Enteric-coated Huoxiang Zhengqi soft capsule and preparation method thereof

Abstract

The enteric-coated Huoxiang Zhengqi soft capsule is prepared from rhizoma atractylodis, pericarpium citri reticulatae, cortex magnoliae officinalis (processed with ginger), radix angelicae, poria cocos, pericarpium arecae, a raw rhizoma pinelliae extract, licorice extract, patchouli oil, perilla leaf oil and an enteric-coated soft capsule shell material. According to the preparation method, heating extraction is replaced by wet grinding extraction, volatile oil and extractum are synchronously collected in the evaporation and concentration process through a scraper film evaporator, the heating time for evaporation and concentration of feed liquid through the scraper film evaporator is short, and heat-sensitive components in a prescription can be prevented from being damaged by heat; the enteric soft capsule shell of the enteric Huoxiang Zhengqi soft capsule is a completely sealed capsule shell, can overcome volatilization and loss of volatile oil in existing tablets and pills, can overcome volatilization and loss of volatile oil caused by poor sealing of an assembly gap between an upper shell and a lower shell of a hard-shell capsule, and can overcome the defects that the enteric soft capsule shell material is insoluble in a gastric solution, so that the enteric soft capsule shell material cannot be dissolved in the gastric solution and cannot be dissolved in the gastric solution. The medicine is dissolved and released in an intestinal environment, so that the damage of gastric acid to medicinal components is avoided.

Description

Technical Field

[0001] This invention relates to traditional Chinese medicine preparation technology, and in particular to an enteric-coated Huoxiang Zhengqi soft capsule and its preparation method. Background Technology

[0002] Various dosage forms of Huoxiang Zhengqi Powder, based on the ancient formula Huoxiang Zhengqi Powder from the Taiping Huimin Heji Jufang (Formulary of the Bureau of Imperial Medical Services for the Benefit of the People), are already circulating in the market, including Huoxiang Zhengqi Water, Huoxiang Zhengqi Pills, Huoxiang Zhengqi Mixture, Huoxiang Zhengqi Tablets, Huoxiang Zhengqi Capsules, and Huoxiang Zhengqi Soft Capsules. Among these, Huoxiang Zhengqi Water contains ethanol, which is highly irritating. Patients experience a burning sensation in the throat and stomach after taking it, significant stomach irritation, vomiting, nausea, and there is also a risk of allergic reactions. Although Huoxiang Zhengqi Mixture does not contain ethanol, the aroma of Atractylodes lancea in the prescription can cause discomfort, leading to poor patient compliance. Huoxiang Zhengqi Pills and Tablets dissolve slowly and take effect slowly, deviating from the efficacy of the original powder formula. Li Dongyuan, one of the four famous physicians of the Jin-Yuan period, said, "Powders are for dispersing, used to treat acute illnesses." "Pills are for slow treatment, not quick relief." Ancient powder formulas avoided the loss of volatile oils during decoction. They were prepared using stone mills, preventing the destruction of heat-sensitive components. Although ancient powder formulas retain the components of each herb in the prescription, they are plant powder particles. The active ingredients need to dissolve in gastric juices after oral administration. The different swelling characteristics of each herb result in varying dissolution rates, leading to asynchronous onset of action and hindering the effective function of the prescription.

[0003] The 2005 edition of the Pharmacopoeia of the People's Republic of China includes Huoxiang Zhengqi Soft Capsules, which are formulated with Atractylodes lancea 195g, Citrus reticulata peel 195g, Magnolia officinalis (processed with ginger) 195g, Angelica dahurica 293g, Poria cocos 293g, Areca catechu peel 293g, Pinellia ternata 195g, Glycyrrhiza uralensis extract 24.4g, Pogostemon cablin oil 1.95ml, and Perilla frutescens leaf oil 0.98ml.

[0004] The drug preparation process is as follows:

[0005] Step 1: Extract Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis, and Angelica dahurica twice with ethanol, combine the ethanol extracts, concentrate them into a clear paste, and obtain the ingredients.

[0006] Step 2: Boil Poria and Areca Peel twice with water, combine the decoctions, filter, and collect the filtrate to obtain the ingredients.

[0007] Step 3: Soak raw Pinellia ternata in cold water, changing the water every 8 hours until thoroughly soaked. Then add 16.5g of dried ginger, decoct twice, filter, and collect the filtrate to obtain the ingredients.

[0008] Step 4: Prepare the ingredients Ingredients The mixture was combined, concentrated, and then precipitated with alcohol. The supernatant was collected and concentrated into a clear paste to obtain the ingredients.

[0009] Step 5: Crush the licorice extract, boil it in water to dissolve it, precipitate it with alcohol, and concentrate the supernatant to make a clear extract, thus obtaining the ingredients.

[0010] Step 6: Combine the above ingredients Ingredients Ingredients Combine the ingredients, add patchouli oil, perilla leaf oil and appropriate excipients, mix well, and make 1000 soft capsules, which are called Huoxiang Zhengqi soft capsules.

[0011] Literature-documented component studies

[0012] The main medicinal components of patchouli include patchouli oil, whose main components are patchouli ketone and patchouli alcohol, α-patchoene and β-patchoene, and baicaleol.

[0013] The main medicinal components of Magnolia officinalis include magnolol, honokiol, isomagnolol, trihydroxymagnolol, and detrihydroxymagnolol, among which magnolol and honokiol are the main components; it also contains eucalyptol, cymene, and caryophyllene; according to literature: pharmacokinetic studies have shown that the absorption characteristics of magnolol, the main component of Magnolia officinalis, were studied from the aspects of absorption site and drug concentration using an in vivo rat intestinal reflux experiment. The results showed that magnolol was best absorbed in the upper part of the small intestine [Ding Wanping, Tang Xing, Tao Jimei. Small intestinal absorption characteristics of the main components of Magnolia officinalis extract [J]. Journal of Shenyang Pharmaceutical University, 2003, 20(6): 399].

