A traditional Chinese medicine composition for treating cholelithiasis and its preparation method and application

Abstract

This invention relates to a choleretic traditional Chinese medicine composition, its preparation method, and its application, belonging to the field of traditional Chinese medicine preparation technology. The microcapsules prepared from this choleretic traditional Chinese medicine composition consist of a core and a coating. The core contains a traditional Chinese medicine extract, pregelatinized starch, sodium alginate, and croscarmellose sodium. The coating contains hydroxypropyl cellulose and hydroxypropyl methylcellulose E5, PEG4000, and talc. The traditional Chinese medicine extract is made from Artemisia capillaris, Lysimachia christinae, Rheum palmatum, Scutellaria baicalensis, Taraxacum mongolicum, Forsythia suspensa, Curcuma longa, Curcuma longa, Bupleurum chinense, Citrus aurantium, and Aucklandia lappa. This choleretic traditional Chinese medicine composition has the effects of promoting bile flow and expelling gallstones, detoxifying and reducing swelling, with a stable drug release rate, definite efficacy, and few toxic side effects. It can be used for the prevention and / or treatment of acute and chronic gallstones and / or cholecystitis.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparations, and in particular to a choleretic traditional Chinese medicine composition, its preparation method, and its application. Background Technology

[0002] Acute and chronic cholelithiasis refers to the sudden obstruction of the cystic duct by gallstones, leading to impaired bile drainage, accompanied by gallbladder smooth muscle spasm and acute inflammatory response. Chronic cholelithiasis refers to the long-term presence of gallstones in the gallbladder, without complete obstruction of the cystic duct or with repeated relief of obstruction, resulting in a course of disease exceeding 3 months. Cholecystitis is an inflammatory disease of the gallbladder caused by bacterial infection, bile stasis, and other factors. All of these diseases involve abnormal bile metabolism and are caused by bile stasis resulting from cystic duct obstruction. Gallstones are the most significant causative factor of cholecystitis. With improved living standards, an increased proportion of high-fat and high-sugar diets, and sedentary lifestyles, the proportion of patients with acute and chronic cholelithiasis and cholecystitis in my country continues to rise, becoming one of the most common acute abdominal conditions in clinical practice.

[0003] Currently, medications used to treat acute and chronic gallstones and cholecystitis include piperacillin-tazobactam, ceftriaxone, cefotaxime, ciprofloxacin, levofloxacin, metronidazole, ornidazole, imipenem, meropenem, anisodamine, compound azithromycin enteric-coated tablets, pinaverium bromide, otelidum bromide, omeprazole, etc. However, these Western medicines have significant side effects, which can cause adverse reactions such as dry mouth, rapid heart rate, dizziness, nausea, diarrhea, rash, headache, constipation, and hair loss.

[0004] Traditional Chinese medicine (TCM) considers acute gallstones (or acute attacks of cholelithiasis) to fall under the categories of "hypochondriac pain," "jaundice," and "abdominal distension." Its core pathogenesis lies in stagnation of liver and gallbladder qi and accumulation of damp-heat, leading to impaired bile drainage. Prolonged stagnation generates heat, which scorches the bile, eventually causing it to solidify into stones. These stones obstruct the bile duct, triggering severe acute symptoms. TCM descriptions of acute gallstones focus on two core pathogenesis factors: "stagnation of liver and gallbladder qi" and "accumulation of damp-heat," and the resulting pathological changes of "bile duct obstruction, causing pain due to obstruction." Acute attacks manifest as four main symptom clusters: "hypochondriac pain, nausea and vomiting, abdominal pain, and jaundice (as stated in *Jinkui Yaolue*: "The course of jaundice is eighteen days."). Differential diagnosis can be made based on the nature of the pathogenic factors (qi stagnation, damp-heat, or heat toxicity). Acute gallstones often result from emotional imbalance and improper diet, leading to liver qi stagnation and heat, which scorches the liver and gallbladder, eventually forming stones. Gallstones obstructing the bile duct can cause severe acute symptoms. Treatment emphasizes clearing, dredging, promoting circulation, and unblocking.

[0005] The formation of chronic gallstones is closely related to liver and gallbladder dysfunction, internal damp-heat, and qi stagnation and blood stasis. It falls under the categories of "hypochondriac pain," "abdominal distension," "jaundice," and "anorexia." The etiology and pathogenesis are related to dietary imbalances. The *Shang Han Lun* states, "If there is fullness and hard pain below the heart, this is chest obstruction." Emotional distress or infestation by maggots can disrupt the flow of qi in the liver and gallbladder, leading to liver dysfunction, which in turn generates heat over time. This damp-heat accumulates in the liver and gallbladder, and the heat and toxins combine with bile, eventually forming stones that obstruct the bile duct and cause fullness. Traditional Chinese medicine treats "acute cases by addressing the symptoms, and chronic cases by addressing the root cause." The principle of treating chronic gallstones is to promote bile flow, remove stones, detoxify, and eliminate carbuncles, thus fundamentally eliminating the disease. The onset of chronic gallstones is often due to emotional imbalance and improper diet, leading to liver stagnation and heat, which then stagnates the liver and gallbladder, eventually forming stones. Furthermore, emotional depression can disrupt the smooth flow of liver qi, leading to qi stagnation, impaired bile secretion, and the formation of gallstones. This obstruction of the gallbladder meridians causes pain, resulting in hypochondriac pain. The disease is believed to originate in the liver and gallbladder, primarily due to damp-heat in the liver and gallbladder. Therefore, the treatment principle focuses on promoting bile flow, expelling stones, detoxifying, and reducing swelling.

