CN102552575A - Medicine composition for treating chronic cholecystitis and preparation method thereof - Google Patents
Medicine composition for treating chronic cholecystitis and preparation method thereof Download PDFInfo
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- CN102552575A CN102552575A CN2012100071525A CN201210007152A CN102552575A CN 102552575 A CN102552575 A CN 102552575A CN 2012100071525 A CN2012100071525 A CN 2012100071525A CN 201210007152 A CN201210007152 A CN 201210007152A CN 102552575 A CN102552575 A CN 102552575A
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Abstract
The invention discloses a medicine composition for treating chronic cholecystitis and a preparation method thereof. The medicine composition is mainly prepared from Chinese medicinal herbs including white paeony root, corydalis tuber, Angelica sinensis, bighead atractylodes rhizome, capillary artemisia powder, toosendan fruit, cluster mallow fruit, Poria cocos, rhizoma alismatis, Cape jasmine, baked concha arcae, gizzard pepsin and liquorice. The medicine composition has the functions of regulating liver, benefiting gallbladder, regulating the flow of qi to alleviate pain, tonifying spleen and clearing dampness, so as to treat the chronic cholecystitis with the symptoms of estrangement of the liver and the gallbladder, epigastric distention caused by stagnation of fluid-dampness, right shoulder pain, abdominal distension and less eating, bitter taste, coated tongue and the like.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a pharmaceutical composition for treating chronic cholecystitis and a preparation method thereof.
Background
Chronic cholecystitis (Chronic cholecystitis) refers to Chronic inflammatory pathological changes of gallbladder, most of which are Chronic calculous cholecystitis accounting for 85-95%, and the disease incidence rate is always at a higher level and 10%. The recurrent attacks affect the life quality of the patients. For chronic cholecystitis, modern medicine has insufficient drug treatment means except gallbladder removal operation, and the treatment is anti-inflammatory and anti-infection treatment after acute attack in most cases. However, the traditional Chinese medicine has certain advantages for treating chronic cholecystitis and cholelithiasis, namely symptoms can be improved and diseases can be treated by reasonably taking the traditional Chinese medicine through treatment based on syndrome differentiation, the operative treatment proportion can be reduced, and the pain of patients is relieved.
Chronic cholecystitis belongs to the categories of diseases such as gallbladder distention, hypochondriac pain and the like in traditional Chinese medicine. The traditional Chinese medicine considers that the liver is one of five internal organs, mainly stores blood, mainly dredges and relieves depression with joy and nod in nature. The gallbladder is the fu organ, which stores essence and acts as the general way to descend. Liver and gallbladder are exterior and interior, and the descending and dredging of gallbladder depends on the smoothing flow of liver, so the function of gallbladder is normal, which is good for liver regulation. If the emotion is uncomfortable, stagnation of liver qi or carelessness in daily life, damp-heat will invade the gallbladder; or improper diet, preference for greasy, fat and sweet food, damp-heat entering the gallbladder, which can cause disorder of liver and gallbladder, disorder of qi flow and stagnation of qi, pain and distention. When qi stagnation of liver and gallbladder occurs, the spleen and stomach are not healthy, and the internal and external causes often cause prolonged or repeated attack of pathogenic conditions, lingering and difficult healing, resulting in disharmony of liver and gallbladder and retention of damp-heat, manifested as distending pain in upper abdomen or hypochondrium, pain in right shoulder and back, abdominal distension, poor appetite, bitter taste in the mouth, greasy tongue coating, etc. In the course of the disease, liver-gallbladder disharmony and stagnation of liver qi can cause spleen deficiency and insufficient transportation and transformation, retention of water-dampness, damp stagnation and heat transformation, liver depression and dredging, and bile flow and descending obstruction, so that malignant circulation is formed, the disease is delayed and repeated, and the disease is not easy to cure. The key of pathogenesis lies in liver and gallbladder disharmony and retention of damp-heat, and the treatment medicine is used for soothing the liver and benefiting the gallbladder, and has the advantages of paying attention to strengthening the spleen and promoting diuresis, smoothing the liver and the spleen, achieving qi movement and promoting the transportation and transformation of the spleen and the stomach, and then stopping damp-heat and clearing the gallbladder, thereby achieving the purposes of treating the root cause and clearing the source and treating both the symptoms and root causes.
According to the search, about twenty medicines with national standards (approved literature) such as danning tablets, golden gall tablets, gall bladder, gallstone dredging, inflammation diminishing and gallbladder benefiting tablets are used as indications at present, most medicines mainly take clearing heat, resolving dampness and dredging liver and gall as main treatment methods, and the acute and chronic cholecystitis is indicated as an indication, is biased to bitter and clear, has less consideration on the characteristics of the chronic cholecystitis, so that the curative effect is ideal and the spleen and stomach are easily injured.
Disclosure of Invention
The invention overcomes the defects of the existing chronic cholecystitis medicaments, and provides a medicinal composition for treating chronic cholecystitis, which treats both principal and secondary aspects of diseases. The medicinal composition has the formula idea of soothing the liver and benefiting the gallbladder, and simultaneously emphasizes the functions of strengthening the spleen and removing dampness, and cold and cool heat are not too much to reduce the possibility of damaging the original qi of the spleen and the stomach and influencing recovery. On the basis, the prescription is used with less bitter diarrhea, the tonic products such as white paeony root, Chinese angelica, largehead atractylodes rhizome and the like are added in the liver soothing, gallbladder smoothing, heat clearing and dampness eliminating processes, and calcined concha arcae, chicken's gizzard-membrane and the like are used for harmonizing the stomach, so that the unique medicine characteristics of the user are formed. Compared with the similar species with the existing national standard, the Chinese medicinal preparation has more definite functional main treatment positioning and better accords with the pathogenesis characteristics of chronic cholecystitis.
In order to achieve the purpose, the invention provides the following scheme:
a pharmaceutical composition for treating chronic cholecystitis is mainly prepared from the following raw material medicines in parts by weight: 10-15 parts of white paeony root, 8-12 parts of corydalis tuber, 8-12 parts of angelica, 8-12 parts of bighead atractylodes rhizome, 10-15 parts of oriental wormwood, 8-12 parts of szechwan chinaberry fruit, 6-11 parts of cluster mallow fruit, 10-15 parts of poria cocos, 6-11 parts of rhizoma alismatis, 6-11 parts of cape jasmine fruit, 6-11 parts of calcined concha arcae, 6-11 parts of endothelium corneum gigeriae galli and 3-6 parts of liquorice.
Preferably, the weight parts of the traditional Chinese medicine raw materials are as follows: 14 parts of white paeony root, 12 parts of corydalis tuber, 12 parts of angelica, 12 parts of bighead atractylodes rhizome, 15 parts of oriental wormwood, 12 parts of szechwan chinaberry fruit, 10 parts of cluster mallow fruit, 15 parts of tuckahoe, 11 parts of rhizoma alismatis, 11 parts of cape jasmine fruit, 11 parts of calcined concha arcae, 11 parts of endothelium corneum gigeriae galli and 6 parts of liquorice.
The pharmaceutical composition can be decocted according to the weight ratio and a conventional method for taking, and preferably, the endothelium corneum gigeriae galli is independently added after other medicines are decocted.
