and the amount of ethanol solution added is 2 to 3 times the volume of the precipitate (clear extract).

[0047] In Scheme 1 and Scheme 2, optionally, the extraction of Poria cocos, Areca peel and raw Pinellia ternata by solvent in step (2) to obtain separate extracts is carried out by: Poria cocos, Areca peel and raw Pinellia ternata are extracted with water as solvent. The extraction method of Poria cocos is: Poria cocos is boiled in water and then soaked at 80°C, filtered and the filtrate is collected. The extraction method of Areca peel is: Areca peel is boiled in water, filtered and the filtrate is collected. The extraction method of raw Pinellia ternata is: raw Pinellia ternata is soaked in water until thoroughly soaked, and then 8%-10% of the weight of dried ginger of raw Pinellia ternata is added, boiled in water, filtered and the filtrate is collected.

[0048] In Scheme 1 and Scheme 2, optionally, the pharmaceutically acceptable excipients include at least one of fillers, flavoring agents, suspending agents, and flow aids; preferably, the pharmaceutically acceptable excipients are fillers, flavoring agents, and suspending agents, and the Huoxiang Zhengqi drug preparation is a suspension; or the pharmaceutically acceptable excipients are fillers, flavoring agents, and flow aids, and the Huoxiang Zhengqi drug preparation is a powder; or the pharmaceutically acceptable excipients are fillers and flavoring agents, and the Huoxiang Zhengqi drug preparation is a suspension granule.

[0049] Optionally, without changing the composition and dosage ratio of the raw materials specified in the pharmacopoeia, based on the extraction process of Huoxiang Zhengqi Water and Huoxiang Zhengqi Oral Liquid recorded in the Chinese Pharmacopoeia, the following are included: In Scheme 1 and Scheme 2, the composition of the raw materials is: Atractylodes lancea 160g, Citrus reticulata peel 160g, Magnolia officinalis (processed with ginger) 160g, Angelica dahurica 240g, Poria cocos 240g, Areca catechu peel 240g, Pinellia ternata 160g, Glycyrrhiza uralensis extract 20g, Pogostemon cablin oil 1.6ml, and Perilla frutescens leaf oil 0.8ml.

[0050] Preferably, when the patchouli oil and perilla leaf oil are combined and encapsulated, the ratio of the total volume of the patchouli oil and perilla leaf oil to the mass of the beta-cyclodextrin encapsulating the patchouli oil and perilla leaf oil is 2.4 ml: 15-40 g.

[0051] Preferably, when the patchouli oil and perilla leaf oil are combined with the volatile oil and / or distillate collected during the extraction of angelica dahurica, atractylodes lancea, and tangerine peel to obtain a combined liquid and then encapsulated, the ratio of the total volume of patchouli oil and perilla leaf oil to the mass of beta-cyclodextrin encapsulating the combined liquid is 2.4 ml: 20-80 g.

[0052] In Scheme 1 and Scheme 2, it is optional whether water or alcohol is used as the solvent. The extract can be obtained by a single extraction and then used, or the extract can be obtained by two or more extractions and then combined for use.

[0053] In Scheme 1 and Scheme 2, optionally, the inclusion compound and the extract are pulverized and mixed, and then excipients are added. After adding the excipients, the mixture is sieved (100 mesh or 120 mesh) to make a powder. After adding the excipients, it is granulated to make a granule or a suspension.

[0054] According to the actual situation and needs of different oral drug preparations, disintegrants, wetting agents, colorants, thickeners, etc. can also be used.

[0055] The pharmaceutically acceptable excipients described in the present invention, according to the needs of the pharmaceutical industry, include but are not limited to fillers: one or several of soluble starch, dextrin, lactose, mannitol, sorbitol, sucrose, etc.; disintegrants: one or several of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, etc.; suspending agents: one or several of carbomer, xanthan gum, tragacanth gum, hypromellose, sodium carboxymethyl cellulose, carrageenan, PVP, etc.; lubricants / glidants: one or several of colloidal silicon dioxide, talc, magnesium stearate, etc.; flavoring agents: one or several of sucralose, steviol glycosides, aspartame, peach essence, strawberry essence, lemon essence, etc.; wetting agents: one or several of poloxamer, sodium lauryl sulfate, polyethylene glycol, etc.; colorants: caramel pigment, etc.; thickeners: pectin, etc.

[0056] By using the preparation method of the Huoxiang Zhengqi drug preparation described above, a suspension, powder or granule can be prepared. These preparations are all oral solid preparations, which are dispersed and suspended with water at the time of use, and are more conducive to children (infants and young children) taking. In addition, tablets, capsules, pills, etc. can also be prepared for teenagers or adults to take. The suspensions not specifically described in the present invention include liquid suspensions and dry suspensions. A liquid suspension is a preparation in which the active ingredient is suspended in a solvent, and a dry suspension is a solid preparation made into granules and containing a suspending agent, which can be taken orally after being suspended with water when taken, and a suspension granule refers to a granule that can be taken orally after being suspended with water when taken.

[0057] The suspension, powder or granule obtained by using the preparation method of the Huoxiang Zhengqi drug preparation described above can be used to prepare drugs for preventing and treating colds caused by exogenous wind-cold, internal injury by dampness, or summer injury by summer dampness, or gastrointestinal colds.

[0058] Compared with the prior art, the present invention has at least the following beneficial effects:

[0059] The present invention uses beta-cyclodextrin to simultaneously encapsulate the ethanol extract and volatile oil of Magnolia officinalis (or Magnolia officinalis and Angelica dahurica). The inclusion compound is insoluble in water and is made into an oral solid preparation, which is dispersed or suspended with water at the time of use. First, it significantly reduces the bitter, numb and astringent taste of Magnolia officinalis and Angelica dahurica and the pungent and irritating taste of the volatile oil in this product, and significantly improves the taste. Second, the inclusion compound improves the stability of components such as volatile oil. Third, this product is prepared into an oral solid preparation, avoiding the use of co-solvents such as Tween 80 and ethanol.

[0060] The Huoxiang Zhengqi pharmaceutical preparation of this invention possesses the efficacy of Huoxiang Zhengshui (water) and oral liquid listed in the 2020 edition of the Chinese Pharmacopoeia. It relieves exterior syndromes and resolves dampness, regulates qi and harmonizes the middle jiao (digestive system), and is used for colds caused by exogenous wind-cold, internal dampness stagnation, or summer heat-dampness, with symptoms such as headache, dizziness, chest tightness, abdominal distension and pain, vomiting, and diarrhea; or for gastrointestinal colds with the above symptoms. Therefore, it has use in the preparation of medicines for preventing and treating colds caused by exogenous wind-cold, internal dampness stagnation, or summer heat-dampness, or gastrointestinal colds.

[0061] In summary, this invention provides a non-Tween and ethanol-free, palatable Huoxiang Zhengqi oral solid dosage form and its preparation method, which is particularly suitable for children (infants) to take, significantly improving compliance, while also making the product quality more stable. Detailed Implementation

[0062] The present invention will be further described in detail below through specific embodiments. However, this should not be construed as limiting the scope of protection of the present invention to the following examples. Various substitutions or modifications made based on ordinary technical knowledge and conventional methods in the art without departing from the above-described technical concept of the present invention should be included within the scope of the present invention.

[0063] I. Implementation Examples

[0064] Example 1

[0065] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0066] The preparation method includes the following steps:

[0067] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0068] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), and Angelica dahurica were extracted separately by percolation with 60% ethanol. Percolates of 10 times their weight-to-volume ratio (8L, 8L, 8L, 12L) were collected for later use. Among them, the percolates of Magnolia officinalis and Angelica dahurica were combined, 200g of beta-cyclodextrin was added, the ethanol was recovered and removed, and then inclusion was carried out according to the conventional method, that is, water was added to about 2000ml and stirred at 55-60℃ for 2 hours, refrigerated overnight, filtered, and the inclusion complex and filtrate were obtained for later use.