[0006] Cholecystitis is located in the gallbladder, but involves the liver and spleen / stomach. Due to dietary imbalances and emotional disturbances, damp-heat remains, leading to stagnation of liver qi, impaired qi flow in the gallbladder, blood stasis, and damp-heat accumulation. This affects the spleen and stomach's digestive function, resulting in recurrent symptoms such as right hypochondriac fullness and pain, poor appetite, and abdominal distension. Based on its etiology and pathogenesis, clinical experience suggests that the treatment principle for damp-heat syndrome of the liver and gallbladder should be to promote bile secretion and expel stones. Its main manifestations include chest and hypochondriac fullness, bloating, nausea, bitter taste in the mouth, poor appetite, alternating constipation and loose stools, and dull pain in the right upper abdomen. These symptoms often fluctuate with emotional changes.

[0007] In summary, the treatment principle for acute and chronic gallstones and cholecystitis should focus on promoting bile flow and expelling stones, as well as detoxifying and reducing swelling. Currently, there are many related traditional Chinese medicine products, such as Xiaoyan Lidan tablets, Jindan tablets, Danning tablets, Dankang capsules, Shudan tablets, Longdan Xiegan pills, Danshitong capsules, Fufang Dantong tablets, Jinqiancao granules, Lidan Zhitong tablets, Danle capsules, Danshu soft capsules, Shugan Yipi capsules, Danweikang capsules, Dahuang Lidan capsules, and Yidan Shu capsules, etc. However, their efficacies differ, and some medications are inconvenient to take, have poor stability, or unpleasant taste, leading to poor patient compliance.

[0008] Therefore, there is still a need to develop other safe, effective, and convenient traditional Chinese medicine preparations that have no adverse reactions. Summary of the Invention

[0009] To address the technical problems in the prior art, this invention provides a choleretic traditional Chinese medicine composition, its preparation method, and its application. The choleretic traditional Chinese medicine composition utilizes a rationally formulated blend of herbs that synergistically promote bile flow, expel gallstones, detoxify, and reduce swelling. The microcapsules prepared by extracting the raw materials using a suitable process and adding specific pharmaceutically acceptable excipients have the advantages of stable drug release rate, definite efficacy, few toxic side effects, and good safety. They can be used for the prevention and / or treatment of acute and chronic gallstones and / or cholecystitis.

[0010] Specifically, the present invention is achieved through the following aspects.

[0011] In a first aspect of the present invention, a choleretic traditional Chinese medicine composition is provided, wherein the microcapsules prepared from the choleretic traditional Chinese medicine composition consist of a core and a coating, wherein the core comprises 40wt% to 60wt% of a traditional Chinese medicine extract, 25wt% to 35wt% of pregelatinized starch, 2wt% to 5.5wt% of sodium alginate and 3wt% to 10wt% of croscarmellose sodium, and the coating comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose E5, PEG4000 and talc in a mass ratio of 1:(0.8 to 2.2):(0.3 to 0.6):(0.9 to 1.2).

[0012] The herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 120-180 parts, Lysimachia christinae 120-180 parts, Rheum palmatum 50-120 parts, Scutellaria baicalensis 50-120 parts, Taraxacum mongolicum 120-180 parts, Forsythia suspensa 50-120 parts, Curcuma longa 50-120 parts, Curcuma longa 50-120 parts, Bupleurum chinense 30-75 parts, Citrus aurantium 30-75 parts, and Aucklandia lappa 50-120 parts.

[0013] The sources and efficacy of the traditional Chinese medicine raw materials in this invention are as follows:

[0014] (1) Artemisia capillaris

[0015] This product is the dried aerial part of *Artemisia capillaris* Thunb., a plant belonging to the Asteraceae family. It is harvested in spring when the seedlings are 6-10 cm tall, impurities and old stems are removed, and then it is sun-dried. Origin: Sichuan Province. Chemical components include coumarins, flavonoids, organic acids, and volatile oils. It possesses choleretic, antipyretic, hepatoprotective, lipid-lowering, blood pressure-lowering, antiasthmatic, antibacterial, antiviral, diuretic, anticancer, analgesic, anti-caries, and anti-inflammatory effects, and has an inhibitory effect on hepatitis viruses.

[0016] (2) Moneywort

[0017] This product is the dried whole herb of *Lysimachia christinae* Hance, a plant in the Primulaceae family. It is harvested in summer and autumn, impurities are removed, and it is sun-dried. Origin: Guangxi. Chemical components include flavonoids, phenolic acids, volatile compounds, saponins, and sugars. It has the effects of clearing heat and detoxifying, promoting diuresis and expelling stones, and promoting blood circulation and removing blood stasis. It can be used to treat intrahepatic bile duct stones, gallstones, cholecystitis, urinary system stones, jaundice hepatitis, edema, traumatic injuries, burns, snake bites, and other conditions. Modern medical research shows that *Lysimachia christinae* has various pharmacological effects, including choleretic, diuretic, anti-inflammatory, analgesic, and stone-expelling properties.