A preparation method of a pharmaceutical composition for treating chronic cholecystitis comprises the following steps:
(1) crushing the chicken's gizzard-membrane into fine powder for later use according to the weight parts;
(2) mixing the angelica, the bighead atractylodes rhizome and the oriental wormwood in parts by weight, and distilling the mixture for 4 to 6 hours by using 6 to 10 times of water to obtain volatile oil; clathrating with beta-CD 6-10 times of volatile oil at 30 deg.C for 2-4 hr to obtain beta-CD clathrate, and collecting the residue;
(3) mixing rhizoma corydalis and fructus gardeniae according to the weight parts, adding 60-80% ethanol in an amount which is 4-8 times of the weight of the mixture, performing reflux extraction for 2 times, and combining ethanol extract for 1-3 hours, preferably 1.5-2.5 hours, for later use; optionally further concentrating the ethanol extractive solution under reduced pressure to obtain ethanol extract; the extracted medicine residue is kept for standby;
(4) decocting calcined concha arcae in 8-12 times of water for 30-60 minutes, mixing with the radix paeoniae alba, the szechwan chinaberry fruit, the cluster mallow fruit, the poria cocos, the rhizoma alismatis and the liquorice in parts by weight, and adding 6-10 times of water for decocting for 1-2.5 hours, preferably 1.5-2.5 hours;
(5) mixing the mixture decocted in the step (4) with the dregs extracted in the step (2) and the step (3), and decocting the mixture for 1 to 2.5 hours, preferably 1.5 to 2.5 hours, by using 6 to 10 times of water;
(6) filtering the solution obtained after decoction in the steps (4) and (5), combining, centrifuging, and concentrating the centrifugate under reduced pressure to obtain an extract with the relative density of about 1.10 at 60 ℃;
(7) mixing the ethanol extract obtained in the step (3) with the centrifugate obtained in the step (6), concentrating under reduced pressure to obtain an extract, adding the fine powder of the endothelium corneum gigeriae galli obtained in the step (1), mixing, drying, and then crushing into fine powder to obtain the active ingredient of the medicament, or mixing the ethanol extract obtained in the step (3) with the extract obtained in the step (6), adding the fine powder of the endothelium corneum gigeriae galli obtained in the step (1), mixing, drying, crushing into fine powder, adding a beta-CD inclusion compound, and uniformly mixing to obtain the active ingredient of the medicament.
Wherein, the active ingredients of the medicine in the step (7) are mixed with excipient or auxiliary material uniformly and can be prepared into any common preparation formulation, preferably tablets, capsules and pills.
Based on the formulation design of the invention and in combination with the traditional Chinese medicine formulation theory, one or more medicinal components as an 'enabling' medicament, such as liquorice, can be introduced by the technical personnel in the field, and even one or more medicinal components as an 'assisting' medicament can be introduced, and all of the medicinal components are covered by the scope of the invention.
In the pharmaceutical composition according to the invention, one or several excipients or other adjuvants commonly used in the pharmaceutical field of traditional Chinese medicine may also be incorporated in order to prepare the composition into various suitable dosage forms. For solid compositions, conventional excipients include, for example, lactose, starch, magnesium stearate, talc, microcrystalline cellulose, glucose, sucrose, aerosil, low substituted hydroxypropylcellulose, povidone, opadry, zein, sodium carboxymethyl starch, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing (etc.) the active compounds described herein and optional pharmaceutical excipients in an excipient, such as water, aqueous dextrose, ethanol, and the like, thereby forming a suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary excipients, such as wetting or emulsifying agents and the like.
For oral administration, the compositions will generally be in the form of tablets or capsules, or may be aqueous or anhydrous solutions, suspensions or syrups. Tablets and capsules are the preferred oral administration forms. Tablets and capsules for oral use typically include one or more conventional excipients, such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When a suspension is used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring agents, color imparting agents and/or sweeteners may also be added. Other optional excipients that may be incorporated into the oral formulation include preservatives, suspending agents, thickening agents and the like.
For example, aerosil, povidone, microcrystalline cellulose, magnesium stearate, etc. may be incorporated into the composition of the present invention, and a binder, a lubricant, etc. may also be added, and these auxiliaries are readily available in the market at home and abroad.
The pharmaceutical composition provided by the invention has good effect on chronic cholecystitis, and is suitable for symptoms such as epigastric or hypochondriac distending pain caused by liver-gallbladder disharmony and damp-heat retention, right shoulder and back pain, abdominal distension and poor appetite, bitter taste in the mouth, greasy tongue coating and the like, and chronic cholecystitis with the symptoms. The pharmaceutical composition has unique formula, exact drug effect, strong pertinence and strict compatibility. The medicines used are less bitter and laxative, the tonic products such as white peony root, angelica, bighead atractylodes rhizome and the like are added in the liver soothing, gallbladder smoothing, heat clearing and dampness eliminating medicines, and the stomach harmonizing is carried out by using calcined concha arcae, endothelium corneum gigeriae galli and the like, so that the aim of treating diseases and seeking the root cause is achieved.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The following medicinal composition is adopted:
14 parts of white paeony root, 15 parts of oriental wormwood and poria cocos respectively, 12 parts of rhizoma corydalis, angelica sinensis, bighead atractylodes rhizome and szechwan chinaberry fruit respectively, 10 parts of cluster mallow fruit, 11 parts of rhizoma alismatis, gardenia, calcined concha arcae and endothelium corneum gigeriae galli respectively, and 6 parts of liquorice.
The composition can be decocted by conventional method, and endothelium corneum Gigeriae Galli can be added after decocting.
Example 2
6 parts by weight of endothelium corneum gigeriae galli is crushed into fine powder for standby; 8 parts of angelica and 10 parts of atractylodes and 10 parts of oriental wormwood by weight are respectively added with 8 times of water and distilled for 6 hours to obtain volatile oil, and the volatile oil is coated by beta-CD with 8 times of the volatile oil, the coating temperature is 30 ℃, and the coating time is 3 hours to obtain the beta-CD clathrate compound for later use. Pulverizing rhizoma corydalis 8 weight parts and fructus Gardeniae 6 weight parts into coarse powder, reflux-extracting with 70% ethanol twice, and reflux-extracting with 7 times of ethanol for 2.0 hr for the first time; adding 6 times of ethanol, refluxing for 1.5 hr, mixing ethanol extractive solutions, and concentrating under reduced pressure to obtain ethanol extract with relative density of 1.10 (measured at 60 deg.C). Adding 10 times of water into 6 parts of concha arcae by weight, decocting for 30 minutes, mixing the mixture with 10 parts of white paeony root and poria cocos by weight respectively, 8 parts of szechwan chinaberry fruit by weight, 6 parts of cluster mallow fruit and rhizoma alismatis by weight respectively and 3 parts of liquorice by weight, decocting twice, and adding 10 times of water for decocting for 2.0 hours for the first time; mixing the second time with the dregs after alcohol extraction and the dregs after volatile oil extraction, adding 8 times of water for decocting for 1.5 hours, filtering, mixing the filtrates, carrying out tubular centrifugation (16000rpm) to obtain a centrifugal liquid, concentrating under reduced pressure to obtain an extract with a relative density of about 1.10 (measured at 60 ℃), mixing with the alcohol extract, concentrating under reduced pressure to obtain a thick paste with a relative density of about 1.35 (measured at 60 ℃), vacuum drying (drying temperature 60 ℃ and vacuum degree-0.08 Mpa) to obtain a dry paste, crushing to obtain a dry powder, adding 6 parts by weight of the chicken's gizzard-membrane fine powder and 1 part by weight of microcrystalline cellulose, mixing, preparing a soft material by using a 3% povidone ethanol solution, preparing into granules (12 meshes of inclusion compound), drying at 60-80 ℃ at low temperature, grading (20-40 meshes), adding beta-CD (beta-CD) in an equivalent incremental manner, adding 0.12 parts by weight of magnesium stearate, mixing, tabletting.