[0069] (3) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours each time, adding 10 times and 8 times the amount of water respectively, filter it and keep the filtrate for later use.

[0070] (4) Soak raw Pinellia ternata in water until thoroughly soaked, then add 67.5g of dried ginger, add 10 times the amount of water (8L) and decoct twice, 2 hours each time, filter, and keep the filtrate for later use;

[0071] (5) Add 10 times and 8 times the amount of water to the peel of the areca, decoct twice, one hour each time, filter, and keep the filtrate for later use.

[0072] (6) Combine the filtrates from steps (2), (3), (4), and (5), concentrate to a clear paste (relative density 1.05-1.10), add licorice extract, mix well, add 2 times the amount of 95% ethanol to precipitate, take the supernatant, add the percolation of Atractylodes lancea and Citrus reticulata from step (2), recover the ethanol, concentrate, dry, and obtain the extract for later use.

[0073] (7) Take 150g of beta-cyclodextrin, add water to 1500ml and heat to dissolve. Stir at 45-50℃ and add patchouli oil and perilla leaf oil (diluted with 1 volume of 95% ethanol). Continue stirring for 2 hours, refrigerate overnight, filter to obtain inclusion complex for later use.

[0074] (8) The inclusion complexes from steps (2) and (7) and the extract from step (6) are pulverized into ultrafine powder, and appropriate amounts of fillers, suspending agents, flavoring agents and other excipients are added, mixed well, granulated, and packaged into 1025 bags to obtain the dry suspension.

[0075] Example 2

[0076] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0077] The preparation method includes the following steps:

[0078] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0079] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), and Angelica dahurica were extracted twice by reflux with 10 times (8L, 8L, 8L, 12L) and 8 times (6.4L, 6.4L, 6.4L, 9.6L) of 70% ethanol, respectively, for 2 hours and 1 hour each time. The extracts were filtered to obtain ethanol extracts for later use. The ethanol extracts of Magnolia officinalis and Angelica dahurica were combined, the ethanol was recovered and removed, and 100g of beta-cyclodextrin was added. Inclusion was carried out according to the conventional method, that is, water was added to about 1000ml and stirred at 45-50℃ for 3 hours, refrigerated overnight, filtered, and the inclusion complex and filtrate were obtained for later use.

[0080] (3) Add 12 times and 10 times the amount of water to the peel of the areca, decoct twice, each time for 2 hours, filter, and keep the filtrate for later use;

[0081] (4) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours and 1 hour each time, adding 12 times and 10 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0082] (5) Soak raw Pinellia ternata in water until thoroughly soaked, then add 67.5g of dried ginger, add 8 times the amount of water (6.4L) and decoct twice, for 2 hours and 1.5 hours each time. Filter and keep the filtrate for later use.

[0083] (6) Combine the filtrates from steps (2), (3), (4), and (5), concentrate to a clear paste (relative density of about 1.1), add licorice extract, mix well, add 3 times the amount of 80% ethanol to precipitate, remove the precipitate, add the ethanol extract of Atractylodes lancea and Citrus reticulata from step (2), recover the ethanol, concentrate and dry to obtain the extract for later use.

[0084] (7) Take 75g of beta-cyclodextrin, add water to 750ml and heat to dissolve. Stir and add patchouli oil and perilla leaf oil (diluted with 1 volume of anhydrous ethanol) at 40-45℃. Continue stirring for 3 hours, refrigerate overnight, filter to obtain inclusion complex for later use.

[0085] (8) The inclusion complexes from steps (2) and (7) and the extract from step (6) are pulverized into the finest powder, and appropriate amounts of flavoring agents, micronized silica gel and other excipients are added, mixed well, and packaged to obtain the powder.

[0086] Example 3

[0087] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0088] The preparation method includes the following steps:

[0089] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0090] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger) and Angelica dahurica were extracted twice by reflux with 8 times and 7 times 65% ethanol, respectively, for 1 hour each time. The extracts were filtered to obtain ethanol extracts for later use.

[0091] ① Combine the ethanol extracts of Atractylodes lancea and Citrus reticulata, recover and remove the ethanol, concentrate into a clear extract, and set aside for later use;

[0092] ② Combine the ethanol extracts of Magnolia officinalis and Angelica dahurica, add 1000g of beta-cyclodextrin, recover and remove the ethanol, and then perform inclusion by conventional method, i.e. add water to 3000ml and treat (mill) in a colloid mill at 50-55℃ for 1 hour, filter, and obtain the inclusion compound and filtrate for later use.

[0093] (3) Boil the peel of the areca nut in 15 times the amount of water for 3 hours, filter, and keep the filtrate for later use;

[0094] (4) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours each time, adding 11 times and 9 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0095] (5) Soak raw Pinellia ternata in water until thoroughly soaked, then add 67.5g of dried ginger, add 12 times the amount of water and decoct twice, for 3 hours and 2 hours each time. Filter and keep the filtrate for later use.

[0096] (6) Combine the filtrates from steps (2), (3), (4), and (5), concentrate to a relative density of 1.02-1.05, add licorice extract and the clear extract from step (2), mix well, concentrate and dry to obtain the extract for later use;

[0097] (7) Take 200g of beta-cyclodextrin, add water to 600ml, add patchouli oil and perilla leaf oil (diluted with 1 volume of 95% ethanol), treat with a colloid mill (grind) at 45-50℃ for 0.5 hours, filter, and obtain the inclusion complex for later use;

[0098] (8) The inclusion complexes in steps (2) and (7) and the extract in step (6) are pulverized into fine powder, and appropriate amounts of fillers and flavoring agents are added, mixed well, granulated, and packaged into 1025 bags to obtain dry suspension granules.

[0099] Example 4

[0100] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0101] The preparation method includes the following steps:

[0102] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0103] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger) and Angelica dahurica were extracted twice by reflux with 9 times and 7 times 80% ethanol, respectively, for 1 hour and 0.5 hours each time. The extracts were filtered to obtain ethanol extracts for later use.

[0104] ① Combine the ethanol extracts of Atractylodes lancea and Citrus reticulata, recover and remove the ethanol, concentrate into a clear extract, and set aside for later use;

[0105] ② Combine the ethanol extracts of Magnolia officinalis and Angelica dahurica, add 400g of beta-cyclodextrin, recover and remove the ethanol, and then perform inclusion by conventional method, i.e. add water to 1500ml and treat (mill) in a colloid mill at 55-60℃ for 0.5 hours, filter, and obtain the inclusion compound and filtrate for later use;

[0106] (3) Add 10 times and 8 times the amount of water to the peel of the areca, decoct twice, for 1 hour and 0.5 hours each time, filter, and keep the filtrate for later use;

[0107] (4) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours each time, adding 10 times and 8 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0108] (5) Soak raw Pinellia ternata in water until thoroughly soaked, then add 80g of dried ginger, and decoct twice with 12 times and 10 times the amount of water respectively, for 2 hours and 1 hour each time. Filter and keep the filtrate for later use.

[0109] (6) Combine the filtrates from steps (2), (3), (4), and (5), concentrate them to a relative density of 1.02-1.05, add licorice extract and the clear extract from step (2), mix well, concentrate and dry to obtain the extract for later use.

[0110] (7) Take 100g of beta-cyclodextrin, add water to 1000ml and heat to dissolve. Add patchouli oil and perilla leaf oil (diluted with 1 volume of anhydrous ethanol) by ultrasonic stirring at 40-45℃, continue ultrasonic stirring for 1 hour, refrigerate overnight, filter to obtain inclusion complex for later use.

[0111] (8) The inclusion complexes from steps (2) and (7) and the extract from step (6) are pulverized into fine powder, thoroughly mixed, and then an appropriate amount of fillers, disintegrants and other excipients are added, mixed evenly, made into pills, and packaged to obtain pills.

[0112] Example 5

[0113] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0114] The preparation method includes the following steps:

[0115] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0116] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger) and Angelica dahurica were extracted by reflux with 12 times the amount of 50% ethanol for 2 hours, filtered, and the ethanol extract was prepared for use.