[0014] The main medicinal components of Angelica dahurica include coumarins and volatile oils, which are the main active ingredients of Angelica dahurica. The main coumarin components include imperatorin, eugenol, and isoeugenol; the volatile oils mainly contain methylcyclodecane and 1-tetradecene.

[0015] The main medicinal components of Poria cocos include triterpenoids, polysaccharides, sterols, and volatile oils.

[0016] Triterpenoids include pachymic acid, porphyric acid C, and dehydrotomolic acid;

[0017] Polysaccharides include β-pachyman and heteropolysaccharides, with water-soluble polysaccharides being the main active polysaccharides among the polysaccharide components;

[0018] Sterols include stigmasterol, piperateol, and ergosterol;

[0019] Volatile oils include α-cedrol, borneol, and terpinene.

[0020] The main medicinal components of dried tangerine peel include volatile oils and flavonoids;

[0021] The main medicinal components of Atractylodes lancea include volatile oils, sesquiterpenes, phenols, and organic acids; it also contains sesquiterpene lactones, sesquiterpene glycosides, polysaccharides, and flavonoids.

[0022] The main medicinal components of Pinellia ternata include Pinellia ternata protein, alkaloids, β-sitosterol, carotene, polysaccharides, amino acids, volatile oils and inorganic elements. Pinellia ternata alkaloids include ephedrine hydrochloride, choline, guanosine, thymidine, and hypoxanthine nucleoside.

[0023] According to literature, the toxicity of Pinellia ternata is due to the irritant components of raw Pinellia ternata, namely calcium oxalate needle crystals and lectin protein. Calcium oxalate needle crystals have a significant inflammatory effect, and the lectin protein in the calcium oxalate needle crystals is the toxic protein. Soaking in alum and decocting with ginger can reduce the toxicity of Pinellia ternata. The aluminum ions in alum can complex the oxalic acid in the calcium oxalate needle crystals, destroying the crystal structure of the needle crystals. The gingerol components in ginger can antagonize the inflammatory cascade caused by the binding of lectin protein to receptors, thereby playing a detoxifying role in the body [Tao Xingbao's study on the detoxification mechanism, expectorant effect and related material basis of Pinellia ternata processing [D] Nanjing University of Traditional Chinese Medicine 2022].

[0024] The main medicinal components of Areca peel include alkaloids, such as arecoline, arecoline, demethylarecoline, and arecoline paraalkaloid.

[0025] The medicinal components of licorice mainly include triterpenoid saponins such as glycyrrhizic acid, glycyrrhetinic acid, and glycyrrhizin, as well as flavonoids such as glycyrrhizin and isoglycyrrhizin.

[0026] The main medicinal components of perilla leaves include volatile oils, terpenes, sterols, phenolic acids and cinnamic acid, glycosides, and flavonoids, including perillaldehyde, limonene, linalool, furanone derivatives, eugenol, myristole, pinene, menthol, benzaldehyde, eugenol, oleanolic acid, ursolic acid, β-sitosterol, stigmasterol, perillin A, perillin B, perillin C, perillin D, perillin E, caffeic acid, ferulic acid, apigenin, and luteolin.

[0027] Based on literature review, existing preparation methods have the following drawbacks;

[0028] In process 1, each of the following herbs—Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis, and Angelica dahurica—contains volatile oil components. However, the volatile oil was not collected during the ethanol extraction concentration process, resulting in a deficiency of volatile oil components in the prepared formulation, which inevitably leads to differences in efficacy compared to the original powder prescription. This is especially true for Citrus reticulata peel volatile oil, one of the main active ingredients, accounting for approximately 2% of the total medicinal material mass. It primarily contains monoterpenes and sesquiterpenes [Li Haoxiang et al., A review of the chemical components, pharmacological effects, and comprehensive utilization of Citrus reticulata peel (Guangdong and Xinhui varieties) [J] Shi Zhen Guo Yi Guo Yao, 2019, Vol. 30, No. 6, pp. 1460-1463]; the volatility of Citrus reticulata peel... The components may be the material basis for its qi-regulating effect [Chen Jun. Study on the material basis of the qi-regulating effect of tangerine peel [D]. Changsha: Hunan University of Traditional Chinese Medicine, 2012]. The chemical components of tangerine peel volatile oil in Liu Jun Zi Tang are linearly correlated with its efficacy, and its gastrointestinal regulatory effect is the result of the combined action of multiple chemical components. Pharmacological studies have shown that tangerine peel has obvious effects on the digestive and respiratory systems, and the volatile oil has a more obvious effect on the respiratory system [Xu Peng et al. Comparison of the pharmacological effects of tangerine peel water extract and tangerine peel volatile oil [J]. Journal of Jiangxi University of Traditional Chinese Medicine, 1998, 10(4): 172].

[0029] The phenolic components in Magnolia officinalis are easily destroyed by heat, and the process of concentrating it into a clear paste is not limited to a low temperature range.

[0030] Literature records that dragon's blood mainly contains flavonoids, volatile oils, phenols, and steroidal compounds [Zhang Li et al., Research progress on chemical components and pharmacological effects of dragon's blood and dragon's blood [J]. Chinese Journal of Modern Applied Pharmacy, October 2019, Vol. 36, No. 20, pp. 26.5-26.11].

[0031] Studies on the thermal stability of dragon's blood showed that heating at 90℃ for 15 min reduced the content of dragon's blood extract by 46.6%; heating at 80℃ for 15 min reduced the content of dragon's blood extract by 38.3% [Xu Shuqing et al., Study on the stability of traditional Chinese medicine dragon's blood [J], Chinese Patent Medicine, 2005, 27(5)].

[0032] Analgesic, hemostatic, and anti-inflammatory experiments on dragon's blood showed that the small dose (0.25 g / kg) of dragon's blood extracted by the heat-free process can achieve the same effect as the large dose (1.0 g / kg) of dragon's blood extracted by the traditional heating process. The bioactivity of dragon's blood extracted by the heat-free process is 4 times that of dragon's blood extracted by the traditional heating process [Cao Guangjun et al., Comparison of anti-inflammatory, analgesic, and hemostatic effects of dragon's blood extracted by different processes [J]. Tianjin Pharmaceutical Journal, June 2005, Vol. 17, No. 3, pp. 31-34].