Example 3
8 parts by weight of endothelium corneum gigeriae galli is crushed into fine powder for standby; 9 parts of angelica and atractylodes and 11 parts of oriental wormwood by weight are respectively added with 8 times of water and distilled for 6 hours to obtain volatile oil, and the volatile oil is coated by beta-CD with 8 times of the volatile oil, the coating temperature is 30 ℃, and the coating time is 3 hours to obtain the beta-CD clathrate compound for later use. 9 parts of corydalis tuber and 7 parts of gardenia by weight are crushed into coarse powder, 70 percent ethanol is added for reflux extraction twice, and 8 times of ethanol is added for reflux extraction for 2.0 hours for the first time; adding 7 times of ethanol, refluxing for 1.5 hr, mixing ethanol extractive solutions, and concentrating under reduced pressure to obtain ethanol extract with relative density of 1.10 (measured at 60 deg.C). Adding 10 times of water into 7 parts of concha arcae by weight, decocting for 30 minutes, mixing the mixture with 11 parts of each of radix paeoniae alba and poria cocos by weight, 9 parts of szechwan chinaberry fruit by weight, 7 parts of each of cluster mallow fruit and rhizoma alismatis by weight and 4 parts of liquorice by weight, decocting twice, and adding 10 times of water for decocting for 2.0 hours for the first time; mixing the second time with the dregs after alcohol extraction and the dregs after volatile oil extraction, adding 8 times of water for decocting for 1.5 hours, filtering, mixing the filtrates, carrying out tubular centrifugation (16000rpm) to obtain a centrifugal liquid, concentrating under reduced pressure to obtain an extract with a relative density of about 1.10 (measured at 60 ℃), mixing with the alcohol extract, concentrating under reduced pressure to obtain a thick paste with a relative density of about 1.35 (measured at 60 ℃), vacuum drying (drying temperature 60 ℃ and vacuum degree-0.08 Mpa) to obtain a dry paste, crushing to obtain a dry powder, adding 7 parts by weight of the fine powder of endothelium corneum gigeriae galli and 1 part by weight of microcrystalline cellulose, mixing, preparing a soft material with an ethanol solution of 3% povidone, preparing into granules (12 meshes of inclusion compound), drying at low temperature of 60-80 ℃, grading (20-40 meshes), adding beta-CD (beta-CD) in an equivalent incremental manner, adding 0.10 parts by weight of magnesium stearate, mixing, tabletting, coating.
Example 4
6 parts by weight of endothelium corneum gigeriae galli is crushed into fine powder for standby; 8 parts of angelica and 10 parts of atractylodes and 10 parts of oriental wormwood by weight are respectively added with 8 times of water and distilled for 6 hours to obtain volatile oil, and the volatile oil is coated by beta-CD with 8 times of the volatile oil, the coating temperature is 30 ℃, and the coating time is 3 hours to obtain the beta-CD clathrate compound for later use. Pulverizing rhizoma corydalis 8 weight parts and fructus Gardeniae 6 weight parts into coarse powder, reflux-extracting with 70% ethanol twice, and reflux-extracting with 7 times of ethanol for 2.0 hr for the first time; adding 6 times of ethanol, refluxing for 1.5 hr, mixing ethanol extractive solutions, and concentrating under reduced pressure to obtain ethanol extract with relative density of 1.10 (measured at 60 deg.C). Adding 10 times of water into 8 parts of concha arcae by weight, decocting for 30 minutes, mixing with 12 parts of white paeony root and poria cocos each, 10 parts of szechwan chinaberry fruit by weight, 8 parts of cluster mallow fruit and rhizoma alismatis each and 5 parts of liquorice by weight, decocting twice, and adding 10 times of water for decocting for 2.0 hours for the first time; mixing the second time with the dregs after alcohol extraction and the dregs after volatile oil extraction, adding 8 times of water for decocting for 1.5 hours, filtering, mixing the filtrates, carrying out tubular centrifugation (16000rpm) to obtain a centrifugal liquid, concentrating under reduced pressure to obtain an extract with a relative density of about 1.10 (measured at 60 ℃), mixing with the alcohol extract, concentrating under reduced pressure to obtain a thick paste with a relative density of about 1.35 (measured at 60 ℃), vacuum drying (drying temperature 60 ℃ and vacuum degree-0.08 Mpa) to obtain a dry paste, crushing to obtain a dry powder, adding 6 parts by weight of the chicken's gizzard-membrane fine powder and 1 part by weight of microcrystalline cellulose, mixing, preparing a soft material by using a 3% povidone ethanol solution, preparing into granules (12 meshes of inclusion compound), drying at low temperature of 60-80 ℃, grading (20-40 meshes), adding beta-CD (beta-CD) in an equivalent incremental manner, adding 0.0625 parts by weight of magnesium stearate, mixing, tabletting, coating.
Example 5
6 parts by weight of endothelium corneum gigeriae galli is crushed into fine powder for standby; 10 parts of angelica and atractylodes and 12 parts of oriental wormwood are respectively added with 8 times of water and distilled for 6 hours to obtain volatile oil, and the volatile oil is coated by beta-CD with 8 times of volatile oil, the coating temperature is 30 ℃, and the coating time is 3 hours to obtain the beta-CD clathrate compound for later use. 10 parts by weight of rhizoma corydalis and 8 parts by weight of gardenia are crushed into coarse powder, 70 percent ethanol is added for reflux extraction twice, and 6 times of ethanol is added for reflux extraction for 2.0 hours for the first time; adding 4 times of ethanol, refluxing for 1.5 hr, mixing ethanol extractive solutions, and concentrating under reduced pressure to obtain ethanol extract with relative density of 1.10 (measured at 60 deg.C). Adding 10 times of water into 8 parts of concha arcae by weight, decocting for 30 minutes, mixing with 14 parts of white paeony root and poria cocos by weight respectively, 12 parts of szechwan chinaberry fruit by weight, 10 parts of cluster mallow fruit and rhizoma alismatis by weight respectively and 7 parts of liquorice by weight, decocting twice, and adding 10 times of water for decocting for 2.0 hours for the first time; mixing the second time with the dregs after alcohol extraction and the dregs after volatile oil extraction, adding 8 times of water for decocting for 1.5 hours, filtering, mixing the filtrates, carrying out tubular centrifugation (16000rpm) to obtain a centrifugal liquid, concentrating under reduced pressure to obtain an extract with a relative density of about 1.10 (measured at 60 ℃), mixing with the alcohol extract, concentrating under reduced pressure to obtain a thick paste with a relative density of about 1.35 (measured at 60 ℃), vacuum drying (drying temperature 60 ℃ and vacuum degree-0.08 Mpa) to obtain a dry paste, crushing to obtain a dry powder, adding 6 parts by weight of the chicken's gizzard-membrane fine powder and 1 part by weight of microcrystalline cellulose, mixing, preparing a soft material by using a 3% povidone ethanol solution, preparing into granules (12 meshes of inclusion compound), drying at low temperature of 60-80 ℃, grading (20-40 meshes), adding beta-CD (beta-CD) in an equivalent incremental manner, adding 0.0625 parts by weight of magnesium stearate, mixing, tabletting, coating.