[0117] ① Combine the ethanol extracts of Atractylodes lancea and Citrus reticulata peel and set aside for later use;

[0118] ② Combine the ethanol extracts of Magnolia officinalis and Angelica dahurica, recover and remove the ethanol, add 600g of betacyclodextrin, and perform inclusion complexation according to the conventional method, that is, add water to about 6000ml, stir at 55-60℃ for 2 hours, refrigerate overnight, filter, and obtain the inclusion complex and filtrate for later use;

[0119] (3) Add 9 times and 7 times the amount of water to the peel of the areca, decoct twice, each time for 2 hours, filter, and keep the filtrate for later use;

[0120] (4) After boiling Poria cocos in water, soak it twice at 80°C for 3 hours and 1 hour each time, adding 9 times and 7 times the amount of water respectively. Filter the solution and keep the filtrate for later use.

[0121] (5) Soak raw Pinellia ternata in water until thoroughly soaked, then add 64g of dried ginger, add 8 times the amount of water and decoct twice, for 3 hours and 1 hour each time. Filter and keep the filtrate for later use.

[0122] (6) Combine the filtrates from steps (2), (3), (4), and (5), concentrate to a thin clear paste, add licorice extract, concentrate to a clear paste with a relative density of about 1.1, add 2.5 times the amount of 90% ethanol to precipitate, remove the precipitate, add the ethanol extract of Atractylodes lancea and Citrus reticulata from step (2), recover the ethanol, concentrate and dry to obtain the extract for later use.

[0123] (7) Take 125g of beta-cyclodextrin, add water to 1250ml and heat to dissolve. Stir at 50-55℃ and add patchouli oil and perilla leaf oil (diluted with 1 volume of 95% ethanol). Continue stirring for 2 hours, refrigerate overnight, filter to obtain inclusion complex for later use.

[0124] (8) The inclusion complexes from steps (2) and (7) and the extract from step (6) are pulverized into fine powder, and appropriate amounts of fillers, disintegrants, glidants and other excipients are added, mixed well, compressed into tablets, and packaged to obtain tablets.

[0125] Example 6

[0126] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0127] The preparation method includes the following steps:

[0128] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0129] (2) Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger) and Angelica dahurica were extracted by percolation with 60% ethanol, and the percolation was collected at a weight-to-volume ratio of 8.

[0130] ① Combine the ethanol extracts of Atractylodes lancea and Citrus reticulata peel and set aside for later use;

[0131] ② Combine the ethanol extracts of Magnolia officinalis and Angelica dahurica, recover and remove the ethanol, add 400g of betacyclodextrin, and perform inclusion complexation according to the conventional method, that is, add water to about 3200ml, stir at 55-60℃ for 3 hours, refrigerate overnight, filter, and obtain the inclusion complex and filtrate for later use;

[0132] (3) Add 12 times the amount of water to the peel of the areca nut, decoct for 3 hours, filter, and keep the filtrate for later use;

[0133] (4) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours and 1 hour each time, adding 10 times and 8 times the amount of water respectively. Filter the solution and keep the filtrate for later use.

[0134] (5) Soak raw Pinellia ternata in water until thoroughly soaked, then add 67.5g of dried ginger, add 8 times the amount of water and decoct twice, for 2 hours and 1 hour each time. Filter and keep the filtrate for later use.

[0135] (6) Take 100g of beta-cyclodextrin, add water to 1000ml and heat to dissolve. Stir at 50-55℃ and add patchouli oil and perilla leaf oil (diluted with 1 volume of anhydrous ethanol). Continue stirring for 2 hours, refrigerate overnight, filter to obtain inclusion complex for later use.

[0136] (7) The inclusion complexes in steps (2) and (6) are pulverized into the finest powder and set aside;

[0137] (8) Combine the filtrates from steps (2), (3), (4), and (5), concentrate them, add licorice extract, mix well, add twice the amount of 95% ethanol to precipitate, filter to remove the precipitate, add the ethanol extract of Atractylodes lancea and Citrus reticulata from step (2), recover and remove the ethanol, add appropriate amounts of the inclusion complex, suspending agent, and water from step (7), mix well, add water to make a total volume of 10250ml, dispense, and obtain the (liquid) suspension.

[0138] Example 7

[0139] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0140] The preparation method includes the following steps:

[0141] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0142] (2) Magnolia officinalis (processed with ginger) was heated and refluxed with 10 times the amount of 60% ethanol (8L) for 1 hour, filtered, and 80g of betacyclodextrin was added to the extract. The ethanol was recovered and removed. Then, the inclusion was carried out by conventional method, i.e., water was added to about 800ml and stirred at 55-60℃ for 2 hours, refrigerated overnight, filtered, and the inclusion complex and filtrate were obtained for later use.

[0143] (3) Add 10 times the amount of water (28L) to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill. Collect 8400ml of distillate. Filter the distilled aqueous solution and keep the filtrate for later use.

[0144] (4) Add 10 times and 8 times the amount of water to the peel of the areca nut, decoct twice, one hour each time, filter, and keep the filtrate for later use.

[0145] (5) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours each time, adding 10 times and 8 times the amount of water respectively, filter it and keep the filtrate for later use.

[0146] (6) Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, add 10 times the amount of water (8L) and decoct twice, one hour each time, filter, and keep the filtrate for later use;

[0147] (7) Combine the filtrates from steps (2), (3), (4), (5), and (6), concentrate to a clear extract (relative density 1.04-1.06), add licorice extract, mix well, add 2 times the amount of 95% ethanol to precipitate, take the supernatant, recover and remove the ethanol, concentrate, dry, and obtain the extract for later use.

[0148] (8) Take the distillate from step (3) and add 400g of betacyclodextrin. Stir at 45-50℃ and add patchouli oil and perilla leaf oil (diluted with 1 volume of 95% ethanol). Continue stirring for 2 hours, refrigerate overnight, filter, and obtain the inclusion complex for later use.

[0149] (9) Combine the inclusion complexes from steps (2) and (8) and the extract from step (7) and pulverize them into ultrafine powder. Add appropriate amounts of fillers, suspending agents, flavoring agents and other excipients, mix well, granulate, and package to obtain the dry suspension.

[0150] Example 8

[0151] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0152] The preparation method includes the following steps:

[0153] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0154] (2) Magnolia officinalis (processed with ginger) was extracted with 9 times and 8 times 70% ethanol (7.2L and 6.4L) respectively, and heated under reflux for 1 hour and 0.5 hours. After filtration, 160g of betacyclodextrin was added to the extract, the ethanol was recovered and removed, and then inclusion was carried out by conventional method, that is, water was added to about 1600ml and stirred at 45-50℃ for 3 hours, refrigerated overnight, filtered, and the inclusion complex and filtrate were obtained for later use.

[0155] (3) Add 8 times the amount of water (22.4L) to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill for 4 hours. Collect about 7ml of volatile oil. Filter the distilled aqueous solution. Add 7 times the amount of water (19.6L) to the residue and decoct for 1 hour. Filter and combine the two filtrates for later use.

[0156] (4) Add 12 times and 10 times the amount of water to the peel of the areca, decoct twice, for 2 hours and 1 hour each time, filter, and keep the filtrate for later use.

[0157] (5) After boiling Poria cocos in water, soak it twice at 80°C for 1 hour each time, adding 12 times and 10 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0158] (6) Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, add 12 times the amount of water (9.6L) and decoct twice, 1.5 hours each time, filter, and keep the filtrate for later use;

[0159] (7) Combine the filtrates from steps (2), (3), (4), (5), and (6), concentrate to a clear paste (relative density of about 1.1), add licorice extract, mix well, add 3 times the amount of 80% ethanol to precipitate, remove the precipitate, recover the ethanol, concentrate and dry to obtain the extract for later use.