[0018] (3) Rhubarb

[0019] This product is the dried root and rhizome of *Rheum palmatum* L., a plant belonging to the Polygonaceae family. It is harvested in late autumn before the stems and leaves wither. Fine roots are removed, the outer skin is scraped off, and the roots are cut into segments or sections and dried directly. Origin: Sichuan Province. Chemical components include anthracene derivatives, glycosides, tannins, organic acids, volatile oils, fatty acids, and phytosterols. It possesses laxative, antibacterial, hemostatic, choleretic, and therapeutic effects on chronic renal insufficiency, uremia, choleretic, anti-inflammatory, analgesic, psychotropic, immune-enhancing, antitumor, and renal failure-delaying properties.

[0020] (4) Scutellaria baicalensis

[0021] This product is the dried root of *Scutellaria baicalensis* Georgi, a plant belonging to the Lamiaceae family. It is harvested in spring and autumn, with the fibrous roots and soil removed, then sun-dried, the outer bark is removed by pounding, and finally dried completely. Origin: Shanxi Province. It contains various flavonoids, mainly baicalin, baicalein, wogonin, baicalein I, baicalein II, norwogonin, 7-methoxybaicalein, and 7-methoxydemethylwogonin. It also contains volatile oils and phenylethyl glycosides. It possesses significant anti-inflammatory, antibacterial, antioxidant, and antitumor effects.

[0022] (5) Dandelion

[0023] This product is the dried whole herb of *Taraxacum mongolicum* Hand.–Mazz., a plant belonging to the Asteraceae family. It is harvested from spring to autumn when the flowers are just beginning to bloom, impurities are removed, it is washed, and then sun-dried. Origin: Hebei Province. It contains various chemical components, mainly flavonoids, terpenes, phenolic acids, dandelion pigments, phytosterols, sesquiterpene lactones, and coumarins. It possesses excellent broad-spectrum antibacterial, anti-free radical, antiviral, anti-infective, antitumor, anticoagulant, and immune-enhancing pharmacological effects.

[0024] (6) Forsythia

[0025] This product is the dried fruit of *Forsythia suspensa* (Thunb.) Vahl, a plant belonging to the Oleaceae family. It is harvested in autumn when the fruit is still green and just beginning to ripen. Impurities are removed, the fruit is steamed, and then sun-dried. Origin: Shanxi Province. Its chemical composition is complex and diverse, primarily consisting of phenylethanol and its glycosides, C6-C2 natural alcohols, lignans, as well as flavonoids, pentacyclic triterpenoids, alkaloids, volatile oils, and trace elements. Modern pharmacological studies have shown that *Forsythia suspensa* possesses broad-spectrum antimicrobial activity, anti-inflammatory, antipyretic, antiemetic, diuretic, cardiotonic, hepatotoxic, analgesic, anti-endotoxin, and antioxidant effects.

[0026] (7) Turmeric

[0027] This product is the dried tuberous root of *Curcuma wenyujin* Y.H.Chen et C.Ling, a plant belonging to the ginger family. It is harvested in winter after the stems and leaves wither, and the soil and fine roots are removed. It is then steamed until thoroughly cooked and dried. Origin: Guangxi. Chemical components include: curcuminoids, volatile oil, polysaccharides, trace elements, starch, fatty oil, yellow dye, β-sitosterol, alkaloids, 6-Methyl-7-(3-oxobutyl)-bicyclo[4.1.0]heptan-3-one, ferulic acid, and ferulic acid ethanol, etc. It has the effects of promoting blood circulation and removing blood stasis, clearing the heart and relieving depression, regulating qi and relieving pain, promoting bile secretion and reducing jaundice, protecting the liver, promoting bile secretion and excretion, lowering blood lipids, inhibiting the central nervous system, affecting the digestive system, and anti-tumor effects.

[0028] (8) Turmeric

[0029] This product is the dried rhizome of Curcuma Longa L., a plant belonging to the ginger family. It is harvested in winter when the stems and leaves wither, washed, boiled until thoroughly cooked, sun-dried, and the fibrous roots removed. Origin: Sichuan Province. Chemical components include: curcumin, demethoxycurcumin, dedimethoxycurcumin, hexahydrocurcumin, polysaccharides, sesquiterpenes, and phenolic sesquiterpenes. It possesses hepatoprotective, choleretic, antibacterial, anti-inflammatory, antitumor, anti-AIDS, antifertility, lipid-lowering, antimicrobial and antiprotozoal, wound-healing, and anti-mutagenic effects.

[0030] (9) Bupleurum

[0031] This product is the dried root of *Bupleurum chinense* DC., a plant belonging to the Apiaceae family. It is harvested in spring and autumn, with stems, leaves, and soil removed before drying. Origin: Shanxi Province. Chemical components include: saikosaponins, volatile oils, polysaccharides, polyacetylenes, lignans, flavonoids, fatty acids, sterols, coumarins, and alkaloids, among other active ingredients. It possesses anti-inflammatory, antipyretic, sedative, analgesic, antitussive, anticonvulsant, liver-damaging, bile-promoting, blood pressure-lowering, serum cholesterol-lowering, hemolytic, anti-ulcer, antibacterial, antiviral, antitumor, blood glucose-raising, blood lipid-lowering, and radiation-damage-resistant effects.