Example 6 pharmacological evaluation
1. Material
1.1 drugs and reagents
The tested drugs are: the pharmaceutical composition of the present invention (the test drug may be a tablet prepared according to any one of examples 2 to 5, and in this example, the tablet prepared according to example 5 is used, hereinafter referred to as drug group), and the clinically intended amount is 34g (crude drug)/day, and the extract thereof is used in the experiment at a concentration of 3.8g (crude drug)/g, and is orally administered 4 tablets at a time, 3 times a day. Provided by the institute of pharmacy, lot number: 20030508.
the positive medicine (I) and the compound dantong tablet mainly comprise the following components: herba Artemisiae Scopariae, caulis et folium Lactucae Sativae, herba Rabdosiae Lophanthoidis, herba Andrographitis, and radix et rhizoma Rhei etc. and has effects of clearing heat and promoting bile flow, relieving spasm and relieving pain. Can be used for treating acute and chronic cholecystitis, cholangitis, cholecystolithiasis, and biliary calculus complicated with infection. Specification: each tablet contains 0.1g of bile powder and 0.6g of tablet weight; the dosage is as follows: orally taken, 6 tablets/day. Manufactured by Yongkang pharmaceutical industry Co., Ltd, Guangdong province, batch number: 030502.
positive drug (ii), trapitong tablet (shudantong tablet): can be used for treating cholecystitis and biliary tract diseases. Specification: 40 mg/tablet, 3 tablets/day for clinical use, produced by Qianjin Xiangjiang pharmaceutical industry GmbH, Hunan, batch number: 030904.
the positive medicine (III) and the atropine sulfate tablet have the specification of 0.3 mg/tablet, the dosage is 1-2 tablets/time and 3 times/day, and the product is produced by Sanjiu Wangrong pharmaceutical industry Limited liability company of Sanjiu enterprises, and the batch number is as follows: 020104.
positive drug (iv), amoxicillin capsules, specification 0.25 g/granule, seakohl pharmaceutical limited, lot No.: 020401.
morphine hydrochloride injection, 10 mg/ml/count, manufactured by sheng yang first pharmaceutical factory, lot number: 010401.
escherichia coli, a hemolytic streptococcus standard strain and a clinical isolate were provided by the institute of traditional Chinese medicine, university of Hunan, the laboratory of microbial research.
Other agents such as glacial acetic acid, Ewenlan, Carrageenan, etc. are all AR or CP.
1.2 animals
The ICR-line and BALB/C-line clean mice, weighing 18-24g, were provided by Shanghai Sphere-BiKai laboratory animals Co. Certificate number: SCXK (Shanghai) No. 2003-0002.
SD is a clean grade rat weighing 180-. Certificate number: SCXK (Shanghai) No. 2003-0002.
Guinea pig, male and female half, body weight 350-; the rabbits, male and female, are provided by the large experimental animal farm in Hunan agriculture.
Laboratory animal environmental facility certification number: 027 No. C.
1.3 instruments and apparatus
751G-W Spectrophotometer, manufactured by Shanghai analytical instruments Ltd.
CO2 incubator, manufactured by Yamato scientific Co., Japan.
2. Method and results
(statistical methods: measurements are expressed as + -s, variance-uniform by variance-difference analysis and group-t-test analysis; variance-non-uniform by rank-sum test analysis, counts by X2 test analysis, grades by Ridit test analysis.)
2.1 Studies on bacterial cholecystitis model Guinea pigs
2.1.1 methods
Molding: narcotizing guinea pig with ether, making a 2-3cm incision along the midline of abdomen, exposing gallbladder, sucking bile with 1ml syringe, injecting into Escherichia coli (3 × 104/ml) 0.5ml, immediately ligating eye, sterilizing, and suturing wound for 10 days to obtain bacterial cholecystitis model.
Grouping and administration: taking 90 guinea pigs with weight of 370.7 +/-18.2 g without limitation, randomly taking 10 guinea pigs according to weight as a blank control group (ig distilled water 10ml/kg), modeling other animals according to the method, basically healing wounds of all guinea pigs after 3 days (12 animals die after operation, 8 animals are reserved), randomly dividing into a model control group (ig distilled water 10ml/kg), a compound gallbladder slice group (ig compound gallbladder slice weight 0.6 g/kg, 2 times of clinical equivalent dose), a trapiton slice group (ig trapiton 0.02g/kg, 2 times of clinical equivalent dose), a low, medium and high dose groups (ig drugs 2.7, 5.4 and 10.8g crude drugs/kg, respectively, are 1, 2 and 4 times of clinical equivalent dose). All guinea pigs were dosed at the dose of table 1, 1 time a day, for 7 consecutive days, 3 days after molding.
Observation indexes are as follows: the following day following the last dose, animals were sacrificed, the gallbladder was removed by laparotomy, and the characteristics and contents inside and outside the gallbladder were visually observed and recorded: whether the color of the gall bladder is changed or not, whether the gall bladder is adhered or not and whether the color of the gall is abnormal or not; the contents were removed, fixed with formalin, histological sections of conventional paraffin, HE-stained, and the pathological changes were observed: the gallbladder mucosa has no folds basically, the inherent membrane has no inflammatory cells, and the inherent layer has no fibrous tissue hyperplasia (-); secondly, the gallbladder mucosa has folds or folds are widened 1/4, the inherent membrane has a small amount of inflammatory cells, the inherent layer has fibrocytes or fibers which are slightly increased, and the inherent layer is slightly thickened (+); ③ the gallbladder mucosa has more folds or wider folds 1/2, the inherent membrane has inflammatory cells, the inherent layer has fibrocytes and increased fiber degree, and the inherent layer has moderate thickening (+ +); fourthly, the gall bladder mucosa is greatly folded or the folds are widened more than 1/2, the inherent membrane has a large amount of inflammatory cells and is in diffuse infiltration, the inherent layer has a large amount of fiber cells and fibers, the height of the inherent layer is thickened or is lengthened along with the folds of the mucosa, and the inherent layer and the fiber are mutually connected into a net shape (+++).
2.1.2 results
Gallbladder appearance results: the appearance of the gallbladder of the model control guinea pig mostly appears black or dark red, part of the gallbladder is adhered, and the bile is black or dark red. The appearance of the compound Dantong tablet and the Qupibuntong tablet is mostly dark green, no adhesion and the bile is dark green or green. As can be seen from Table 1, the appearance of gallbladder tissue in the high dose group was significantly reduced compared to the model control group.
As can be seen from Table 2, the weight gain of the model control guinea pigs was significantly reduced compared to that of the blank control group; compared with the model control group, the weight increase of the guinea pigs in the high-dose group of Yanshao cholagogic tablet has a significant difference, and the weight increase of the guinea pigs in other drug treatment groups is accelerated to a certain extent.
The pathological histological examination shows that most gallbladder mucosa of the guinea pig model with the bacterial cholecystitis has a large amount of folds or folds are widened above 1/2, the inherent membrane has a large amount of inflammatory cells, the inherent layer has increased height of fibrocytes and fibers, and the height of the inherent layer is thickened or is lengthened along with folds of the mucosa and is connected with each other to form a net; the gallbladder mucosa of the guinea pigs in Yanshao cholagogic tablet, the compound dantong tablet and the qupibuntong tablet only shows a small amount of wrinkles, the height of the inherent layer is not thickened, and the pathological symptoms are obviously improved. As shown in Table 3, through the Ridit test, compared with the model control group, the gallbladder histopathology of the guinea pig in the medium and high dose groups is obviously changed, which shows that the Yanshao cholagogue tablet has better treatment effect on the guinea pig bacterial cholecystitis
TABLE 1 Effect on gallbladder appearance in guinea pig model with bacterial cholecystitis
Warp X2Testing, comparing with model control group, P < 0.05, P < 0.01
TABLE 2 Effect on weight of guinea pig in bacterial cholecystitis model (+ -s)
Comparing with model control group by t test, P is less than 0.05, P is less than 0.01
TABLE 3 Effect on bacterial cholecystitis model Guinea pig gallbladder histopathology
Comparing with model control group by Ridit test, P is less than 0.05, P is less than 0.01
2.2 Effect on suppurative cholecystitis model rabbits
2.2.1 methods
Molding: weighing rabbits, performing 3% pentobarbital sodium intravenous injection at a dose of 25mg/kg for anesthesia, fixing, shearing hairs, sterilizing, spreading a sterile hole towel, making a 5-6cm abdominal center incision under xiphoid process, entering abdominal cavity, exposing common bile duct, separating, placing 1mm sterile plastic tube along the common bile duct, ligating with No. 1 silk thread, pulling out to cause local stenosis of the common bile duct, exposing gallbladder, inserting needle into body, withdrawing about 1ml bile, injecting 1ml fecal suspension prepared from 1 granule of feces and 10ml normal saline, ligating needle opening, sterilizing, suturing muscle skin, sterilizing skin every day after operation, and continuously sterilizing for 3 days to obtain suppurative cholecystitis model.