[0160] (8) Patchouli oil, perilla leaf oil and the volatile oil from step (3) were encapsulated with beta-cyclodextrin using conventional methods. Specifically, 100g of beta-cyclodextrin was weighed, water was added to about 1000ml and heated to dissolve. The above volatile oil was added dropwise while stirring at 40-45℃ (the volatile oils were combined and diluted with 1 volume of anhydrous ethanol). Stirring was continued for 3 hours, and the mixture was refrigerated overnight. After filtration, the encapsulation complex was obtained and set aside for later use.

[0161] (9) Combine the inclusion complexes from steps (2) and (8) with the extract from step (7) and grind them into the finest powder. Add appropriate amounts of flavoring agents, micronized silica gel and other excipients, mix well, and package to obtain the powder.

[0162] Example 9

[0163] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0164] The preparation method includes the following steps:

[0165] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0166] (2) Add 10 times and 8 times 65% ethanol to Magnolia officinalis (processed with ginger), heat under reflux for 2 hours, filter, recover the ethanol from the extract, add 400g betacyclodextrin, and then perform inclusion by conventional method, that is, add water to about 1500ml and treat (mill) at 50-55℃ in a colloid mill for 1 hour, filter, and obtain the inclusion complex and filtrate for later use;

[0167] (3) Add 9 times the amount of water to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill for 6 hours. Collect about 8 ml of volatile oil. Filter the distilled aqueous solution and keep the filtrate for later use.

[0168] (4) Add 11 times and 9 times the amount of water to the peel of the areca, decoct twice, for 3 hours and 1.5 hours each time, filter, and keep the filtrate for later use;

[0169] (5) After boiling Poria cocos in water, soak it twice at 80°C for 3 hours and 1 hour each time, adding 11 times and 9 times the amount of water respectively. Filter the solution and keep the filtrate for later use.

[0170] (6) Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, add 11 times the amount of water (8.8L) and decoct twice, for 2 hours and 1.5 hours each time. Filter and keep the filtrate for later use.

[0171] (7) Combine the filtrates from steps (4), (5), and (6), concentrate to a relative density of 1.04-1.06, add the filtrates from steps (2) and (3) and licorice extract, mix well, filter, concentrate and dry to obtain extract for later use;

[0172] (8) Patchouli oil, perilla leaf oil and the volatile oil from step (3) were encapsulated with beta-cyclodextrin using conventional methods. Specifically, 200g of beta-cyclodextrin was weighed, water was added to about 700ml, and the above volatile oil was added (the volatile oils were combined and diluted with 1 volume of 95% ethanol). The mixture was then treated (milled) at 45-50℃ for 0.5 hours, filtered, and the encapsulated mixture was obtained for later use.

[0173] (9) The inclusion complexes in steps (2) and (8) and the extract in step (7) are pulverized into fine powder, and appropriate amounts of fillers and flavoring agents are added, mixed well, granulated, and packaged to obtain suspension granules.

[0174] Example 10

[0175] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0176] Weigh the raw materials according to the above prescription and proportions.

[0177] Magnolia officinalis (processed with ginger) was pulverized, and 10 times the amount of 60% ethanol (8L) was added. The mixture was heated under reflux for 1 hour and filtered. 160g of betacyclodextrin was added to the extract, and the ethanol was recovered and removed. The inclusion was then carried out by conventional method, i.e., water was added to 1600ml and stirred at 55-60℃ for 3 hours. The mixture was refrigerated overnight and filtered to obtain the inclusion complex and filtrate for later use.

[0178] Powder Atractylodes lancea, Citrus reticulata peel and Angelica dahurica, add 6 times the weight of water, distill at 100℃±3℃ for 6 hours, collect the distillate, let the distillate stand to separate into layers, and take the upper layer of volatile oil for later use (4.3 ml of volatile oil is obtained). Filter the distilled aqueous solution and the residue, and keep the filtrate for later use.

[0179] Powder the peel of the areca nut, add 10 times and 8 times the amount of water respectively, decoct twice, one hour each time, filter, and keep the filtrate for later use;

[0180] Powder the Poria cocos, add water and boil, then immediately cool to about 80°C. Soak twice for 2 hours each time, adding 10 times and 8 times the amount of water respectively. Filter and keep the filtrate for later use.

[0181] Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, add 8L of water and decoct twice, one hour each time. Filter and keep the filtrate for later use.

[0182] Combine the above filtrates and concentrate them to a clear extract with a relative density of about 1.1 (50°C). Add licorice extract, mix well, add 2 times the amount of 95% ethanol to precipitate, filter, recover the ethanol, concentrate, dry, and obtain the extract for later use.

[0183] Add 300g of betacyclodextrin to the distillate of the separated volatile oil, and add 4.3ml of the volatile oil obtained from the distillation, 8ml of patchouli oil, and 4ml of perilla leaf oil (the volatile oils are combined and diluted with 1 volume of 95% ethanol) while stirring at 45℃. Continue stirring at 400 rpm for 2 hours, refrigerate overnight, filter, and obtain the inclusion complex for later use.

[0184] The above-mentioned inclusion complex and extract are pulverized into the finest powder, and an appropriate amount of suspending agent and dextrin are added, mixed well, granulated, and packaged into 1025 bags to obtain the dry suspension.

[0185] Example 11

[0186] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0187] The preparation method includes the following steps:

[0188] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0189] (2) Magnolia officinalis (processed with ginger) was extracted with 8 times and 7 times 80% ethanol respectively, heated under reflux for 1 hour, filtered, the extract was recovered to remove ethanol, 240g betacyclodextrin was added, and then inclusion was carried out according to the conventional method, that is, water was added to about 800ml and treated (milled) at 55-60℃ in a colloid mill for 0.5 hours, filtered, and the inclusion complex and filtrate were obtained for later use;

[0190] (3) Add 7 times the amount of water to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill for 5 hours. Collect about 7 ml of volatile oil. Filter the distilled aqueous solution. Add 7 times the amount of water to the residue and decoct for 0.5 hours. Filter and combine the two filtrates for later use.

[0191] (4) Add 10 times and 8 times the amount of water to the peel of the areca, decoct twice, for 1 hour and 0.5 hours each time, filter, and keep the filtrate for later use;

[0192] (5) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours each time, adding 10 times and 8 times the amount of water respectively, filter it and keep the filtrate for later use.

[0193] (6) After soaking raw Pinellia ternata in water until thoroughly soaked, add 64g of dried ginger, add 12 times and 10 times the amount of water (9.6L and 8L) and decoct twice, for 2 hours and 1 hour each time. Filter and keep the filtrate for later use.

[0194] (7) Combine the filtrates from steps (2), (3), (4), (5), and (6), concentrate them to a relative density of 1.02-1.05, add licorice extract, mix well, filter, concentrate and dry to obtain extract for later use.

[0195] (8) Patchouli oil, perilla leaf oil and the volatile oil from step (3) were encapsulated with beta-cyclodextrin using conventional methods. Specifically, 150g of beta-cyclodextrin was weighed, water was added to about 500ml, and the above volatile oil was added (the volatile oils were combined and diluted with 1 volume of anhydrous ethanol). The mixture was then treated (milled) at 40-45℃ for 1 hour, filtered, and the encapsulated mixture was obtained for later use.

[0196] (9) The extracts from steps (2), (8) and (7) are pulverized into fine powder, mixed thoroughly, and then an appropriate amount of filler, disintegrant and other excipients are added, mixed evenly, made into pills, and packaged to obtain pills.

[0197] Example 12

[0198] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0199] The preparation method includes the following steps:

[0200] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0201] (2) Add 12 times the amount of 50% ethanol to Magnolia officinalis (processed with ginger), heat and reflux for 3 hours, filter, add 40g of betacyclodextrin to the extract, recover and remove the ethanol, and then perform inclusion by conventional method, that is, add water to about 400ml and stir at 55-60℃ for 2 hours, refrigerate overnight, filter, and obtain the inclusion complex and filtrate for later use.

[0202] (3) Add 12 times the amount of water to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill. Collect 14000 ml of the distillate. Redistill and collect 3000 ml of the redistillate for later use. Filter the distilled aqueous solution and keep the filtrate for later use.