[0032] (10) Fructus Aurantii Immaturus

[0033] This product is the dried, immature fruit of *Citrus aurantium* L. (Rutaceae family) and its cultivated varieties. Harvested in July when the peel is still green, it is cut in half horizontally from the middle and sun-dried. Origin: Jiangxi Province. Chemical components include volatile oils, flavonoids, alkaloids, coumarins, and organic acids. It possesses various pharmacological effects, including regulating gastrointestinal motility, promoting bile flow and stone expulsion, raising blood pressure, anti-shock, anti-thrombotic, lipid-lowering, and anti-tumor effects. It shows great promise in the treatment of gastrointestinal diseases, gallstones, ureteral stones, cervical spondylosis, and lumbar disc herniation.

[0034] (11) Costus root

[0035] This product is the dried root of *Aucklandia lappa* Decne., a plant in the Asteraceae family. It is harvested in autumn and winter, and the soil and fibrous roots are removed. The roots are cut into sections, and larger roots are further split longitudinally. After drying, the outer bark is removed. Origin: Yunnan Province. Chemical components include: costunolactone, dihydrocostunolactone, saponin, costane lactone, and dihydrocostane lactone, etc. It has the functions of promoting qi circulation and relieving pain, strengthening the spleen and promoting digestion. It is used to treat symptoms such as chest and rib pain, abdominal distension and pain, diarrhea, tenesmus, indigestion, loss of appetite, and other symptoms. *Aucklandia lappa* contains various aromatic volatile oils, which have the effects of promoting qi circulation and relieving pain, warming the middle and harmonizing the stomach, relieving spasms and lowering blood pressure, and antibacterial properties. It can also be used to dispel dampness, eliminate phlegm, and detoxify.

[0036] The herbal composition of this invention consists of eleven herbs: Artemisia capillaris, Lysimachia christinae, Rheum palmatum, Scutellaria baicalensis, Taraxacum mongolicum, Forsythia suspensa, Curcuma longa, Curcuma longa, Bupleurum chinense, Citrus aurantium, and Aucklandia lappa. It has the functions of promoting bile secretion and expelling gallstones, detoxifying and reducing swelling. It is used for right upper quadrant abdominal pain, dull pain, colic, nausea, vomiting, fever, jaundice, abdominal distension, diarrhea, and anorexia caused by damp-heat in the liver and gallbladder; and for acute and chronic gallstones and cholecystitis with the above symptoms.

[0037] Preferably, the herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 140-165 parts, Lysimachia christinae 140-165 parts, Rheum palmatum 65-90 parts, Scutellaria baicalensis 65-90 parts, Taraxacum mongolicum 140-165 parts, Forsythia suspensa 65-90 parts, Curcuma longa 65-90 parts, Curcuma longa 65-90 parts, Bupleurum chinense 45-65 parts, Citrus aurantium 45-65 parts, and Aucklandia lappa 65-90 parts.

[0038] More preferably, the herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 155.6 parts, Lysimachia christinae 155.6 parts, Rheum palmatum 77.8 parts, Scutellaria baicalensis 77.8 parts, Taraxacum mongolicum 155.6 parts, Forsythia suspensa 77.8 parts, Curcuma longa 77.8 parts, Curcuma longa 77.8 parts, Bupleurum chinense 55.6 parts, Citrus aurantium 55.6 parts, and Aucklandia lappa 77.8 parts.

[0039] Traditional Chinese medicine decoctions or compound preparations are bulky, unstable, have poor taste, and are difficult to carry and store. While granulation can improve some of these issues, the high hygroscopicity of Chinese medicine still presents stability problems, leading to unstable drug release. In contrast, microspheres made from choleretic Chinese medicine compositions have small and uniform particle sizes, resulting in a wider distribution area in the gastrointestinal tract and more complete drug dissolution and absorption. This effectively avoids absorption differences caused by uneven dissolution in granules and concentration fluctuations in compound preparations. Furthermore, the release rate of microspheres is more stable, resulting in significantly higher bioavailability than the aforementioned dosage forms.

[0040] However, in the traditional Chinese medicine composition of this invention, the volatile oil in Aucklandia lappa is sensitive to temperature, light, and oxygen, and is easily volatilized and oxidized upon heating, resulting in easy loss during extraction and storage. Furthermore, curcumin in Curcuma longa and Curcuma aromatica, as well as saponins and flavonoids in Bupleurum chinense and Citrus aurantium, are relatively sensitive to light, oxygen, or pH, thus placing demands on the extraction and preparation processes of the traditional Chinese medicine raw materials.

[0041] The herbal extract of the present invention is prepared by the following method: each herbal raw material is weighed according to the proportion and pulverized into powder; the volatile oil of Costus root is extracted by steam distillation and encapsulated with β-cyclodextrin to obtain a volatile oil inclusion complex; the remaining herbal raw materials are added with 60% to 75% ethanol and refluxed for 2 to 3 times, each time for 1 to 1.5 hours, the ethanol is recovered, and the extract is concentrated to a relative density of 1.20 to 1.30 at 60°C. The above volatile oil inclusion complexes are combined to obtain the final product.

[0042] The types and proportions of excipients in the pellet core formulation determine the sphericity, particle size distribution, and mechanical strength of the pellets. Improper proportions can lead to pellet breakage, adhesion, or uneven particle size, failing to meet the coating requirements for surface smoothness. Furthermore, for traditional Chinese medicine extracts, the use of pregelatinized starch can reduce the extract's viscosity and decrease component adsorption, facilitating the formulation process. Insufficient disintegrant in the pellet core will result in delayed disintegration, while excessive amounts may reduce the core's strength.