Grouping and administration: taking 60 rabbits with female and male property and weight of 1.999 +/-0.212 kg, randomly taking 10 rabbits according to weight as a blank control group (false operation), modeling the other rabbits according to the method, randomly dividing the rabbits into 5 groups according to weight on the next day, wherein the 5 groups are respectively a model control group (ig distilled water 10ml/kg), a compound dantong group (ig compound dantong tablet 0.4g tablet weight/kg, which is 2 times of clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group (ig drug groups 1.6, 3.2 and 6.4g crude drugs/kg, which are respectively 1, 2 and 4 times of clinical equivalent dose). All animals were dosed on day 2 of molding as per table 4, 1 time a day for 10 consecutive days.
Observation indexes are as follows: appearance signs: observing animal hair, activity, diet and defecation; ② weight: measuring the weights of the rabbits before and after the test; ③ observing gallbladder with naked eyes: on day 2 of the last administration, animals were sacrificed, the gallbladder was dissected away, and the inside and outside of the gallbladder and the contents were observed; A. the gall bladder has no color change and no adhesion, and the color of the bile is normal (-); B. the gallbladder is slightly adhered, the color of the bile is deepened, and purulent substances (+); C. white fibrosis of gallbladder part, attached to liver, bile is pink purulent (+ +); D. white fibrosis of gallbladder, embedding in liver, dark purulent bile (+++) pathological observation of gallbladder: A. the mucosa of the gallbladder wall is normal, edema and inflammatory cells are not generated, and fibrous tissue hyperplasia (-) is not generated; B. edema, congestion, partial necrosis of the cystic wall mucosa, inflammatory cells and small focal ulcer, fibrous tissue hyperplasia (+); C. edema, congestion and necrosis of gallbladder wall mucosa, inflammatory cells and small focal ulcer, and obvious proliferation of fibrous tissues (++); D. necrosis of the gallbladder wall mucosa, massive inflammatory cell infiltration and ulcer formation, basic fibrosis of the submucosal tissue, adenomatous hyperplasia (+++).
2.2.2 results
Characterization observations: the hair of the rabbits in the model control group is dull, the actions are slow, the ears are fallen down, the diet is reduced, the stool is reduced or is thin, the stool color is brown yellow, the anus periphery is unclean, and the individual stool is red; after the drug group and the compound dantong tablet are administrated for treatment, the diet is basically normal, the excrement is granulated, and the urine is normal.
Observing the gallbladder with naked eyes: the rabbit in the model control group has adhesion of stomach, intestine, gallbladder and liver, the gallbladder is buried in the liver, the outer side of the gallbladder is white, the gallbladder is grey white, and the gallbladder is filled with purulent substances or black mud substances, compared with the blank control group, the gallbladder wall is obviously thickened, the biliary tract is narrow, and the liver and the gallbladder have induration and are in serious inflammation pathological states. The gall bladder of the low-dose group of the medicine group of the rabbit becomes small, the stomach and the intestine basically have no adhesion, the gall is purulent or black mud, and the gall is buried in the liver; in the medium-dose group, the stomach and the intestine are not adhered, the bile has a small amount of purulent substances, and the gallbladder part is white and fibrous; the gall bladder of the high-dose group of rabbits is attached to the liver and can be separated basically, and purulent substances are not generated in the sac basically. As can be seen from Table 4, the appearance of gall bladder tissue of rabbits in the drug group and the high dose group was significantly reduced compared to the model control group.
As can be seen from Table 5, the weight gain of the model control group rabbits was significantly slowed down compared to the blank control group; compared with the model control group, the weight increase of animals in each dose group of the drug group has significant difference, and the weight increase of rabbits is accelerated.
Pathological histological examination shows that most of rabbits in the suppurative cholecystitis model have mucosa necrosis of the cystic wall, a large amount of inflammatory cells and ulcer, hyperplasia in the form of adenomatous tumor and basic fibrosis of submucosal tissues; the Yanshao Lidan tablet group of rabbit gallbladder wall mucosa is edematous, hyperemia and partial necrosis, and has inflammatory cells, small focal ulcer, fibrous tissue hyperplasia and obviously improved pathological symptoms. As can be seen from Table 6, through the Ridit test, compared with the model control group, the gallbladder histopathology of the rabbits in the middle and high dose groups of Yanshao cholagogic tablet is significantly changed, which indicates that the medicine group has a better treatment effect on the rabbit suppurative cholecystitis.
TABLE 4 influence on appearance of gall bladder of rabbit model with suppurative cholecystitis
Comparing with model control group by Ridit test, P is less than 0.05, P is less than 0.01
TABLE 5 influence on weight of rabbits (S) model of suppurative cholecystitis
P < 0.05, P < 0.01, compared to model control
TABLE 6 influence of drug groups on histopathology of rabbit gallbladder in model of suppurative cholecystitis
Comparing with model control group by Ridit test, P is less than 0.05, P is less than 0.01
2.3 study of the actions of benefiting gallbladder and relieving spasm
2.3.1 Effect on bile secretion in rats
2.3.1.1 method
Taking 72 SD-series clean-grade rats with half female and half male, and 198.1 +/-13.3 g of weight, administering according to a random weight table, wherein the weight is 10ml/kg of blank control group ig distilled water, 0.6g of compound Dantong tablet group ig compound Dantong tablet weight/kg (2 times of clinical equivalent dose), 0.02g/kg of trapbuttong tablet group ig traptong tablet (2 times of clinical equivalent dose), 3.0, 6.0 and 12.0g of crude drug/kg of drug in low, medium and high dose groups of traptong tablets (1, 2 and 4 times of clinical equivalent dose respectively), each group has 10 data, and the next animal with no or unsmooth bile drainage is supplemented. All animals are fasted for 16h, ig normal saline is 2.5 ml/animal before test, 40ml/kg sodium pentobarbital is injected subcutaneously after 30min for anesthesia, the rat is fixed on the back, the skin is cut along the midline of the abdomen, the abdominal cavity is opened, the common bile duct is separated, the common bile duct is ligated to the end close to the intestinal breast, a scalp needle filled with normal saline is inserted into the common bile duct towards the liver, ligation is carried out, after bile outflow is confirmed, a plastic catheter is fixed, and bile is collected. After operation is stable for 30min, collecting bile flow for 30min as bile flow before administration (0 min); then, the corresponding medicine is given to the duodenum according to a random table at 10ml/kg, and the bile flow rate is recorded at 30min, 60min and 90min after the administration.
TABLE 7 Effect on rat bile flow (. + -. s)
Comparing with model control group by t test, P is less than 0.05, P is less than 0.01
2.3.1.2 results
As can be seen from Table 7, compared with the blank control group, the endocrine increase of rats in the drug group and the high-dose group is significantly different in 30-90min after administration, and the bile increase of rats in the trapbutong group is obvious.
2.3.2 Effect on bile secretion in mice
2.3.2.1 method
60 ICR clean-grade mice with weight of 20.0 +/-1.3 g are selected, and randomly divided into a blank control group (10 ml/kg of ig distilled water), a compound dantong tablet group (1.0 g of ig compound dantong tablets, the weight of which is 2 times of the clinical equivalent dose), a trapbuttong tablet group (0.03 g/kg of trapbuttong, the weight of which is 2 times of the clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group according to the weight (respectively 4.3, 8.6 and 17.2g of crude drugs/kg of the ig drug groups, which are respectively 1, 2 and 4 times of the clinical equivalent dose). All animals are fasted for 16h, corresponding medicines are given according to table 8 for 10ml/kg, the carotid artery is bled to kill the mice after 1h of administration, the abdominal cavity is opened, the liver is exposed, the gallbladder and the common bile duct are separated, the common bile duct close to the intestinal end and the common bile duct are ligated by a 10cm line, the outer end of the ligation is cut off, the gallbladder and the ligated common bile duct are taken out together, redundant tissues are stripped, the weighing is carried out, the gallbladder is cut off, the inner wall of the gallbladder is cleaned, filter paper is sucked dry, the weighing is carried out again, and the difference between the two is the 1h of the secretion amount of the bile in.