[0203] (4) Add 9 times and 7 times the amount of water to the peel of the areca, decoct twice, each time for 2 hours, filter, and keep the filtrate for later use;

[0204] (5) After boiling Poria cocos in water, soak it twice at 80°C for 3 hours and 2 hours each time, adding 9 times and 7 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0205] (6) Soak raw Pinellia ternata in water until thoroughly soaked, then add 80g of dried ginger, and decoct twice with 10 times and 8 times the amount of water respectively, for 3 hours and 1 hour each time. Filter and keep the filtrate for later use.

[0206] (7) Combine the filtrates from steps (3), (4), (5), and (6), concentrate them to a thin clear paste, add the filtrate from step (2) and licorice extract, concentrate them to a clear paste with a relative density of 1.05-1.08, add 2.5 times the amount of 90% ethanol to precipitate, remove the precipitate, recover the ethanol, concentrate and dry to obtain the extract for later use.

[0207] (8) Take 3000ml of the redistilled liquid from step (2), add 300g of betacyclodextrin, heat and stir to dissolve, then add patchouli oil and perilla leaf oil (diluted with 1 volume of anhydrous ethanol), continue stirring at 50-55℃ for 2 hours, refrigerate overnight, filter to obtain inclusion complex for later use;

[0208] (9) The inclusion complexes in steps (2) and (8) and the extract in step (7) are pulverized into fine powder, and appropriate amounts of fillers, disintegrants, glidants and other excipients are added, mixed well, compressed into tablets, and packaged to obtain tablets.

[0209] Example 13

[0210] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0211] The preparation method includes the following steps:

[0212] (1) Weigh the raw materials according to the above prescription in the specified weight ratio;

[0213] (2) Magnolia officinalis (processed with ginger) was heated and refluxed with 10 times the amount of 60% ethanol for 1 hour, filtered, and 160g of betacyclodextrin was added to the extract. The ethanol was recovered and removed. The inclusion was then carried out by conventional method, i.e., water was added to about 1600ml and stirred at 55-60℃ for 2 hours, refrigerated overnight, filtered, and the inclusion complex and filtrate were obtained for later use.

[0214] (3) Add water to Atractylodes lancea, Citrus reticulata peel and Angelica dahurica and distill, collect 5000ml of distillate for later use; filter the distilled aqueous solution and keep the filtrate for later use.

[0215] (4) Add 10 times and 8 times the amount of water to the peel of the areca nut, decoct twice, one hour each time, filter, and keep the filtrate for later use.

[0216] (5) After boiling Poria cocos in water, soak it twice at 80°C for 2 hours and 1 hour each time, adding 10 times and 8 times the amount of water respectively, filter it, and keep the filtrate for later use.

[0217] (6) Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, and decoct twice with 10 times and 8 times the amount of water respectively, for 2 hours each time. Filter and keep the filtrate for later use.

[0218] (7) Take 5000ml of the distillate from step (3), add 300g of betacyclodextrin, heat and stir to dissolve, add patchouli oil and perilla leaf oil (diluted with 1 volume of anhydrous ethanol) dropwise at about 50℃, continue stirring for 2 hours, refrigerate overnight, filter to obtain inclusion complex for later use;

[0219] (8) The inclusion complexes in steps (2) and (7) are pulverized into the finest powder and set aside;

[0220] (9) Combine the filtrates from steps (2), (3), (4), (5), and (6), concentrate to a clear extract, add licorice extract, mix well, add twice the amount of 95% ethanol to precipitate, filter, recover the filtrate to remove ethanol, add appropriate amounts of the inclusion complex, suspending agent, and water from step (8), mix well, add water to make a total volume of 10250ml, dispense, and obtain the (liquid) suspension.

[0221] II. Study on Enclosure Modes

[0222] The following specific research results further demonstrate the beneficial effects of the present invention.

[0223] I. The Influence of Different Enclosure Methods on Enclosure Effectiveness

[0224] (I) Encapsulation of Magnolia officinalis ethanol extract with betacyclodextrin

[0225] 1000g of Magnolia officinalis (processed with ginger) was crushed, and 10 times the amount of 60% ethanol (10L) was added. The mixture was heated under reflux for 1 hour, filtered, and the ethanol extract was obtained. The volume was adjusted to 9000ml with 60% ethanol and set aside.

[0226] 1. Enclosure method

[0227] Inclusion method I: Take 1800 ml of the above ethanol extract (equivalent to 200 g Magnolia officinalis), add 40 g beta-cyclodextrin, recover and remove the ethanol, add water to 400 ml, stir at 55-60℃ for 3 hours, refrigerate overnight, filter, dry, and pulverize to obtain inclusion compound I and filtrate I, for later use.

[0228] For inclusion method II, take 1800 ml of the above ethanol extract, remove the ethanol, add 40 g of beta-cyclodextrin, add water to 400 ml, and operate in the same way. Stir at 55-60℃ for 3 hours, refrigerate overnight, filter, dry, and pulverize to obtain inclusion compound II and filtrate II for later use.

[0229] For inclusion method III, take 1800 ml of the above ethanol extract, recover and remove the ethanol, centrifuge the aqueous solution, and separate the lower precipitate and aqueous solution. Dissolve the precipitate in anhydrous ethanol and set aside. Add 40 g of betacyclodextrin to the aqueous solution, add water to 400 ml, stir at 55-60℃, add the above ethanol solution dropwise, stir for 3 hours, refrigerate overnight, filter, dry, and pulverize to obtain inclusion compound III and filtrate III, and set aside.

[0230] 2. Inclusion rate determination

[0231] Inclusion rate is the main indicator for evaluating inclusion compounds. The inclusion rates of inclusion compounds I, II and III were determined separately [Reference: Huang Yu et al., Study on the Influence of Solvent on Inclusion Rate Determination in Volatile Oil Inclusion Process, China Medical Herald, 2009, 6(22): 80-81], and the determination methods are as follows:

[0232] The HPLC chromatographic conditions and content determination methods were performed in accordance with the "Content Determination" method under the Magnolia officinalis section of the 2020 edition of the Chinese Pharmacopoeia.

[0233] 2.1 Determination of total magnolol content

[0234] Chromatographic conditions and system suitability test; chromatographic column: Agilent Eclipse XDB-C 18 (4.6×250mm, 5μm); Column temperature: 35℃; Mobile phase: methanol-water (78:22); Flow rate: 1.0ml / min; Detection wavelength: 294nm. The theoretical plate number, calculated based on the magnolol peak, should be no less than 3800.

[0235] Preparation of the reference solution: Take an appropriate amount of magnolol reference standard, accurately weigh it, and add methanol to prepare a solution containing 40ug of magnolol per ml.

[0236] Preparation of the test solution: Weigh approximately 50 mg of inclusion complex powder accurately, place it in a 50 ml volumetric flask, add 45 ml of 70% ethanol, sonicate for 30 min, cool, dilute to the mark with 70% ethanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0237] The determination method involves precisely pipetting 5-10 μL of the above reference solution and test solution into a liquid chromatograph, determining the total content of magnolol in the inclusion complex, and then calculating the result.

[0238] 2.2 Determination of non-encapsulated magnolol content

[0239] Preparation of the test solution: Weigh approximately 50 mg of the inclusion complex powder accurately, wash with 30 ml of petroleum ether (unincluded magnolol), collect the petroleum ether washing liquid, evaporate to dryness, dilute to 25 ml with methanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0240] The rest of the procedure is the same as above. Calculate the content of unincluded magnolol in the inclusion complex.

[0241] 2.3 Inclusion rate

[0242] The inclusion ratio of the inclusion compound is calculated using the following formula:

[0243] Inclusion rate = [(Total magnolol content - Unincluded magnolol content) / Total magnolol content] × 100%

[0244] 2.4 Results

[0245] The inclusion rates of inclusion compounds I, II, and III were 75.8%, 60.3%, and 74.1%, respectively, indicating that inclusion methods I and III were superior to inclusion method II.