[0043] As a preferred technical solution, the core of the microcapsules of the present invention contains 42wt% to 50wt% of traditional Chinese medicine extract, 28wt% to 32wt% of pregelatinized starch, 3.5wt% to 5wt% of sodium alginate and 5wt% to 8wt% of cross-linked sodium carboxymethyl cellulose, and the coating contains hydroxypropyl cellulose and hydroxypropyl methyl cellulose E5 in a mass ratio of 1: (1.3 to 2.0).

[0044] In a second aspect of the present invention, a method for preparing the above-mentioned choleretic traditional Chinese medicine composition is provided, comprising the following steps:

[0045] (1) Weigh each Chinese herbal raw material according to the proportion and crush it into powder; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain the volatile oil inclusion complex; add 60% to 75% ethanol to the remaining Chinese herbs, reflux extract 2 to 3 times, 1 to 1.5 hours each time, recover the ethanol, concentrate it to an extract with a relative density of 1.20 to 1.30 at 60℃, combine the above volatile oil inclusion complexes to obtain the Chinese herbal extract;

[0046] (2) Add pregelatinized starch, sodium alginate and croscarmellose sodium cellulose to the Chinese herbal extract, use 30% to 40% ethanol solution to make soft material, extrude into strips, place in a rolling mill to roll into micro pellets, and dry to obtain pellet core;

[0047] (3) Dissolve hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in 50% ethanol solution, add PEG4000 and talc, stir well to obtain coating solution;

[0048] (4) Put the core pellets into the fluidized bed, adjust the air inlet temperature to 40℃~60℃, and spray the coating liquid through the spray gun to increase the weight by 2wt%~4wt%.

[0049] In step (1), it is preferable to pulverize the Chinese herbal raw materials to 20-40 mesh.

[0050] In step (1), the preferred mass ratio of volatile oil to β-cyclodextrin is 1:(6-9).

[0051] The preferred percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution is 4wt% to 6wt%.

[0052] In a third aspect of the invention, the use of the above-mentioned choleretic traditional Chinese medicine composition is also provided, namely, its use in the preparation of a medicament for treating acute and chronic gallstones and / or cholecystitis.

[0053] Compared with the prior art, the choleretic traditional Chinese medicine composition of the present invention has the following advantages:

[0054] (1) The traditional Chinese medicine composition of the present invention is reasonably formulated and works together to promote bile secretion, expel stones, detoxify and eliminate carbuncles. It can be used for right upper quadrant pain, dull pain, colic, nausea and vomiting, fever, jaundice, abdominal distension, diarrhea and anorexia caused by damp heat in the liver and gallbladder; and for acute and chronic gallstones and cholecystitis with the above symptoms.

[0055] (2) The microspheres prepared from the choleretic traditional Chinese medicine composition of the present invention have a particle size of 0.8-1.2 mm, good roundness, smooth surface, wide distribution area in the gastrointestinal tract, more complete drug dissolution and absorption, and disintegration time of 8-10 min. They can effectively avoid the absorption differences caused by uneven dissolution of granules and concentration fluctuations of compound preparations. The drug release rate of microspheres is more stable and the bioavailability is also significantly higher.

[0056] (3) The present invention is to extract Chinese herbal raw materials through a suitable process and add specific pharmaceutically acceptable excipients to make micro-pills. These micro-pills have the advantages of stable drug release rate, definite efficacy, few toxic side effects and good safety. They can be used for the prevention and / or treatment of acute and chronic gallstones and / or cholecystitis. Detailed Implementation

[0057] To make the technical solution and effects of the present invention clearer, this section provides a more detailed description of the technical solution of the present invention through the following specific embodiments. However, the specific embodiments described are only for explaining the present invention and should not be construed as limiting the scope of protection of the claims.

[0058] Example 1:

[0059] The formula of the choleretic Chinese herbal combination is as follows: Artemisia capillaris 155.6g, Lysimachia christinae 155.6g, Rheum palmatum 77.8g, Scutellaria baicalensis 77.8g, Taraxacum mongolicum 155.6g, Forsythia suspensa 77.8g, Curcuma longa 77.8g, Curcuma longa 77.8g, Bupleurum chinense 55.6g, Citrus aurantium 55.6g, and Aucklandia lappa 77.8g.

[0060] Preparation method: (1) Weigh each Chinese herbal raw material according to the proportion and pulverize it into powder of 40 mesh; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain volatile oil inclusion complex. The mass ratio of volatile oil to β-cyclodextrin is 1:8; add 70% ethanol to the remaining Chinese herbal raw materials and reflux extract three times, 1.5h each time, recover the ethanol, concentrate to an extract with a relative density of 1.21 at 60℃, combine the above volatile oil inclusion complex to obtain the Chinese herbal extract; (2) add 92.2g of pregelatinized starch, 13.1g of sodium alginate and 26.1g of cross-linked carboxymethyl cellulose to the Chinese herbal extract. Sodium carbonate was prepared using a 40% ethanol solution to form a soft material, which was then extruded into strips and rolled into microspheres in a spheronizing machine. The microspheres were then dried to obtain the core. (3) 1.9g of hydroxypropyl cellulose and 3.2g of hydroxypropyl methylcellulose E5 were dissolved in a 50% ethanol solution, and 0.6g of PEG4000 and 1.7g of talc were added and stirred to obtain a coating solution. The percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution was 4.5wt%. (4) The core was placed into a fluidized bed, and the air inlet temperature was adjusted to 50℃. The coating solution was sprayed into the fluidized bed through a spray gun to increase the weight by 3wt%.