2.3.2.2 results
As can be seen from table 8, compared with the blank control group, the bile flow of the mice in the high-dose group of the drug group has a significant difference in the increase of the secretion after administration for 60min, and the bile flow of the mice in the trapbutong group is increased.
TABLE 8 Effect on mouse bile flow (. + -. s)
By t-test, P < 0.05
2.4 Effect on Rabbit common bile duct sphincter spasm
2.4.1 methods
Weighing rabbits, injecting 3% sodium pentobarbital intravenously at the ear margin according to a dose of 25mg/kg for anesthesia, fixing, performing conventional laparotomy, displaying and separating common bile duct at the descending part of duodenum, ligating the middle part of common bile duct, inserting two infusion tubes (the diameter is about 2mm) into an upper segment bile duct respectively to record bile flow, inserting a lower segment bile duct downwards to the ampulla, and connecting a water pressure meter and an injector through a three-way pipe; then the stomach wall trocar is inserted into the duodenum, and the catheter is externally connected for administration. After 30min of stabilization, the impedance of the lower segment of the common bile duct and the tension of the sphincter of Oddis were measured by direct reading. After physiological saline (35 +/-1 ℃) is slowly injected into the lower common bile duct by a syringe to be inflated, the prestress of the water pressure meter is increased to 300mmH2O, then a channel between the water pressure meter and the common bile duct is opened, and the time spent by reducing the pressure from 300mmH2O to 200mmH2O is measured and recorded (reflecting the impedance of the common bile duct and the Oddis sphincter); the channel was opened for 10min and the lowest overpressure at which pressure stabilized (reflecting the sphincter tension value of Oddis) was measured, while bile flow was measured within 10 min. Then, 0.3mg/kg of morphine hydrochloride was subcutaneously injected to induce Oddis sphincter spasm, and the measurement of the above parameters was repeated 15min later. After 25min of model making and administration, the duodenum catheters of each group are respectively administered with physiological saline, atropine 60ug/kg and drug groups 1.6, 3.2 and 6.4g crude drugs/kg (respectively equivalent to 1, 2 and 4 times of clinical equivalent dose), and the parameters are repeatedly measured for 30, 60 and 90 min.
2.4.2 results
As can be seen from Table 9, compared with the blank control group, the impedance of the common bile duct sphincter of the rabbits after morphine hydrochloride injection is obviously increased, and the impedance of the common bile duct sphincter of the rabbits after 30-90min of duodenum administration of the drug group is obviously reduced, so that the effect is basically equivalent to that of atropine sulfate.
As can be seen from Table 10, compared with the blank control group, the tension of the common bile duct sphincter of the rabbits was significantly increased after morphine hydrochloride injection, and the tension of the common bile duct sphincter of the rabbits was significantly decreased after 30-90min duodenal administration of the drug group, and the effect was substantially equivalent to that of atropine sulfate.
As can be seen from Table 11, the bile secretion of the rabbits was significantly decreased after morphine hydrochloride injection, significantly increased after the drug was administered to the duodenum for 30-90min, and significantly increased after the drug was administered to the middle and high dose groups for 60-90min, as compared to atropine sulfate.
TABLE 9 Effect of drug groups on the impedance of the common bile duct sphincter in rabbits (+ -s)
Comparing with model control group by t test, P is less than 0.05, P is less than 0.01
TABLE 10 Effect of drug groups on Rabbit common bile duct sphincter tone (+ -s)
Comparing with model control group by t test, P is less than 0.05, P is less than 0.01
TABLE 11 influence of drug groups on bile flow in rabbits (+ -s)
Comparing with model control group by t test, P is less than 0.05, P is less than 0.01; compared with atropine tablet group, # P < 0.05, # P < 0.01
2.5 study of the spleen-invigorating Effect
2.5.1 Effect on intestinal propulsive locomotion in mice
2.5.1.1 methods
50 ICR mice are divided into 5 groups with weight of 19.2 +/-1.6 g at each half of male and female, wherein the 5 groups are respectively a blank control group (ig distilled water is 10ml/kg), a compound dantong group (ig compound dantong tablet is 1.0g tablet weight/kg, which is 2 times of the clinical equivalent dose), and a low-dose group, a medium-dose group and a high-dose group (respectively ig drug groups are 4.3, 8.6 and 17.2g crude drugs/kg, which are respectively 1, 2 and 4 times of the clinical equivalent dose). Before the test, all animals are fasted for 16h, the drug is taken the next day to be prepared into suspension with 5 percent of charcoal powder and 10 percent of Arabic gum, the stomach is irrigated according to the dose of 10ml/kg, the animals are killed after 20min, and the charcoal powder propulsion rate (%) is measured.
2.5.1.2 results
As can be seen in table 12, the intestinal propulsion rate was significantly reduced in the drug group and the high dose group compared to the blank control group, indicating that the drug group was able to reduce the intestinal propulsion rate of mice.
TABLE 11 Effect of drug groups on intestinal motility (. + -. s) in mice
| Group of | Animal number (only) | Dosage (g/Kg) | Push rate (%) |
| Blank control group | 10 | DW | 59.82±8.98 |
| Compound dantong tablet set | 10 | 1.0 | 51.32±8.90* |
| Medicine group lower | 10 | 4.3 | 53.89±5.97 |
| In | 10 | 8.6 | 50.13±4.62** |
| Height of | 10 | 17.2 | 49.70±8.98* |
P < 0.05, P < 0.01, compared to the blank control group
2.5.2 Effect on gastric emptying in mice
2.5.2.1 method
50 ICR mice are divided into 5 groups with weight of 19.2 +/-1.6 g at each half of male and female, wherein the 5 groups are respectively a blank control group (ig distilled water is 10ml/kg), a compound dantong group (ig compound dantong tablet is 1.0g tablet weight/kg, which is 2 times of the clinical equivalent dose), and a low-dose group, a medium-dose group and a high-dose group (respectively ig drug groups are 4.3, 8.6 and 17.2g crude drugs/kg, which are respectively 1, 2 and 4 times of the clinical equivalent dose). After administration for 6 days by gavage, fasting for 12 hours, and subcutaneous injection of the corresponding drug (sterile filtration treatment) at 7 days, 10ml/kg, 40min, 0.1% methyl orange 0.2ml per mouse was gavage, and after 20min, the animals were sacrificed, and the methyl orange residual rate (%) in the stomach was measured by the literature () method.
TABLE 12 influence of drug groups on gastric emptying motility (. + -. s) in mice
| Group of | Animal number (only) | Dosage (g/Kg) | Residual ratio (%) |
| Blank control group | 10 | DW | 33.38±7.28 |
| Compound dantong tablet set | 10 | 1.0 | 40.24±7.20* |
| Medicine group lower | 10 | 4.3 | 40.01±8.88 |
| In | 10 | 8.6 | 42.68±9.28* |
| Height of | 10 | 17.2 | 43.02±7.64** |
P < 0.05, P < 0.01, compared to the blank control group
2.5.2.2 results
As can be seen in table 13, compared with the blank control group, the residual rate of methyl orange in the stomach of the animals in the drug group and the high-dose group is significantly increased, which indicates that the drug group has an obvious inhibition effect on gastric emptying movement.