[0033] Phenolic compounds may be oxidized when heated, forming quinone compounds or other oxidation products.

[0034] In steps 2, 3, and 4, after concentration and alcohol precipitation, the supernatant is concentrated into a clear extract, and the alcohol precipitate is discarded. Polysaccharides are not extracted from the alcohol precipitate; Poria cocos polysaccharides and Pinellia ternata polysaccharides are lost.

[0035] According to literature, Pinellia ternata polysaccharide is a high molecular weight polymer composed of aldoses or ketoses, which is easily soluble in water but poorly soluble in ethanol [Huang Jiansheng et al., Research progress on the separation, extraction and pharmacological activity of Pinellia ternata polysaccharide [J] Shaanxi Journal of Traditional Chinese Medicine, September 2024, Vol. 45, No. 9, 1283-1289]. It can be seen from the literature that the polysaccharide is a water-soluble substance that precipitates with alcohol precipitation.

[0036] According to literature, Poria cocos is extracted by reflux, concentrated by vacuum distillation, precipitated with alcohol, centrifuged, the precipitate is collected, dissolved in distilled water, precipitated with alcohol again, and dried at low temperature to obtain crude Poria cocos polysaccharide [Li Jun et al., Extraction and content determination of Poria cocos polysaccharide [J] Chinese Journal of Modern Applied Pharmacy, February 2000, Vol. 17, No. 1, pp. 49-50].

[0037] As can be seen from the literature, the extraction of Poria cocos polysaccharides must make full use of alcohol precipitation.

[0038] Existing formulations are mainly gastric-soluble, meaning the active ingredients remain in the gastric juice for a relatively long time. Gastric juice contains a large amount of gastric acid, the main component of which is hydrochloric acid (HCl). The pH value of gastric juice is usually between 0.9 and 1.5, making it highly acidic.

[0039] Stomach acid can damage the chemical structure of some drugs, causing them to degrade before reaching the small intestine for absorption, thus reducing their efficacy.

[0040] The following uncertainties still exist regarding the presence of some active pharmaceutical ingredients in gastric juice:

[0041] Changes in solubility: Some drugs become more soluble in acidic environments, while others may become less soluble. Changes in solubility directly affect the rate at which drugs are absorbed in the stomach.

[0042] Ionization: Stomach acid can affect the ionization state of drugs; generally, an acidic environment increases the non-ionized form of drugs, and non-ionized drugs are more easily absorbed through cell membranes.

[0043] Some Chinese medicine components may be unstable in an acidic environment and easily degraded by gastric acid, thus losing their activity. For example, phenolic and alkaloid components may decompose under the action of gastric acid. Some alkaloids may be more stable in an acidic environment, while others may be degraded. Many glycosides are easily hydrolyzed in an acidic environment, releasing aglycones and sugars, which may change their original medicinal properties. Summary of the Invention

[0044] In view of the shortcomings of the existing technology, the purpose of this invention is to propose an enteric-coated Huoxiang Zhengqi soft capsule and its preparation method that overcomes the problems of loss of some volatile oils of medicinal ingredients, failure to extract some polysaccharides of medicinal ingredients, and denaturation of phenols due to heat in the existing preparation process, and improves the gastric-soluble type to enteric-coated type to avoid the destruction of the active ingredients by gastric acid.

[0045] The technical solution for the present invention is an enteric-coated Huoxiang Zhengqi soft capsule.

[0046] An enteric-coated Huoxiang Zhengqi soft capsule includes Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, Areca catechu peel, Pinellia ternata extract, Glycyrrhiza uralensis extract, Patchouli oil, Perilla frutescens leaf oil, and enteric-coated soft capsule shell material.

[0047] The enteric-coated soft capsule shell material comprises gelatin, glycerin, and distilled water; wherein gelatin is a film-forming agent, glycerin is a plasticizer, and distilled water is a solvent, and the composition ratio of gelatin, glycerin, and distilled water is: gelatin: glycerin: distilled water = 2:1:2;

[0048] When soft capsules made of gelatin and glycerin enter the gastric environment, the surface of the soft capsule comes into contact with gastric acid, causing the gelatin layer on the surface to swell. The swollen capsule surface forms the capsule wall, preventing gastric acid from dissolving the inner capsule layer. The drug encapsulated in the inner capsule layer remains sealed by the undissolved inner capsule layer. Gelatin has excellent gelling properties, which can further gel the surface of the swollen capsule to form a soft capsule wall. The gelled surface structure can further prevent gastric acid from penetrating the soft capsule shell, thus achieving the stability of the drug inside the capsule in a sealed state in the gastric environment. Gelatin has good solubility in an alkaline environment. After the surface of the soft capsule swells in gastric acid, it enters the intestine under the peristalsis of the stomach and intestines. In the alkaline environment of the intestine, the capsule wall, the gelled surface, and the inner soft capsule layer gradually dissolve in sequence. The time for capsule penetration is related to the thickness of the capsule shell. After the capsule penetrates, the drug inside the capsule is released into the intestinal environment, thereby achieving the purpose of avoiding the destruction of the active ingredients by gastric acid.

[0049] A method for preparing enteric-coated Huoxiang Zhengqi soft capsules comprises the following steps:

[0050] Step 1: Chop the medicinal slices: Chop the Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, and Areca catechu peel; chop the medicinal slices of different shapes and sizes into particles ≤3μm; so that they can be soaked and swelled and then wet-processed in the next step.

[0051] Step 2, Soaking and Swelling: Soak the chopped medicinal slices in water with a solid-liquid mass ratio of 1:10, control the water temperature at 20-25℃, and soak for 24 hours to allow the chopped medicinal slices to fully swell, resulting in a swelled granule mixture.