[0061] Example 2:

[0062] The formula of the choleretic Chinese herbal combination is as follows: Artemisia capillaris 140g, Lysimachia christinae 140g, Rheum palmatum 80g, Scutellaria baicalensis 80g, Taraxacum mongolicum 140g, Forsythia suspensa 80g, Curcuma longa 80g, Curcuma longa 80g, Bupleurum chinense 50g, Citrus aurantium 50g, and Aucklandia lappa 80g.

[0063] Preparation method: (1) Weigh each Chinese herbal raw material according to the proportion and pulverize it into powder of 20 mesh; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain volatile oil inclusion complex. The mass ratio of volatile oil to β-cyclodextrin is 1:6; add 75% ethanol to the remaining Chinese herbs and reflux extract three times for 1.2h each time. Recover the ethanol and concentrate it to an extract with a relative density of 1.20 at 60℃. Combine the above volatile oil inclusion complex to obtain the Chinese herbal extract; (2) Add 88.5g of pregelatinized starch, 12.5g of sodium alginate and 25g of cross-linked carboxymethyl cellulose to the Chinese herbal extract. Sodium carbonate was prepared using a 30% ethanol solution to form a soft material, which was then extruded into strips and rolled into microspheres in a spheronizing machine. The microspheres were then dried to obtain the core. (3) 1.8g of hydroxypropyl cellulose and 2.8g of hydroxypropyl methylcellulose E5 were dissolved in a 50% ethanol solution, and 0.7g of PEG4000 and 1.5g of talc were added. The mixture was stirred to obtain a coating solution. The percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution was 4wt%. (4) The core was placed into a fluidized bed, and the air inlet temperature was adjusted to 40℃. The coating solution was sprayed into the fluidized bed through a spray gun to increase the weight by 2wt%.

[0064] Example 3:

[0065] The formula for a choleretic Chinese herbal combination is as follows: Artemisia capillaris 160g, Lysimachia christinae 160g, Rheum palmatum 65g, Scutellaria baicalensis 65g, Taraxacum mongolicum 160g, Forsythia suspensa 65g, Curcuma longa 65g, Curcuma longa 65g, Bupleurum chinense 65g, Citrus aurantium 65g, and Aucklandia lappa 65g.

[0066] Preparation method: (1) Weigh each Chinese herbal raw material according to the proportion and pulverize it into powder of 40 mesh; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain volatile oil inclusion complex. The mass ratio of volatile oil to β-cyclodextrin is 1:9; add 75% ethanol to the remaining Chinese herbal raw materials and reflux extract twice, 1.5h each time, recover the ethanol, concentrate to an extract with a relative density of 1.25 at 60℃, combine the above volatile oil inclusion complex to obtain the Chinese herbal extract; (2) add 90g of pregelatinized starch, 11.5g of sodium alginate and 24g of cross-linked carboxymethyl cellulose to the Chinese herbal extract. Sodium hydroxypropyl cellulose (SHC) was prepared using a 40% ethanol solution to form a soft material. It was then extruded into strips, rolled into microspheres in a spheroidizing machine, and dried to obtain the pellet core. (3) 1.8g of hydroxypropyl cellulose and 3g of hydroxypropyl methylcellulose E5 were dissolved in a 50% ethanol solution. 0.9g of PEG4000 and 1.5g of talc were added and stirred to obtain a coating solution. The percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution was 6wt%. (4) The pellet core was placed into a fluidized bed, the air inlet temperature was adjusted to 60℃, and the coating solution was sprayed into the fluidized bed through a spray gun to increase the weight by 4wt%.

[0067] Example 4:

[0068] The formula of the choleretic Chinese herbal combination is as follows: Artemisia capillaris 120g, Lysimachia christinae 120g, Rheum palmatum 90g, Scutellaria baicalensis 90g, Taraxacum mongolicum 120g, Forsythia suspensa 90g, Curcuma longa 90g, Curcuma longa 90g, Bupleurum chinense 30g, Citrus aurantium 30g, and Aucklandia lappa 90g.

[0069] Preparation method: (1) Weigh each Chinese herbal raw material according to the proportion and pulverize it into powder of 30 mesh; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain volatile oil inclusion complex. The mass ratio of volatile oil to β-cyclodextrin is 1:7; add 65% ethanol to the remaining Chinese herbs and reflux extract three times, 1 hour each time, recover the ethanol, concentrate to an extract with a relative density of 1.28 at 60℃, combine the above volatile oil inclusion complex to obtain the Chinese herbal extract; (2) add 84.7g of pregelatinized starch, 12g of sodium alginate and 25g of croscarmellose sodium to the Chinese herbal extract. , Use 35% ethanol solution to make soft material, extrude into strips, place in a rolling mill to roll into micro pellets, and dry to obtain pellet cores; (3) Dissolve 1.7g hydroxypropyl cellulose and 2.8g hydroxypropyl methylcellulose E5 in 50% ethanol solution, add 0.5g PEG4000 and 1.4g talc powder, stir well to obtain coating solution, the percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution is 6wt%; (4) Put the pellet core into a fluidized bed, adjust the air inlet temperature to 60℃, and spray the coating solution into the fluidized bed through a spray gun to increase the weight by 2wt%.