[0246] Encapsulation method I is the preferred method of this invention, which is simple and efficient to operate, has a high encapsulation rate, and produces unexpected results. This method involves directly adding beta-cyclodextrin to the ethanol extract of Magnolia officinalis, simultaneously recovering the ethanol and performing encapsulation, resulting in uniform dispersion and high encapsulation efficiency. In encapsulation method II, because ethanol is recovered and removed, lipid-soluble components such as magnolol have already precipitated. Adding beta-cyclodextrin at this point results in poor solubility and dispersibility, and the encapsulation effect is also unsatisfactory. Encapsulation method III is a conventional operation in the field, using methods such as centrifugation to obtain the precipitate of lipid-soluble components such as magnolol, which is then dissolved in ethanol and added dropwise to the cyclodextrin aqueous solution for encapsulation. However, this increases the production process, reduces production efficiency, and increases production costs.

[0247] Further research shows that increasing the amount of beta-cyclodextrin further improves the inclusion rate. For example, in inclusion method I described above, adding 80g of beta-cyclodextrin resulted in an inclusion rate of 89.5%. Reducing the amount of beta-cyclodextrin also decreases the inclusion rate. Of course, this beta-cyclodextrin inclusion complex can be further treated with coating or other flavor-masking and taste-correcting processes. In addition, the total amount of magnolol in filtrate I, filtrate II, and filtrate III of the above inclusion complex was determined. The results showed that the total amount of magnolol in the filtrate was approximately 2% of the total amount of magnolol in the inclusion complex, that is, approximately 98% of magnolol was present in the inclusion complex. The applicant believes that in the above inclusion complex, most of the magnolol entered the intramolecular cavity of the beta-cyclodextrin molecule in molecular form and was included, while some magnolol was adsorbed by beta-cyclodextrin to form external inclusion, both of which formed precipitates that are insoluble in water.

[0248] (II) Encapsulation of Magnolia officinalis and Angelica dahurica ethanol extracts with beta-cyclodextrin

[0249] Magnolia officinalis (processed with ginger) and Angelica dahurica were pulverized. 320g of Magnolia officinalis and 480g of Angelica dahurica were extracted separately by percolation with 60% ethanol using conventional methods. Eight times the volume of percolate (2560ml and 3840ml) were collected separately and combined for later use.

[0250] 1. Enclosure method

[0251] Inclusion method I: Take half of the above percolate (equivalent to 400g of crude drug), add 80g of beta-cyclodextrin, recover and remove ethanol, add water to 800ml, stir at 55-60℃ for 3 hours, refrigerate overnight, filter, dry, and pulverize to obtain inclusion compound I, for later use.

[0252] For inclusion method II, take the other half of the above percolate (equivalent to 400g of crude drug), recover and remove the ethanol, add 80g of betacyclodextrin, add water to 800ml, and operate in the same way. Stir at 55-60℃ for 3 hours, refrigerate overnight, filter, dry, and pulverize to obtain inclusion compound II for later use.

[0253] 2. Inclusion rate determination

[0254] Using magnolol and imperatorin as representative components, the inclusion rates of inclusion complex I and inclusion complex II were determined using the following methods:

[0255] The HPLC chromatographic conditions and content determination methods were performed in accordance with the "Content Determination" method under the Magnolia officinalis and Angelica dahurica entries in the 2020 edition of the Chinese Pharmacopoeia.

[0256] 2.1 Determination of total magnolol content

[0257] Chromatographic conditions and system suitability test; chromatographic column: Agilent Eclipse XDB-C 18 (4.6×250mm, 5μm); Column temperature: 35℃; Mobile phase: methanol-water (78:22); Flow rate: 1.0ml / min; Detection wavelength: 294nm. The theoretical plate number, calculated based on the magnolol peak, should be no less than 3800.

[0258] Preparation of the reference solution: Take an appropriate amount of magnolol reference standard, accurately weigh it, and add methanol to prepare a solution containing 40ug of magnolol per ml.

[0259] Preparation of the test solution: Weigh approximately 50 mg of inclusion complex powder accurately, place it in a 25 ml volumetric flask, add 20 ml of 70% ethanol, sonicate for 30 min, remove, cool, dilute to the mark with 70% ethanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0260] The determination method involves precisely pipetting 5-10 μL of the above reference solution and test solution into a liquid chromatograph, determining the total content of magnolol in the inclusion complex, and then calculating the result.

[0261] 2.2 Determination of non-encapsulated magnolol content

[0262] Preparation of the test solution: Weigh approximately 100 mg of the inclusion complex powder accurately, wash with 30 ml of petroleum ether (unincluded magnolol), collect the petroleum ether washing liquid, recover and evaporate to dryness, dilute to 10 ml with methanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0263] The rest of the procedure is the same as above. Calculate the content of unincluded magnolol in the inclusion complex.

[0264] 2.3 Determination of total content of imperatorin

[0265] Chromatographic conditions and system suitability test: Column: Taiwei Technology JADE-PAK ODS-AQ (4.6×250mm, 5μm); Column temperature: 35℃; Mobile phase: methanol-water (60:40); Flow rate:

[0266] 1.0 ml / min; detection wavelength 300 nm. The theoretical plate number, calculated based on the eugenol peak, should be no less than 3000.

[0267] Preparation of the reference solution: Take an appropriate amount of imperatorin reference standard, accurately weigh it, and add methanol to prepare a solution containing 10ug per ml.

[0268] Preparation of the test solution: Weigh approximately 100 mg of inclusion complex powder accurately, place it in a 25 ml volumetric flask, add 20 ml of 70% ethanol, sonicate for 30 min, remove, cool, add 70% ethanol to the mark, shake well, filter, and collect the filtrate to obtain the test solution.

[0269] The determination method involves precisely pipetting 5-10 μL of the above reference solution and test solution into a liquid chromatograph, determining the total content of imperatorin in the inclusion complex, and calculating the result.

[0270] 2.4 Determination of the content of non-encapsulated imperatorin

[0271] Preparation of the test solution: Weigh approximately 100 mg of the inclusion complex powder accurately, wash with 30 ml of petroleum ether (unincluded imperatorin), collect the petroleum ether washing liquid, evaporate to dryness, dilute to 10 ml with methanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0272] The rest of the procedure is the same as above. Calculate the content of unincluded imperatorin in the inclusion complex.

[0273] 2.5% inclusion rate

[0274] The inclusion ratio of the inclusion compound is calculated using the following formula:

[0275] Inclusion rate = [(Total content of magnolol or imperatorin - content of unincluded magnolol or imperatorin) / Total content of magnolol or imperatorin] × 100%

[0276] Results: The inclusion rates of magnolol and imperatorin in inclusion complex I were 78.1% and 82.4%, respectively, while the inclusion rates of magnolol and imperatorin in inclusion complex II were 63.5% and 68.7%, respectively, indicating that inclusion complex I was superior to inclusion complex II.

[0277] Encapsulation method I is the preferred method of this invention. It is simple and efficient to operate, has a high encapsulation rate, and produces unexpected results. This method involves directly adding beta-cyclodextrin to the ethanol percolate, simultaneously recovering the ethanol and performing encapsulation, resulting in uniform dispersion and high encapsulation efficiency. In encapsulation method II, because ethanol is recovered and removed, lipid-soluble components such as magnolol and imperatorin have already precipitated. Adding beta-cyclodextrin at this point results in poor solubility and dispersibility, and the encapsulation effect is also inferior.

[0278] Further research shows that increasing the amount of beta-cyclodextrin further improves the inclusion rate. For example, in inclusion method I mentioned above, adding 160g of beta-cyclodextrin resulted in inclusion rates of 88.9% and 92.3% for magnolol and imperatorin, respectively. Reducing the amount of beta-cyclodextrin also decreases the inclusion rate. Of course, this beta-cyclodextrin inclusion complex can be further treated with coating or other flavor-masking and taste-correcting processes.