[0052] Step 3, wet pulverization; The swollen mixture completed in step 2 is wet pulverized using a high-speed shear machine. In the wet pulverization process of the high-speed shear machine, the soaked and swollen medicinal slices are broken. During the wet pulverization process, the plant tissue is squeezed and deformed, and the high-speed shearing breaks the cells, so that the soluble substances inside and between the cells, including volatile oils, are fully dissolved in the clear water solution. During the wet pulverization process, the temperature of the clear water solution is controlled at 45-50℃ to obtain a solid-liquid mixture (1).

[0053] Step 4: Solid-liquid separation; the solid-liquid mixture (1) obtained by wet pulverization in step 3 is separated by using either a plate and frame filter or a centrifuge to collect the filtrate (I); the dregs are collected to obtain liquid-containing dregs (Is);

[0054] Step 5: Secondary wet pulverization. The liquid-containing medicinal residue (Is) is pulverized twice by wet pulverization. That is, the liquid-containing medicinal residue (Is) is added to a 60% ethanol aqueous solution, and the liquid-containing medicinal residue (Is) is pulverized twice by wet pulverization in the manner of step 3 at a mass ratio of 1:3 to 60% ethanol aqueous solution, to obtain a solid-liquid mixture (2).

[0055] Step 6: Solid-liquid separation. The solid-liquid mixture (2) obtained from the second wet pulverization in step 5 is separated by using either a plate and frame filter or a centrifuge to collect the filtrate, which is filtrate (II). The dregs are discarded.

[0056] Step 7: Processing and extraction of raw Pinellia ternata, following the procedure below:

[0057] Step 7.1: Soak in alum water;

[0058] Soak raw Pinellia ternata in 8% alum water for 24 hours at a temperature of 25-30°C. The ratio of raw Pinellia ternata to 8% alum water is 1:1.7 (solid-liquid mass ratio). After soaking for 24 hours, discard the alum water, collect the soaked raw Pinellia ternata, rinse with purified water and filter dry to obtain purified Pinellia ternata.

[0059] Step 7.2: Prepare ginger;

[0060] Mix Pinellia ternata with fresh ginger, with a mass ratio of 1:0.25.

[0061] Process 7.3, Wet grinding;

[0062] The prepared Pinellia ternata and ginger were added to a 60% ethanol aqueous solution at a solid-liquid mass ratio of 1:10. The mixture was then wet-crushed using a high-speed shearing machine. During the wet-crushing process, the prepared Pinellia ternata and ginger were crushed. The plant tissues were compressed and deformed during the wet-crushing process, and the cells were broken, so that the soluble substances inside and between the cells were fully dissolved in the 60% ethanol aqueous solution. The temperature of the 60% ethanol aqueous solution was controlled to be ≤50℃ during the wet-crushing process.

[0063] Process 7.4, solid-liquid separation;

[0064] The solid-liquid mixture obtained from wet pulverization in process 7.3 is separated by centrifugation. The filtrate is collected to obtain filtrate (III), and the residue is discarded.

[0065] Step 8: Preparation of licorice extract; proceed as follows:

[0066] Step 8.1: Take the licorice extract and crush it;

[0067] Step 8.2: Melting with hot water;

[0068] Add the crushed licorice extract from step 8.1 into a warm bath and dissolve it with water at a ratio of 1:1 (by mass). Control the temperature of the warm bath at 60-65℃ to dissolve the crushed licorice extract and obtain a licorice extract solution.

[0069] Step 8.3: Alcohol precipitation;

[0070] Add ethanol to the licorice extract solution dissolved in hot water in step 8.2 to prepare an alcohol precipitation solution containing 60% ethanol. Let it stand for 24 hours at a controlled temperature of 7°C. Collect the supernatant and discard the precipitate to obtain licorice supernatant (IV).

[0071] Step 9: Concentrate the filtrate (I) and collect the volatile oil simultaneously;

[0072] The filtrate (I) is concentrated, and volatile oil is collected simultaneously. A scraped-film evaporator is used for evaporation and concentration, during which volatile oil and extract are collected simultaneously. The scraper rotates and scrapes the wall, evenly distributing the filtrate (I) on the heat transfer wall of the evaporator. The rotating scraping motion ensures that the heat transfer surface of the concentration tank is constantly renewed, preventing material from adhering to the heat transfer wall surface for too long, thus avoiding drying and sticking. The heat transfer wall of the evaporator maintains a high heat transfer coefficient and evaporation intensity. The short residence time of the liquid on the heat transfer wall prevents heat-sensitive components from being damaged by prolonged heating.

[0073] The scraped film evaporator includes a condenser; the condenser collects the vapor evaporated by the scraped film evaporator, the evaporated vapor including water vapor and volatile oil; the collected water vapor is condensed into liquid water, and the collected volatile oil vapor is condensed into liquid oil. The two different substances are separated due to their different specific gravities and physical properties. The volatile oil is collected, and the liquid water is discarded, resulting in concentrated extract (A) and volatile oil (a).

[0074] Step 10: Concentrate the filtrate (II);

[0075] The filtrate (II) is concentrated by evaporation using a scraped film evaporator. During the evaporation and concentration process, ethanol is recovered and the extract is collected simultaneously. The filtrate (II) is concentrated according to step nine to obtain concentrated extract (II), and ethanol is recovered.

[0076] Step 11: Concentrate the filtrate (III) and collect the volatile oil simultaneously;

[0077] The filtration (III) is concentrated and the volatile oil is collected simultaneously. The evaporation and concentration are carried out using a scraped film evaporator. During the evaporation and concentration process, the volatile oil and extract are collected simultaneously. Step eleven refers to step nine. Concentrated extract (C) is obtained, and volatile oil (b) is obtained.

[0078] Step 12: Alcohol precipitation of the extract;

[0079] The concentrated extract is precipitated by alcohol by combining concentrated extract (A), concentrated extract (B), and concentrated extract (C), adding ethanol to dissolve and dilute, stirring thoroughly, cooling, and allowing to stand, so that the portion insoluble in the ethanol solution precipitates.

[0080] The addition of ethanol refers to combining concentrated extract (A), concentrated extract (B), and concentrated extract (C) and then mixing them with ethanol to form an ethanol mixture containing 60% ethanol.