[0070] Comparative Example 1:

[0071] The formulation and preparation method are the same as in Example 1, except that sodium alginate is replaced with polyvinylpyrrolidone.

[0072] Comparative Example 2:

[0073] The formulation and preparation method are the same as in Example 1, except that cross-linked sodium carboxymethyl cellulose is replaced with cross-linked polyvinyl ketone.

[0074] Comparative Example 3:

[0075] The formulation and preparation method are the same as in Example 1, except that hydroxypropyl cellulose is replaced with acrylic resin IV.

[0076] Experimental Example 1:

[0077] This experiment investigated the changes in the formulation over time under the influence of temperature and humidity, providing a basis for the production, packaging, storage, and transportation of drugs.

[0078] (1) Accelerated testing

[0079] Cholagogue traditional Chinese medicine compositions were prepared according to the formulations and methods of Examples 1-4 and Comparative Examples 1-3. These compositions were packaged in simulated market packaging and placed in an accelerated chamber at a controlled temperature of 40℃±2℃ and a relative humidity of 75%±5%. Samples were taken periodically at 1 month, 2 months, 3 months, and 6 months for testing, and the results were compared with the data from the 0-month test. The experimental results are shown in Tables 1 and 2.

[0080] Table 1. Results of accelerated tests for each group

[0081]

[0082]

[0083] (2) Long-term experiment

[0084] Cholagogue traditional Chinese medicine compositions were prepared according to the formulations and methods of Examples 1-4 and Comparative Examples 1-3. These compositions were packaged in simulated market packaging and placed in an accelerated chamber at a controlled temperature of 25℃±2℃ and a relative humidity of 60%±5%. Samples were taken periodically at 3, 4, 9, and 12 months and compared with the data from the 0-month test. The experimental results are shown in Table 2.

[0085] Table 2. Results of long-term trials for each group

[0086]

[0087]

[0088] The results showed that the choleretic traditional Chinese medicine compositions of Examples 1-4 of this invention remained stable in both accelerated and long-term experiments. The microspheres exhibited good sphericity, smooth and non-adhesive surfaces, and stable disintegration time. In contrast, when the excipients in the choleretic traditional Chinese medicine compositions changed, the disintegration time was prolonged, and the microspheres showed adhesion or surface wrinkling during storage.

[0089] Experimental Example 2:

[0090] This experiment investigated the clinical pharmacodynamics of the traditional Chinese medicine used in this invention.

[0091] 1. Information on the test subjects

[0092] One hundred outpatients were selected and randomly divided into a treatment group and a control group using a random number table. The treatment group consisted of 51 patients, and the control group consisted of 49 patients. In the treatment group, there were 31 males and 20 females, with a mean age of 23–68 years and a mean disease duration of (39.4±10.3) years. In the control group, there were 28 males and 21 females, with a mean age of 18–66 years and a mean disease duration of (41.5±12.8) years.

[0093] 2. Diagnostic criteria

[0094] According to the consensus opinion on the diagnosis and treatment of cholelithiasis by integrated traditional Chinese and Western medicine (2017), the syndrome is liver qi stagnation.

[0095] Main symptoms: distending pain in the right hypochondrium, irritability and anger, which worsens with anger, and loss of appetite.

[0096] Secondary symptoms: bitter taste in the mouth, dry mouth, nausea and vomiting, constipation.

[0097] Tongue and pulse: The tongue is dark red with a white coating, and the pulse is wiry.

[0098] If two or more of the above primary symptoms and one or more secondary symptoms are met, the test will be included in the scope of the trial, based on the diagnosis of tongue and pulse.

[0099] 3. Treatment methods

[0100] Treatment group: Patients were given the choleretic traditional Chinese medicine composition of Example 1 of the present invention, 6g each time, twice a day.

[0101] Control group: Ursodeoxycholic acid tablets, dosage 10 mg / kg, once daily.

[0102] 4. Criteria for Evaluating Therapeutic Effect

[0103] Treatment efficacy was determined with reference to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs" and the "Consensus Opinions on the Diagnosis and Treatment of Cholelithiasis with Integrated Traditional Chinese and Western Medicine (2017)".

[0104] Cure: Clinical symptoms and signs disappear or basically disappear, imaging examinations such as color Doppler ultrasound show that the stones have disappeared, and the gallbladder or intrahepatic and extrahepatic bile ducts and common bile duct have returned to normal shape.

[0105] Significant effect: Clinical symptoms and signs are significantly improved, the diameter of the gallstones is reduced to more than 0.5 cm, or the dilation of intrahepatic and extrahepatic bile ducts and common bile duct is reduced compared with before.

[0106] Effective: Clinical symptoms and signs improved, and the diameter of the stones shrank to less than 0.5 cm.

[0107] Ineffective: Clinical symptoms and signs do not improve or even worsen, and the stones do not change significantly or increase in size.

[0108] 4. Test Results

[0109] The experimental data were analyzed using SPSS 20.0 statistical software. A p-value < 0.5 was considered statistically significant. The experimental results are shown in Tables 3 and 4.

[0110] Table 3. Clinical efficacy results of the treatment group and the control group.

[0111]

[0112] Table 4. Syndrome scores of the treatment group and the control group before and after treatment.