2.6 Effect on analgesia
2.6.1 Effect on acetic acid-induced pain in mice
2.6.1.1 methods
60 ICR clean-grade mice are selected, the weight of each mouse is 20.2 +/-1.5 g, the mice are randomly divided into 6 groups according to the weight, and the 6 groups are respectively a model control group (ig distilled water is 10ml/kg), a compound Dantong group (ig compound Dantong tablets are 1.0g in weight/kg and 2 times of clinical equivalent dose), a trapbuttong group (ig traptong is 0.03g/kg and 2 times of clinical equivalent dose), a low, medium and high dose group (ig drug groups are respectively 4.3, 8.6 and 17.2g of crude drug/kg and are respectively 1, 2 and 4 times of clinical equivalent dose). The mice were dosed according to table 14, and 30min after dosing, each mouse was intraperitoneally injected with 0.6% glacial acetic acid 0.1ml/10g, and the time from glacial acetic acid injection to writhing reaction of the mice, i.e. the incubation period and the writhing frequency of the mice within 20min after glacial acetic acid injection, were recorded.
2.6.1.2 results
In table 14, compared with the model control group, the pain latency and writhing frequency of mice in the drug group and the high dose group are significantly different, and the mouse writhing reaction caused by acetic acid can be obviously inhibited, which indicates that the drug group has better analgesic effect.
TABLE 13 influence of drug groups on writhing response in mice (. + -. s)
P < 0.05 compared to model control
2.6.2 Effect on Hot plate-induced pain in mice
2.6.2.1 method
Taking 60 BALB/C line female mice meeting the requirement (the average pain threshold is within 30 s), weighing 21.0 +/-1.3 g, and the total average pain threshold is 19.5 +/-1.2 s, segmenting according to the pain threshold, and then dividing into 6 groups, namely a blank control group (ig distilled water 10ml/kg), a compound dantong group (ig compound dantong tablet 1.0g is 2 times of the clinical equivalent dose), a trapbuttong group (ig traptong 0.03g/kg is 2 times of the clinical equivalent dose), a low drug group, a medium drug group and a high drug group (ig drug groups 4.3, 8.6 and 17.2g are equivalent to 1, 2 and 4 times of the clinical equivalent dose). The dosage of the drug is given according to the table 15, the drug is given for 30min, the mouse is placed into a hot plate pain measuring instrument, the temperature of the hot plate is 55 +/-0.5 ℃, the time from the time when the mouse is put into the hot plate to the time when the mouse licks the hind paw is the pain threshold of the mouse, and the pain threshold is measured once every 30min for 3 times.
2.6.2.2 results
As shown in Table 15, compared with the blank control group, the mice in the low, medium and high dose groups of the drug group have significant difference in pain threshold values within 0.5-1.5h after administration, and can obviously improve the heat resistance of the mice, which indicates that the drug group has better analgesic effect.
TABLE 14 influence of drug groups on Hot plate pain threshold in mice (. + -. s)
P < 0.05, P < 0.01, compared to model control
2.7 study of anti-inflammatory action
2.7.1 Effect on Calicina inflamed rat footpad swelling
2.7.1.1 methods
SD-series clean rats with a weight of 187.2 +/-7.2 g are selected and randomly divided into 5 groups according to the weight, wherein the 5 groups are respectively a model control group (ig distilled water is 10ml/kg), a compound Dantong group (ig compound Dantong tablet is 0.6g pill/kg, which is 2 times of clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group (respectively, ig drug groups are 3.0, 6.0 and 12.0g crude drug/kg, which are respectively 1, 2 and 4 times of clinical equivalent dose). The administration was carried out at the dose shown in Table 16, 1 time per day for 3 consecutive days, and the thickness of the hind sole of each mouse was measured at day 3 as the thickness of the sole of the proinflammatory foot, and 0.05 ml/mouse of carrageenan was subcutaneously injected at 1h after the last administration into the hind sole of each mouse, and then the thickness of the hind sole of each mouse was measured once at 1, 2, 3, 4, 5, and 6h after the proinflammation (the thickness of the central sole of each foot at 0.5cm below the ankle joint of the rat was measured with a vernier caliper), and the swelling ratios were calculated and compared.
Swelling rate ═ thickness of postinflammatory metatarsal-thickness of pro-inflammatory metatarsal)/thickness of pro-inflammatory metatarsal × 100%
2.7.1.2 results
Table 16 shows that, compared with the model control group, the rate of swelling of rat foot sole in the high-dose group of the drug group is significantly different within 1-6h, and the rate of swelling is significantly reduced, which indicates that the drug group has significant inhibitory effect on the swelling of rat foot sole caused by carrageen, so that the drug group can inhibit the swelling of rat foot sole caused by carrageen and has certain anti-inflammatory effect.
TABLE 15 influence of drug groups on carrageenan-induced footpad swelling in rats (+ -s)
P < 0.05, P < 0.01, compared to model control
2.7.2 Effect on mouse peritoneal capillary Permeability
2.7.2.1 methods
60 ICR clean-grade mice are selected, the weight of each mouse is 23.2 +/-0.4 g, the mice are randomly divided into 5 groups, and the groups are respectively a model control group (ig distilled water is 10ml/kg), a compound dantong group (ig compound dantong tablet is 1.0g tablet/kg, which is 2 times of the clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group (respectively ig drug groups are 4.3, 8.6 and 17.2g crude drugs/kg, which are respectively 1, 2 and 4 times of the clinical equivalent dose). Each mouse is dosed according to the dosage shown in the table 17, 1 time per day is carried out for 3 days continuously, after 1 hour of the last dosing, each rat tail is injected with 10ml/kg of 0.5% of Evenyland intravenously, 10ml/kg of 0.6% of glacial acetic acid is immediately injected into the abdominal cavity, and after 20 minutes, an abdominal cavity washing solution is taken to measure an OD value, and the OD value represents the capillary permeability. (Note: the number of animals in Table 17 was only 49 because 11 mice were not successfully injected into the tail vein).
2.7.2.2 results
Table 17 shows that, compared with the model control group, the permeability of the capillary vessels in the abdominal cavity of the mice in the high-dose group of the drug group is significantly different, and the value is significantly reduced, which indicates that the drug group has an inhibitory effect on the increase of the permeability of the capillary vessels in the abdominal cavity of the mice caused by acetic acid.
TABLE 16 influence of drug groups on mouse peritoneal capillary permeability (. + -. s)
| Group of | Animal number (only) | Dosage (g/kg) | OD value |
| Model control group | 9 | DW | 0.2486±0.0529 |
| Compound dantong tablet set | 10 | 1.0 | 0.1978±0.0410* |
| Medicine group lower | 10 | 4.3 | 0.2044±0.0649 |
| In | 10 | 8.6 | 0.1979±0.0552 |
| Height of | 10 | 17.2 | 0.1892±0.0354* |
P < 0.05 compared to model control
2.8 study of bacteriostatic action
2.8.1 Effect on the death of mice infected with E.coli Standard and clinical strains
2.8.1.1 method
120 ICR clean-grade mice with weight of 20.6 +/-1.1 g and half of male and female are taken and randomly divided into 6 groups which are respectively a model control group (ig distilled water is 10ml/kg), an amoxicillin group (0.4g/kg, 2 times of clinical equivalent dose), a compound dantong group (ig compound dantong tablet 1.0 g/kg, 2 times of clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group (respectively ig drug groups 4.3, 8.6 and 17.2g crude drugs/kg, which are respectively 1, 2 and 4 times of clinical equivalent dose). The administration is carried out 6 times by gastric gavage according to the dosage of the table 18, 1 time and 3 times are carried out each day before the bacteria injection, 0.5ml of escherichia coli liquid (standard strain) is injected into the abdominal cavity of each mouse 30min after the 3 rd administration (the concentration of 90% mortality of the infected mouse is about 5.0 multiplied by 108/ml by pre-test), the administration is carried out 3 times continuously after 1h, 2 days and 3 days after the escherichia coli injection, the death condition of the mouse within 4 days is observed and recorded, and the statistical comparison is carried out according to the mortality.