[0081] The aforementioned thorough stirring is achieved by using an alcohol precipitation tank with a stirring function, and by using the stirring mechanism of the alcohol precipitation tank to stir at a uniform speed.

[0082] The so-called settling refers to cooling the thoroughly stirred ethanol mixture after it has been fully stirred and then allowing it to stand.

[0083] The cooling and standing process was carried out to keep the temperature of the ethanol mixture constant at 5-7°C for 24 hours. After standing for 24 hours, the supernatant and precipitate were collected separately to obtain the supernatant (V) and precipitate (D).

[0084] Step 13: Polysaccharide separation;

[0085] The polysaccharide separation process involves dissolving the precipitate (D) in hot water at a volume ratio of 1:2 (precipitate (D): hot water) at 75°C, stirring thoroughly, and then filtering using a 100kDa ultrafiltration membrane at a temperature maintained between 60°C and 65°C. This process removes molecules with molecular weights >10×10⁻⁶. 4 Impurities; polysaccharide ultrafiltrate (VI);

[0086] Step Fourteen: Vacuum dehydration and drying;

[0087] The dehydration and drying process involves combining the licorice supernatant (IV), supernatant (V), and polysaccharide ultrafiltrate (VI) and dehydrating them using a vacuum dryer. The vacuum dryer is configured with a drying temperature of 55–60°C and a vacuum pressure of 1000–1100 Pa. The product is dried until the moisture content is ≤3%. Extracts from Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, Areca catechu peel, Pinellia ternata, and licorice are collected to obtain a powder extract (A1).

[0088] Step 15: Dry granulation;

[0089] The dry granulation process involves granulating the powder extract (A1) using a dry granulation machine, with an average particle size of 1-1.5 mm, to obtain granules (A2). The dry granulation process does not require the addition of excipients, and the average particle size of 1-1.5 mm is beneficial for the processability of the filled capsules, giving the granules (A2) better flowability. The more uniform distribution of the granules (A2) can make the density of the filled capsules more consistent.

[0090] Step 16: Freeze and allow to stand to dehydrate the volatile oils;

[0091] The aforementioned dehydration of frozen volatile oil involves combining the collected volatile oils (a) and (b) and injecting them into a glass tube container. The container is then placed in a refrigerator and left to stand for 24 hours, with the temperature controlled between 3.5°C and 4.5°C. During this process, the density of some water in the volatile oil reaches its maximum value. As the temperature decreases, the viscosity of the volatile oil increases, causing it to aggregate and float to the surface, while the water settles, resulting in a water-oil stratification. The floating volatile oil is then extracted using a suction device to obtain anhydrous volatile oil (C).

[0092] Step 17: Mix the liquids;

[0093] The liquid-liquid mixture is prepared by mixing patchouli oil, perilla leaf oil, and anhydrous volatile oil (C) evenly to obtain mixed volatile oil (D);

[0094] Step 18; Liquid-solid mixing via atomization;

[0095] The aforementioned atomization liquid-solid mixing method involves uniformly mixing granular material (A2) with mixed volatile oil (D); using an atomizer to atomize and spray the mixed volatile oil (D) into the granular material (A2) to obtain granular material (A3) containing volatile oil.

[0096] Step 19; Fill the soft capsule;

[0097] The soft capsules are filled using a soft capsule machine, which fills enteric-coated soft capsules with volatile oil particles (A3) to obtain enteric-coated Huoxiang Zhengqi soft capsules.

[0098] The present invention provides an enteric-coated Huoxiang Zhengqi soft capsule and its preparation method, achieving positive effects.

[0099] ① Enteric-coated Huoxiang Zhengqi soft capsules are made of completely sealed capsule shells, which can overcome the loss of volatile oil in existing tablets and pills, and can overcome the loss of volatile oil caused by poor sealing of the assembly gap between the upper and lower shells in hard-shell capsules.

[0100] ② Enteric-coated soft capsules are insoluble in gastric solution but dissolve and release the drug in the intestinal environment, thus avoiding the destruction of the active ingredients by gastric acid.

[0101] ③ The preparation method of enteric-coated Huoxiang Zhengqi soft capsules adopts wet pulverization and extraction, which can avoid the destruction of heat-sensitive active ingredients in the prescription by heat extraction. The volatile oil is collected simultaneously during the concentration process, which overcomes the problem that some volatile oils contained in the medicine are not extracted in the existing technology, so that the active ingredients in the prescription are collected more completely in the medicine.

[0102] ④ To address the toxicity of Pinellia ternata, alum water soaking was used, and Pinellia ternata was mixed with ginger and wet-processed. During the wet-processing, the extracts from Pinellia ternata and ginger were completely mixed, and the components of Pinellia ternata and ginger formed a composite, which allowed the ginger components to antagonize the inflammatory cascade reaction caused by the binding of lectin protein in Pinellia ternata to receptors. Detailed Implementation

[0103] The embodiment is operated according to the following steps:

[0104] Step 1: Chop the medicinal slices;

[0105] Take the following medicinal slices: Atractylodes lancea 975g, Citrus reticulata peel 975g, Magnolia officinalis (processed with ginger) 975g, Angelica dahurica 1465g, Poria cocos 1465g, Areca catechu peel 1465g, and chop them into ≤3mm granules.

[0106] Step 2: Soaking and swelling;

[0107] The soaking and swelling process involves immersing the chopped particles in 73.2L of clean water at a temperature of 20-25°C for 24 hours to allow the chopped medicinal particles to swell, resulting in a swelled particle mixture.

[0108] Step 3: Wet grinding;

[0109] The granular swelling mixture completed in step two is wet-crushed using a high-speed shearing machine. That is, the soaked and swollen medicinal slices are broken up so that the soluble substances inside and between cells, including volatile oils, are fully dissolved in water under high-speed extrusion and shearing. During the wet-crushing process, the temperature is controlled at 45-50℃ to obtain a solid-liquid mixture (1).