[0279] III. Evaluation of the taste of drug samples, reference document samples, and Huoxiang Zhengqi Water and oral liquid in the examples.

[0280] 1. Reference document CN 117257883 A Preparation of Huoxiang Zhengqi Oral Liquid

[0281] Prescription: Atractylodes lancea 800g, Citrus reticulata peel 800g, Magnolia officinalis (processed with ginger) 800g, Angelica dahurica 1200g, Poria cocos 1200g, Areca catechu peel 1200g, Pinellia ternata 800g, Glycyrrhiza uralensis extract 100g, Pogostemon cablin oil 8ml, Perilla frutescens leaf oil 4ml.

[0282] Weigh the raw materials according to the above prescription and proportions.

[0283] Magnolia officinalis (processed with ginger) was pulverized, and 10 times its volume of 60% ethanol (8L) was added. The mixture was heated under reflux for 1 hour, filtered, and the ethanol extract of Magnolia officinalis was obtained for later use.

[0284] Powder Atractylodes lancea, Citrus reticulata peel and Angelica dahurica, add 6 times the weight of water, distill at 100℃±3℃ for 6 hours, collect the distillate, let the distillate stand to separate into layers, and take the upper layer of volatile oil for later use (4.3 ml of volatile oil is obtained). Filter the distilled aqueous solution and the residue, and keep the filtrate for later use.

[0285] Powder the peel of the areca nut, add 10 times and 8 times the amount of water respectively, decoct twice, one hour each time, filter, and keep the filtrate for later use;

[0286] Powder the Poria cocos, add water and boil, then immediately cool to about 80°C. Soak twice for 2 hours each time, adding 10 times and 8 times the amount of water respectively. Filter and keep the filtrate for later use.

[0287] Soak raw Pinellia ternata in water until thoroughly soaked, then add 68g of dried ginger, add 8L of water and decoct twice, one hour each time. Filter and keep the filtrate for later use.

[0288] Water-soluble cyclodextrin (hydroxypropyl cyclodextrin) was mixed with distilled water at a weight-to-volume ratio of 1:1 and stirred at 40-50°C until the cyclodextrin was completely dissolved, yielding a water-soluble cyclodextrin solution. 163 ml of the water-soluble cyclodextrin was taken, and while maintaining the temperature at 40-50°C, 4.3 ml of volatile oil, 8 ml of patchouli oil, and 4 ml of perilla leaf oil were added sequentially with stirring. The mixture was stirred at 400 rpm for 5 hours to obtain a cyclodextrin inclusion complex solution of the volatile oil, patchouli oil, and perilla leaf oil.

[0289] Combine the above filtrates and concentrate to a clear extract with a relative density of approximately 1.15 (50°C). Add licorice extract, mix well, add twice the amount of 95% ethanol to precipitate, filter, and combine the filtrate with the ethanol extract of Magnolia officinalis.

[0290] Ethanol was recovered, and a mixture of water-soluble cyclodextrin, volatile oil, patchouli oil, and perilla leaf oil, along with the distillate from which the volatile oil was separated, was added. The mixture was thoroughly mixed, and water was added to bring the total volume to 10250 ml. The pH was adjusted to 5.8-6.2 with sodium hydroxide solution, allowed to stand, filtered, and dispensed (10 ml / vial). Sterilization was performed to obtain Huoxiang Zhengqi Oral Liquid.

[0291] 2. Taste evaluation experiment

[0292] The taste evaluation of the Huoxiang Zhengqi drug samples from Examples 1, 3, 6, and 10, along with the Huoxiang Zhengqi oral liquid from reference document (CN 117257883 A), commercially available Taiji Huoxiang Zhengqi water, and Taiji Huoxiang Zhengqi oral liquid, was conducted. Evaluation method: Three packets each of the dry suspensions from Examples 1 and 10, and the dry suspension granules from Example 3, were taken and thoroughly suspended in 30ml of purified water. Separately, 30ml each of the Huoxiang Zhengqi oral liquid from reference document, the suspension from Example 6, and the commercially available Huoxiang Zhengqi water and oral liquid were placed in tasting cups. The evaluator then poured the liquid into their mouth at once, held it for 10 seconds, spat it out, and rinsed their mouth with purified water until almost no odor remained. After 10 minutes, the taste evaluation of the next sample began. The experimenter scored each sample based on the evaluator's description and facial expressions. Each sample was evaluated by 5 evaluators, who scored it on a 5-point scale: 1) Very unpalatable, intolerable, 1-2 points; 2) Unpalatable but tolerable, 3-4 points; 3) Unpalatable but acceptable, 5-6 points; 4) Average, acceptable, 7-8 points; 5) Very palatable, no off-flavor, 9-10 points. The evaluation results are shown in Table 1.

[0293] To further improve the taste of the above samples, flavoring agents were added. 300ml each of the Huoxiang Zhengqi Oral Liquid (reference document CN 117257883 A), commercially available Huoxiang Zhengqi Water, and Huoxiang Zhengqi Oral Liquid, along with 300ml of the suspension from Example 6, were taken, flavoring agents were added, and the mixture was stirred well. Separately, 30 sachets each of the dry suspensions from Examples 1 and 10, and the dry suspension granules from Example 3 were taken, and water was added to suspend the granules in 300ml. Flavoring agents were added in the same manner, and the mixture was stirred well. The taste was then evaluated as described above. The evaluation results are shown in Table 2.

[0294] Table 1 Taste Evaluation Scores

[0295] evaluator 1 2 3 4 5 Average score result Commercially available Huoxiang Zhengqi Water 1 2 2 1 2 1.6 It tastes terrible, I can't stand it. Commercially available Huoxiang Zhengqi oral liquid 3 4 3 4 3 3.4 It tastes bad, but it's bearable. Reference document: Huoxiang Zhengqi Oral Liquid 4 4 3 5 3 3.8 It tastes bad, but it's bearable. Example 1: Drug Sample 5 6 7 5 5 5.6 It doesn't taste good, but it's acceptable. Example 3 Drug Sample 5 5 6 5 6 5.4 It doesn't taste good, but it's acceptable. Example 6 Drug Sample 6 6 7 6 5 5 It doesn't taste good, but it's acceptable. Example 10 Drug Sample 7 6 7 6 6 6.4 It doesn't taste good, but it's acceptable.

[0296] Table 2. Taste Evaluation Scores After Adding Flavoring Agents

[0297] evaluator 1 2 3 4 5 Average score result Commercially available Huoxiang Zhengqi Water 2 3 2 2 3 2.4 It tastes terrible, I can't stand it. Commercially available Huoxiang Zhengqi oral liquid 6 7 5 6 6 6 It doesn't taste good, but it's acceptable. Reference document: Huoxiang Zhengqi Oral Liquid 7 8 6 7 7 7 Generally, it's acceptable. Example 1: Drug Sample 8 9 10 9 9 9 It tastes great and has no off-flavors. Example 3 Drug Sample 8 9 9 9 9 8.8 It tastes great and has no off-flavors. Example 6 Drug Sample 8 9 9 8 9 8.6 It tastes great and has no off-flavors. Example 10 Drug Sample 8 9 9 8 9 8.6 It tastes great and has no off-flavors.

[0298] 3. Determination of magnolol content in dry suspensions

[0299] Follow the method described in the section on inclusion rate determination:

[0300] Preparation of the reference solution: Take an appropriate amount of magnolol reference standard, accurately weigh it, and add methanol to prepare a solution containing 40ug of magnolol per ml.

[0301] Preparation of Test Solution I: Weigh approximately 250 mg of the dry suspension powder from Example 1 accurately, place it in a 50 ml volumetric flask, add 45 ml of 70% ethanol, sonicate for 30 min, cool, dilute to the mark with 70% ethanol, shake well, filter, and collect the filtrate to obtain the test solution.

[0302] Preparation of test solution II: Take one bag (1.5g) of the dry suspension from Example 1, add 10ml of water to suspend, centrifuge, take 2ml of the supernatant (centrifuged liquid), dilute to 5ml with methanol, mix well, filter, and take the filtrate to obtain the test solution.