[0113]

[0114] The experimental results show that, compared with the control group, the choleretic traditional Chinese medicine composition of the present invention has better patient compliance and higher efficacy after administration. It has a significant effect on improving clinical symptoms such as right rib pain, nausea and vomiting, dry mouth and bitter taste, loss of appetite and constipation. No adverse reactions occurred during the treatment.

Claims

1. A choleretic traditional Chinese medicine composition, characterized in that, The microcapsules prepared from the choleretic traditional Chinese medicine composition consist of a core and a coating, wherein... The core of the pill contains 40wt%–60wt% of traditional Chinese medicine extract, 25wt%–35wt% of pregelatinized starch, 2wt%–5.5wt% of sodium alginate, and 3wt%–10wt% of croscarmellose sodium. The coating contains hydroxypropyl cellulose, hydroxypropyl methylcellulose E5, PEG4000, and talc in a mass ratio of 1:(0.8–2.2):(0.3–0.6):(0.9–1.2). The herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 120-180 parts, Lysimachia christinae 120-180 parts, Rheum palmatum 50-120 parts, Scutellaria baicalensis 50-120 parts, Taraxacum mongolicum 120-180 parts, Forsythia suspensa 50-120 parts, Curcuma longa 50-120 parts, Curcuma longa 50-120 parts, Bupleurum chinense 30-75 parts, Citrus aurantium 30-75 parts, and Aucklandia lappa 50-120 parts.

2. The choleretic traditional Chinese medicine composition as described in claim 1, characterized in that, The herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 140-165 parts, Lysimachia christinae 140-165 parts, Rheum palmatum 65-90 parts, Scutellaria baicalensis 65-90 parts, Taraxacum mongolicum 140-165 parts, Forsythia suspensa 65-90 parts, Curcuma longa 65-90 parts, Curcuma longa 65-90 parts, Bupleurum chinense 45-65 parts, Citrus aurantium 45-65 parts, and Aucklandia lappa 65-90 parts.

3. The choleretic traditional Chinese medicine composition as described in claim 1, characterized in that, The herbal extract is made from the following raw materials in parts by weight: Artemisia capillaris 155.6 parts, Lysimachia christinae 155.6 parts, Rheum palmatum 77.8 parts, Scutellaria baicalensis 77.8 parts, Taraxacum mongolicum 155.6 parts, Forsythia suspensa 77.8 parts, Curcuma longa 77.8 parts, Curcuma longa 77.8 parts, Bupleurum chinense 55.6 parts, Citrus aurantium 55.6 parts, and Aucklandia lappa 77.8 parts.

4. The choleretic traditional Chinese medicine composition according to any one of claims 1 to 3, characterized in that, The preparation method of the Chinese herbal extract is as follows: weigh each Chinese herbal raw material according to the proportion and crush it into powder; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain the volatile oil inclusion complex; The remaining Chinese herbal medicines were extracted with 60%–75% ethanol and refluxed 2–3 times, each time for 1–1.5 hours. The ethanol was recovered and the extract was concentrated to a relative density of 1.20–1.30 at 60°C. The above volatile oil inclusion complexes were then combined to obtain the final product.

5. The choleretic traditional Chinese medicine composition as described in claim 4, characterized in that, The core of the pill contains 42wt%–50wt% of Chinese herbal extract, 28wt%–32wt% of pregelatinized starch, 3.5wt%–5wt% of sodium alginate, and 5wt%–8wt% of croscarmellose sodium. The coating contains hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in a mass ratio of 1:(1.3–2.0).

6. A method for preparing a choleretic traditional Chinese medicine composition as described in any one of claims 1 to 5, characterized in that, The method includes the following steps: (1) Weigh each Chinese herbal raw material according to the proportion and crush it into powder; extract the volatile oil of Costus root by steam distillation and encapsulate it with β-cyclodextrin to obtain the volatile oil inclusion complex; The remaining Chinese herbal medicines were extracted with 60%–75% ethanol and refluxed 2–3 times, each time for 1–1.5 hours. The ethanol was recovered and the extract was concentrated to a relative density of 1.20–1.30 at 60°C. The above volatile oil inclusion complexes were combined to obtain the Chinese herbal medicine extract. (2) Add pregelatinized starch, sodium alginate and croscarmellose sodium cellulose to the Chinese herbal extract, use 30% to 40% ethanol solution to make soft material, extrude into strips, place in a rolling mill to roll into micro pellets, and dry to obtain pellet core; (3) Dissolve hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in 50% ethanol solution, add PEG4000 and talc, stir well to obtain coating solution; (4) Put the core pellets into the fluidized bed, adjust the air inlet temperature to 40℃~60℃, and spray the coating liquid through the spray gun to increase the weight by 2wt%~4wt%.

7. The method for preparing the choleretic traditional Chinese medicine composition as described in claim 6, characterized in that, In step (1), the Chinese herbal raw materials are pulverized to 20-40 mesh.

8. The method for preparing the choleretic traditional Chinese medicine composition as described in claim 6, characterized in that, In step (1), the mass ratio of volatile oil to β-cyclodextrin is 1:(6-9).

9. The method for preparing the choleretic traditional Chinese medicine composition as described in claim 6, characterized in that, The percentage concentration of hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 in the coating solution is 4wt% to 6wt%.

10. The use of the choleretic traditional Chinese medicine composition according to any one of claims 1 to 5 in the preparation of a medicament for treating acute and chronic gallstones and / or cholecystitis.

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