[0110] Step 4: Solid-liquid separation;

[0111] The solid-liquid mixture obtained from the wet pulverization in step three was separated into solid and liquid components. The mixture was filtered using a plate and frame filter press, and the filtrate was collected to obtain 65 L of filtrate (I). The residue was collected to obtain 14.6 kg of liquid-containing residue (Is).

[0112] Step 5: Secondary wet pulverization. 14.6 kg of liquid residue (Is) from the solid-liquid separation in Step 4 is added to 45 L of 60% ethanol aqueous solution. The secondary wet pulverization is carried out using the wet pulverization method of Step 3 to obtain a solid-liquid mixture (2).

[0113] Step 6: Solid-liquid separation. The solid-liquid mixture (2) obtained from the second wet pulverization in step 5 is separated by a plate and frame filter press. The filtrate is collected to obtain 50 liters of filtrate (II). The residue is discarded.

[0114] Step 7: Processing and extraction of raw Pinellia ternata, following the procedure below:

[0115] Step 7.1: Take 975g of raw Pinellia ternata and soak it in alum water;

[0116] Soak raw Pinellia ternata in 1.6 liters of water containing 8% alum for 24 hours. The temperature of the alum water is 25-30℃. The solid-liquid mass ratio of raw Pinellia ternata to 8% alum water is 1:1.7. After soaking for 24 hours, pour off the alum water, collect the soaked raw Pinellia ternata, rinse it with purified water and filter it to obtain purified Pinellia ternata.

[0117] Step 7.2, Ginger Preparation;

[0118] Take 243.5g of fresh ginger and mix it with Pinellia ternata.

[0119] Process 7.3, Wet grinding;

[0120] The prepared Pinellia ternata and ginger were added to 14.5L of 60% ethanol aqueous solution and wet-crushed using a high-speed shear mill. During the wet-crushing process, the temperature of the 60% ethanol aqueous solution was controlled at 45-50℃ to obtain a solid-liquid mixture.

[0121] Process 7.4, solid-liquid separation;

[0122] The solid-liquid mixture obtained from wet pulverization in process 7.3 was separated by centrifugation. The filtrate was collected to obtain 11.5 L of filtrate (III), and the residue was discarded.

[0123] Step 8: Preparation of licorice extract; proceed as follows:

[0124] Step 8.1: Take 122g of licorice extract and crush it;

[0125] Step 8.2: Melting with hot water;

[0126] Add the licorice extract obtained from step 8.1 to a warm bath, add 122ml of water to dissolve it; maintain the temperature of the warm bath at 60-65℃ to obtain 244g of licorice extract solution.

[0127] Step 8.3: Alcohol precipitation;

[0128] Add 244g of the licorice extract solution dissolved in hot water as described in step 8.2 to 503.5ml of 95% ethanol to prepare an alcohol precipitation solution with 60% ethanol content. Let the solution stand for 24 hours at a controlled temperature of 7°C. Collect the supernatant and discard the precipitate. Obtain 215ml of licorice supernatant (IV).

[0129] Step 9: Concentrate the filtrate (I) and collect the volatile oil simultaneously;

[0130] The filtrate (I) was concentrated and the volatile oil was collected simultaneously. The evaporation and concentration were carried out using a scraped film evaporator. During the evaporation and concentration process, the volatile oil and extract were collected simultaneously. The volatile oil was collected, the extract was concentrated, and 75 ml of volatile oil (a) and 415 g of extract (a) were obtained. The density of extract (a) was 1.0.

[0131] Step 10: Concentrate the filtrate (II);

[0132] The filtrate (II) is concentrated by evaporation using a scraped film evaporator, during which ethanol is recovered and the extract is collected simultaneously. The filtrate (II) is concentrated according to step nine to obtain 135g of extract (B) with a density of 1.0.

[0133] Step 11: Concentrate the filtrate (III) and collect the volatile oil simultaneously;

[0134] The filtrate IV was concentrated and the volatile oil was collected simultaneously. The evaporation and concentration were carried out using a scraped film evaporator. During the evaporation and concentration process, the volatile oil and extract were collected simultaneously. Step eleven was carried out in accordance with step nine. 90g of extract (C) was obtained with a density of 1.0. 6ml of volatile oil (b) was obtained.

[0135] Step 12: Alcohol precipitation of the extract;

[0136] The extract was precipitated with alcohol by combining 415g of extract (A), 135g of extract (B), and 90g of extract (C), adding 1320ml of 95% ethanol to dissolve and dilute, stirring thoroughly, and letting stand to allow the portion insoluble in the ethanol solution to precipitate.

[0137] The addition of ethanol refers to combining concentrated extract (A) and concentrated extract (B) and then mixing them with ethanol to form an ethanol mixture containing 60% ethanol.

[0138] After thorough stirring, let stand; cool down; keep the temperature of the ethanol mixture constant at 5-7℃ for 24 hours. After standing for 24 hours, collect the supernatant and the precipitate separately; obtain 1360ml of supernatant (VI) and 600ml of precipitate (D).

[0139] Step 13: Polysaccharide separation;

[0140] Dissolve 600 ml of precipitate (D) in 1200 ml of 75℃ hot water, stir thoroughly, and filter using a 100 kDa ultrafiltration membrane. Maintain the filtration temperature at 60℃~65℃ to remove molecules with molecular weight >10×10⁻⁶. 4 Impurities; polysaccharide ultrafiltrate (VI) 830ml;

[0141] Step 14: Vacuum dehydration and drying;

[0142] The dehydration and drying process involved combining 215 ml of licorice supernatant (IV), 1360 ml of supernatant (V), and 830 ml of polysaccharide ultrafiltrate (VI) and dehydrating them using a vacuum dryer. The vacuum dryer was operated at a temperature of 55–60°C and a vacuum pressure of 1000–1100 Pa until the moisture content was ≤3%. 2210 g of extracts (A1) from Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, Areca catechu peel, Pinellia ternata, and licorice were collected.

[0143] Step 15: Dry granulation;

[0144] The dry granulation process involves granulating the solid-phase extract (A1) using a dry granulation machine, resulting in an average particle size of 1-1.5 mm for the powder extract (A1), thus yielding 2210 g of granules (A2).