[0303] The determination method involves precisely pipetting 5-10 μL of the above reference solution and test solution into a liquid chromatograph and measuring the results.

[0304] The total amount of magnolol in one bag of dry suspension and its centrifuged liquid (10 ml) was calculated separately. The results showed that the total amount of magnolol in test solution I was 8.7 mg and the total amount of magnolol in test solution II was 1.9 mg. The conclusion is that after the dry suspension is suspended in water, magnolol is mainly present in the suspended particles or powder, and less magnolol is dissolved in water.

[0305] Although the invention has been described herein with reference to illustrative embodiments, it should be understood that many other modifications and implementations can be devised by those skilled in the art, which will fall within the scope and spirit of the principles disclosed herein. More specifically, various variations and modifications can be made to the components and / or layout of the subject matter combination within the scope of this disclosure. Besides variations and modifications to the components and / or layout, other uses will be apparent to those skilled in the art.

Claims

1. A preparation method of Huoxiang Zhengqi pharmaceutical preparation, characterized in that Includes the following steps: (1) Prepare raw materials, which consist of Atractylodes lancea, Citrus reticulata peel, Angelica dahurica, Magnolia officinalis, Poria cocos, Areca catechu peel, Pinellia ternata, Glycyrrhiza uralensis extract, Pogostemon cablin oil and Perilla frutescens leaf oil; (2) Extraction of the active pharmaceutical ingredient, including: Magnolia officinalis extract was obtained by extracting Magnolia officinalis with an alcohol solution containing 50%-80% ethanol by volume. Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica were extracted separately or in combination using solvents to obtain separate extracts or combined extracts. The method for extracting Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica separately involved using a 50%-80% (v / v) ethanol solution as the solvent to extract Atractylodes lancea extract, Citrus reticulata peel extract, and Angelica dahurica extract, respectively. The method for combining Atractylodes lancea, Citrus reticulata peel, and Angelica dahurica was to combine the extracts, add water, and distill, collecting the volatile oil and / or distillate. The distilled aqueous solution was then filtered, and the filtrate ② was collected. Poria cocos, Areca peel, and Pinellia ternata were extracted separately with solvents to obtain separate extracts; (3) Processing the extract, including: Inclusion complexes were obtained by encapsulating patchouli oil and perilla leaf oil separately or together with beta-cyclodextrin. The ratio of the total volume of patchouli oil and perilla leaf oil to the mass of beta-cyclodextrin encapsulating patchouli oil and perilla leaf oil was 2.4 ml: 15-40 g. Alternatively, the patchouli oil and perilla leaf oil can be combined with the volatile oil and / or distillate collected during the extraction of angelica dahurica, atractylodes lancea, and tangerine peel to obtain a combined liquid, and then the mixture can be included to obtain inclusion compound ④. The ratio of the total volume of patchouli oil and perilla leaf oil to the mass of beta-cyclodextrin in the combined liquid is 2.4 ml: 20-80 g. Magnolia officinalis extract and Angelica dahurica extract were encapsulated separately or in combination using beta-cyclodextrin. The method was as follows: beta-cyclodextrin was added to Magnolia officinalis extract and Angelica dahurica extract separately or in combination, and the encapsulation was carried out while ethanol was recovered and removed. The mixture was filtered to obtain encapsulation compound ① and filtrate ①. Atractylodes lancea extract, Citrus reticulata extract, and extracts of Poria cocos, Areca catechu peel and Pinellia ternata were prepared together with the licorice extract and the filtrate ① to make extract ①. Alternatively, the Magnolia officinalis extract can be encapsulated with beta-cyclodextrin to obtain inclusion complex ③ and filtrate ③. The filtrate ②, filtrate ③ and the extracts of Poria cocos, Areca catechu and Pinellia ternata are combined, concentrated, and the licorice extract is added. The mixture is then concentrated and dried to obtain extract ②. The ratio of beta-cyclodextrin added to the Magnolia officinalis extract and the Angelica dahurica extract is as follows: based on the weight ratio of the raw herbs used to prepare the Magnolia officinalis extract and the Angelica dahurica extract, the weight ratio of Magnolia officinalis to beta-cyclodextrin is 10:(0.5-5), and the weight ratio of Angelica dahurica to beta-cyclodextrin is 10:(0.5-5). (4) Mix the inclusion complex, inclusion complex ① with extract ① or the inclusion complex ④ and inclusion complex ③ with extract ② obtained in step (3), and add pharmaceutically acceptable excipients to prepare dry suspension, powder or granules.

2. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 1, characterized in that, Step (2) The extraction method of Atractylodes lancea and Citrus reticulata is as follows: Atractylodes lancea and Citrus reticulata are extracted separately using an alcohol solution as a solvent to obtain Atractylodes lancea extract and Citrus reticulata extract, which are then combined, the ethanol is removed, and the extract is concentrated into a clear paste.

3. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 2, characterized in that, The preparation method of the extract ① in step (3) is as follows: the filtrate ① and the extracts of Poria cocos, Areca catechu and Pinellia ternata are combined, concentrated, the licorice extract is added, ethanol solution is added to remove the precipitate by alcohol precipitation, the Atractylodes lancea extract and Citrus reticulata extract are added, the ethanol is recovered, concentrated, and dried to obtain extract ①; or the filtrate ① and the extracts of Poria cocos, Areca catechu and Pinellia ternata are combined, concentrated, the licorice extract is added, the clear extract is added, concentrated, and dried to obtain extract ①.

4. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 3, characterized in that, The patchouli oil and perilla leaf oil were combined and then encapsulated to obtain inclusion compound ②; The inclusion complex ①, inclusion complex ② and extract ① are pulverized, mixed, and pharmaceutically acceptable excipients are added to prepare a formulation.

5. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 1, characterized in that, The filtrate ② and filtrate ③ mentioned in step (3), as well as the extracts of Poria cocos, Areca peel and raw Pinellia ternata, are combined, concentrated, and the licorice extract is added. Ethanol solution is added to remove the precipitate by alcohol precipitation. After recovering the ethanol, the extract is concentrated and dried to obtain extract ②.

6. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 5, characterized in that, The inclusion complex ③, inclusion complex ④ and the extract ② are pulverized, mixed, and pharmaceutically acceptable excipients are added to prepare a formulation.

7. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 3 or 5, characterized in that, The ethanol solution added for alcohol precipitation is an ethanol solution with a volume fraction of 80%-95%, and the amount of ethanol solution added is 2 to 3 times the volume of the substance to be precipitated.

8. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 7, characterized in that, In step (2), the extracts of Poria cocos, Areca peel, and raw Pinellia ternata were obtained by solvent extraction. The method was as follows: Poria cocos, Areca peel, and raw Pinellia ternata were extracted with water as solvent. The extraction method of Poria cocos was: Poria cocos was boiled in water and then soaked at 80°C, filtered, and the filtrate was collected. The extraction method of Areca peel was: Areca peel was boiled in water, filtered, and the filtrate was collected. The extraction method of raw Pinellia ternata was: raw Pinellia ternata was soaked in water until thoroughly soaked, and then 8%-10% of the weight of dried ginger was added, boiled in water, filtered, and the filtrate was collected.

9. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 1 or 8, characterized in that, The pharmaceutically acceptable excipients include at least one of the following: fillers, flavoring agents, suspending agents, and gliding agents.

10. The method for preparing the Huoxiang Zhengqi pharmaceutical preparation according to claim 9, characterized in that, The raw materials consist of: 160g of Atractylodes lancea, 160g of Citrus reticulata peel, 160g of Magnolia officinalis prepared with ginger, 240g of Angelica dahurica, 240g of Poria cocos, 240g of Areca catechu peel, 160g of Pinellia ternata, 20g of Glycyrrhiza uralensis extract, 1.6ml of Pogostemon cablin oil and 0.8ml of Perilla frutescens leaf oil.