[0145] Step 16: Freeze and allow to stand to dehydrate the volatile oils;

[0146] The aforementioned dehydration of frozen volatile oil involves combining 75 ml of collected volatile oil (a) and 6 ml of volatile oil (b) into a glass tube container, placing it in a refrigerator for 24 hours at a temperature controlled between 3.5°C and 4.5°C. As the water density in the volatile oil reaches its maximum, the viscosity of the volatile oil increases with decreasing temperature, causing it to aggregate and float, while the water sinks, forming stratification. The floating volatile oil is then suctioned out using a suction device to obtain 23 ml of anhydrous volatile oil (C).

[0147] Step 17: Mix the liquids;

[0148] The liquid-liquid mixture is prepared by mixing 9.75 ml of patchouli oil, 4.9 ml of perilla leaf oil, and 23 ml of anhydrous volatile oil (C) evenly to obtain 37.65 ml of mixed volatile oil (D).

[0149] Step 18; Liquid-solid mixing via atomization;

[0150] The atomization liquid-solid mixing method involves uniformly mixing 2210g of granules (A2) with mixed volatile oil (D), and then atomizing 37.65ml of mixed volatile oil (D) into the solid extract (A2) using an atomizer to obtain 2255 granules (A3) containing volatile oil.

[0151] Step 19; Fill with enteric-coated soft capsules;

[0152] The aforementioned enteric-coated soft capsules are made by filling granules (A3) into enteric-coated soft capsules using a soft capsule machine, resulting in 5000 enteric-coated Huoxiang Zhengqi soft capsules, each weighing 0.45g.

Claims

1. An enteric-coated Huoxiang Zhengqi soft capsule, characterized in that: Including Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, Areca catechu peel, Pinellia ternata extract, Glycyrrhiza uralensis extract, Patchouli oil, Perilla frutescens leaf oil, and enteric-coated soft capsule shell material; The enteric-coated soft capsule shell material comprises gelatin, glycerin, and distilled water; wherein gelatin is a film-forming agent, glycerin is a plasticizer, and distilled water is a solvent, and the composition ratio of gelatin, glycerin, and distilled water is: gelatin: glycerin: distilled water = 2:1:

2.

2. A method for preparing enteric-coated Huoxiang Zhengqi soft capsules, characterized in that: Follow these steps; Step 1: Chop the medicinal slices: Chop the Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, and Areca catechu peel; chop the medicinal slices of different shapes and sizes into particles ≤3mm. So that it can be soaked and swollen and then wet-processed and pulverized in the downstream steps; Step 2, Soaking and Swelling: Soak the chopped medicinal slices in water with a solid-liquid mass ratio of 1:10, control the water temperature at 20-25℃, and soak for 24 hours to allow the chopped medicinal slices to fully swell, resulting in a swelled granule mixture. Step 3, wet pulverization; The swollen mixture completed in step 2 is wet pulverized using a high-speed shear machine. In the wet pulverization process of the high-speed shear machine, the soaked and swollen medicinal slices are broken. During the wet pulverization process, the plant tissue is squeezed and deformed, and the high-speed shearing breaks the cells, so that the soluble substances inside and between the cells, including volatile oils, are fully dissolved in the clear water solution. During the wet pulverization process, the temperature of the clear water solution is controlled at 45-50℃ to obtain a solid-liquid mixture (1). Step 4: Solid-liquid separation; the solid-liquid mixture (1) obtained by wet pulverization in step 3 is separated by using either a plate and frame filter or a centrifuge to collect the filtrate (I); the dregs are collected to obtain liquid-containing dregs (Is); Step 5: Secondary wet pulverization. The liquid-containing medicinal residue (Is) is pulverized twice using a wet method. Specifically, the liquid-containing medicinal residue (Is) is added to a 60% ethanol aqueous solution at a mass ratio of 1:3, and then pulverized twice using the wet pulverization method of Step 3 to obtain a solid-liquid mixture (2). Step 6: Solid-liquid separation. The solid-liquid mixture (2) obtained from the second wet pulverization in step 5 is separated by using either a plate and frame filter or a centrifuge to collect the filtrate, which is filtrate (II). The residue is discarded. Step 7: Processing and extraction of raw Pinellia ternata, following the procedure below: Step 7.1: Soak in alum water; Soak raw Pinellia ternata in 8% alum water for 24 hours at a temperature of 25-30°C. The ratio of raw Pinellia ternata to 8% alum water is 1:1.7 (solid-liquid mass ratio). After soaking for 24 hours, discard the alum water, collect the soaked raw Pinellia ternata, rinse with purified water and filter dry to obtain purified Pinellia ternata. Step 7.2: Prepare ginger; Mix Pinellia ternata with fresh ginger, with a mass ratio of 1:0.

25. Process 7.3, Wet grinding; The prepared Pinellia ternata and ginger were added to a 60% ethanol aqueous solution at a solid-liquid mass ratio of 1:

10. The mixture was then wet-crushed using a high-speed shearing machine. During the wet-crushing process, the prepared Pinellia ternata and ginger were crushed. The plant tissues were compressed and deformed during the wet-crushing process, and the cells were broken, so that the soluble substances inside and between the cells were fully dissolved in the 60% ethanol aqueous solution. The temperature of the 60% ethanol aqueous solution was controlled to be ≤50℃ during the wet-crushing process. Process 7.4, solid-liquid separation; The solid-liquid mixture obtained from wet pulverization in process 7.3 is separated by centrifugation. The filtrate is collected to obtain filtrate (III), and the residue is discarded. Step 8: Preparation of licorice extract; Follow these steps: Step 8.1: Take the licorice extract and crush it; Step 8.2: Melting with hot water; Add the crushed licorice extract from step 8.1 into a warm bath and dissolve it with water at a ratio of 1:1 (by mass). Control the temperature of the warm bath at 60-65℃ to dissolve the crushed licorice extract and obtain a licorice extract solution. Step 8.3: Alcohol precipitation; Add ethanol to the licorice extract solution dissolved in hot water in step 8.2 to prepare an alcohol precipitation solution containing 60% ethanol. Let it stand for 24 hours at a controlled temperature of 7°C. Collect the supernatant and discard the precipitate to obtain licorice supernatant (IV). Step 9: Concentrate the filtrate (I) and collect the volatile oil simultaneously; The filtrate (I) is concentrated, and volatile oil is collected simultaneously. A scraped-film evaporator is used for evaporation and concentration, during which volatile oil and extract are collected simultaneously. The scraper rotates and scrapes the wall, evenly distributing the filtrate (I) on the heat transfer wall of the evaporator. The rotating scraping motion ensures that the heat transfer surface of the concentration tank is constantly renewed, preventing material from adhering to the heat transfer wall surface for too long, thus avoiding drying and sticking. The heat transfer wall of the evaporator maintains a high heat transfer coefficient and evaporation intensity. The short residence time of the liquid on the heat transfer wall prevents heat-sensitive components from being damaged by prolonged heating. The scraped film evaporator includes a condenser; the condenser collects the vapor evaporated by the scraped film evaporator, the evaporated vapor including water vapor and volatile oil; the collected water vapor is condensed into liquid water, and the collected volatile oil vapor is condensed into liquid oil. The two different substances are separated due to their different specific gravities and physical properties. The volatile oil is collected, and the liquid water is discarded, resulting in concentrated extract (A) and volatile oil (a). Step 10: Concentrate the filtrate (II); The filtrate (II) is concentrated by evaporation using a scraped film evaporator. During the evaporation and concentration process, ethanol is recovered and the extract is collected simultaneously. The filtrate (II) is concentrated according to step nine to obtain concentrated extract (II), and ethanol is recovered. Step 11: Concentrate the filtrate (III) and collect the volatile oil simultaneously; The filtration (III) is concentrated and the volatile oil is collected simultaneously. The evaporation and concentration are carried out using a scraped film evaporator. During the evaporation and concentration process, the volatile oil and extract are collected simultaneously. Step eleven is the same as step nine. A concentrated extract (C) and a volatile oil (B) are obtained. Step 12: Alcohol precipitation of the extract; The concentrated extract is precipitated by alcohol by combining concentrated extract (A), concentrated extract (B), and concentrated extract (C), adding ethanol to dissolve and dilute, stirring thoroughly, cooling, and allowing to stand, so that the portion insoluble in the ethanol solution precipitates. The addition of ethanol refers to combining concentrated extract (A), concentrated extract (B), and concentrated extract (C) and then mixing them with ethanol to form an ethanol mixture containing 60% ethanol. The aforementioned thorough stirring is achieved by using an alcohol precipitation tank with a stirring function, and by using the stirring mechanism of the alcohol precipitation tank to stir at a uniform speed. The so-called settling refers to cooling the thoroughly stirred ethanol mixture after it has been fully stirred and then allowing it to stand. The aforementioned cooling and standing process; The temperature of the ethanol mixture was kept constant at 5-7°C and allowed to stand for 24 hours. After standing for 24 hours, the supernatant and the precipitate were collected separately to obtain the supernatant (V) and the precipitate (D). Step 13: Polysaccharide separation; The polysaccharide separation process involves dissolving the precipitate (D) in hot water at a volume ratio of 1:2 (precipitate (D): hot water) at 75°C, stirring thoroughly, and then filtering using a 100kDa ultrafiltration membrane at a temperature maintained between 60°C and 65°C. This process removes polysaccharides with molecular weights >10×10⁻⁶. 4 Impurities; polysaccharide ultrafiltrate (VI); Step Fourteen: Vacuum dehydration and drying; The dehydration and drying process involves combining the licorice supernatant (IV), supernatant (V), and polysaccharide ultrafiltrate (VI) and dehydrating them using a vacuum dryer. The vacuum dryer is configured with a drying temperature of 55–60°C and a vacuum pressure of 1000–1100 Pa. The product is dried until the moisture content is ≤3%. Extracts from Atractylodes lancea, Citrus reticulata peel, Magnolia officinalis (processed with ginger), Angelica dahurica, Poria cocos, Areca catechu peel, Pinellia ternata, and licorice are collected to obtain a powder extract (A1). Step 15: Dry granulation; The dry granulation process involves granulating the powder extract (A1) using a dry granulation machine, resulting in an average particle size of 1–1.5 mm to obtain granules (A2). The dry granulation process eliminates the need for excipients, and the average particle size of 1–1.5 mm is beneficial for the processability of the filled capsules, giving the granules (A2) better flowability. The more uniform distribution of the granules (A2) also allows for a more consistent density in the filled capsules. Step 16: Freeze and allow to stand to dehydrate the volatile oils; The aforementioned frozen static volatile oil dehydration involves combining the collected volatile oils (a) and (b) and injecting them into a glass tube container, which is then placed in a refrigerator for 24 hours with the temperature controlled between 3.5℃ and 4.5℃. During this process, the density of some water in the volatile oil reaches its maximum value. As the temperature decreases, the viscosity of the volatile oil increases, causing it to aggregate and float to the surface, while the water settles, resulting in water-oil stratification. The volatile oil that floats to the surface is sucked out using a suction device to obtain anhydrous volatile oil (C); Step 17: Mix the liquids; The liquid-liquid mixture is prepared by mixing patchouli oil, perilla leaf oil, and anhydrous volatile oil (C) evenly to obtain mixed volatile oil (D); Step 18; Liquid-solid mixing via atomization; The aforementioned atomization liquid-solid mixing method involves uniformly mixing granular material (A2) with mixed volatile oil (D); using an atomizer to atomize and spray the mixed volatile oil (D) into the granular material (A2) to obtain granular material (A3) containing volatile oil. Step 19; Fill with enteric-coated soft capsules; The aforementioned enteric-coated soft capsules are made by filling the enteric-coated soft capsule shell with volatile oil-containing granules (A3) using a soft capsule machine to obtain enteric-coated Huoxiang Zhengqi soft capsules.

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