120 ICR clean-grade mice with weight of 20.3 +/-1.0 g in each half of male and female are taken, the administration is carried out according to the method, 0.5ml of Escherichia coli liquid (clinical isolates) is injected (the concentration of 90% death rate of the mice infected by the bacteria is about 1.0 multiplied by 108/ml through pre-test), the death conditions of the mice within 4 days are observed and recorded, and the death rate is used for statistical comparison. The results are shown in Table 18.
2.8.1.2 results
Table 18 shows that, compared with the model control group, the mortality rates of the mice in the drug group and the high-dose group are significantly different, and the mortality rates are significantly reduced, which indicates that the drug group can significantly reduce the mortality rate of the mice infected with escherichia coli, and has a certain antibacterial effect. The amoxicillin capsule as the positive contrast medicine has excellent in-vivo antibacterial effect.
TABLE 17 Effect of drug groups on the death of E.coli infected mice
Comparing with model control group by X2, wherein P is less than 0.05, P is less than 0.01
2.8.2 Effect on death of mice infected with Standard and clinical strains of hemolytic Streptococcus
2.8.2.1 method
120 ICR clean-grade mice with weight of 22.8 +/-2.0 g and half of male and female are randomly divided into 6 groups which are respectively a model control group (ig distilled water is 10ml/kg), an amoxicillin group (0.4g/kg, 2 times of clinical equivalent dose), a compound dantong group (ig compound dantong tablet 1.0 g/kg, 2 times of clinical equivalent dose), a low-dose group, a medium-dose group and a high-dose group (respectively ig drug groups are 4.3, 8.6 and 17.2g crude drugs/kg, and are respectively 1, 2 and 4 times of clinical equivalent dose). The administration is carried out 6 times by intragastric administration according to the dosage of the table 19, 1 time and 3 times are carried out every day before the bacteria injection, 0.5ml of B hemolytic streptococcus liquid (standard strain) is injected into the abdominal cavity of each mouse 30min after the 3 rd administration (the concentration of 90% mortality of the infected mouse is about 2.5 multiplied by 109/ml) is obtained by pre-test, the administration is carried out 3 times continuously after 1h, 2 days and 3 days after the hemolytic streptococcus injection, the death condition of the mouse within 4 days is observed and recorded, and the statistical comparison is carried out by the death rate.
120 ICR clean-grade mice with weight of 20.9 +/-1.0 g in each half of male and female are taken and administered according to the method, 0.5ml of B hemolytic streptococcus liquid (clinical isolate) is injected (the concentration of 90% mortality of the infected mice is about 1.0 multiplied by 109/ml by pre-test), the death condition of the mice within 4 days is observed and recorded, and the mortality is counted and compared. The results are shown in Table 19.
2.8.2.2 results
Table 19 shows that, compared with the model control group, the mortality rate of the mice in the high-dose drug group is significantly different, and the mortality rate is significantly reduced, which indicates that the drug group can significantly reduce the mortality rate of the mice infected with the clinical isolate of hemolytic streptococcus, and has a certain antibacterial effect. The amoxicillin capsule as the positive contrast medicine has excellent in-vivo antibacterial effect.
TABLE 18 influence of drug groups on mortality of hemolytic streptococcal infected mice
Comparing with model control group by X2, wherein P is less than 0.05, P is less than 0.01
3 results
3.1 test results for treatment of bacterial cholecystitis and suppurative cholecystitis
Most of the appearance of the gallbladder of the guinea pig model with the bacterial cholecystitis is black or dark red, part of the gallbladder is adhered, and the bile is black or dark red; the weight gain is obviously slowed down; most gallbladder mucosa has a lot of folds or folds widened above 1/2, and the inherent membrane has a lot of inflammatory cells and fiber cells, and the height of the inherent layer is thickened or lengthened along with the folds of the mucosa, and the inherent membrane is connected with each other to form a net. After the compound dantong tablets and the qupibuntong tablets are orally taken for 10 days, most of the appearance of the gallbladder of the guinea pig is dark green without adhesion, and the bile is dark green or green; the weight gain is obviously recovered; the pathological symptoms are obviously improved. Compared with a model control group, after the treatment of the drug group, the appearance of the gallbladder tissue of the guinea pig is obviously reduced, the weight increase is obviously accelerated, and the histopathology of the gallbladder is obviously changed, which shows that the drug group has better treatment effect on the guinea pig bacterial cholecystitis.
The hair of the rabbit with the suppurative cholecystitis model is dull, the movement of the rabbit is slow, the ears of the rabbit are laid down, the diet is reduced, the stool is reduced or is thin, the stool is brown and yellow, the perianal area is unclean, and the individual stool is reddish; most of stomach, intestine, gallbladder and liver are adhered, the gallbladder is buried on the liver, white membrane is outside, the gallbladder is grey white, purulent substances or black mud substances are filled in the gallbladder, compared with blank control, the gallbladder wall is obviously thickened, biliary tract is narrow, and the liver and the gallbladder are hardened and in a serious inflammation pathological state; the weight gain is obviously slowed down; the pathological histological examination shows that most of the gallbladder wall mucosa are necrosed, a large number of inflammatory cells and ulcers are formed, the proliferation is adenomatous, and the submucosal tissues are basically fibrous. After being treated by the oral medicine group for 10 days, the cholecystitis rabbits basically have normal diet, are granulated in excrement and are normal in urine; the gallbladder becomes small, the stomach and the intestine are basically not adhered, the bile occasionally has purulent substances or black mud substances, most of the gallbladders basically have no purulent substances, and the gallbladder is partially white and fibrous and can be basically separated; the pathological symptoms of the gallbladder are obviously improved. Compared with a model control group, the appearance of the gall bladder tissue of the rabbit is obviously reduced after the treatment of the medicine group; the weight gain is obviously improved, and the pathological change of the gallbladder tissue is obvious, which shows that the medicine group has better treatment effect on rabbit suppurative cholecystitis.
3.2 results of the cholagogic and spasmolytic test
The drug group has obvious promotion effect on the secretion and growth of the bile flow of the rat within 30-90min after administration; the administration time is 60min, and the bile secretion of the mouse can be promoted; after the drug group is administrated in duodenum for 30-90min, the phenomena of impedance and tension increase of common bile sphincter of rabbits after morphine hydrochloride injection and bile secretion reduction can be reduced, and the effect of the drug group is basically equivalent to that of atropine sulfate. The medicine group has better functions of benefiting gallbladder and relieving spasm.
3.3 spleen invigorating test results
The drug group can reduce the intestinal propulsion rate of mice; inhibiting gastric emptying motility.
3.4 results of analgesic test
The drug group can obviously inhibit the writhing reaction of mice caused by acetic acid; can obviously improve the heat resistance of the mice, and shows that the drug group has better analgesic effect.
3.5 anti-inflammatory test results
The rate of the foot sole swelling of the rat is obviously reduced after the medicine group is orally taken for 1 to 6 hours, which shows that the medicine group has obvious inhibition effect on the foot sole swelling of the rat caused by the carrageen, so that the medicine group can inhibit the foot sole swelling of the rat caused by the carrageen and has certain anti-inflammatory effect; after the drug group is orally taken, the permeability of the capillary vessels in the abdominal cavity of the mouse is obviously reduced, which shows that the drug group has an inhibiting effect on the increase of the permeability of the capillary vessels in the abdominal cavity of the mouse caused by acetic acid.
3.6 results of bacteriostatic test
The drug group can obviously reduce the death rate of mice infected by escherichia coli infection standard strains and clinical strains, reduce the death rate of mice infected by hemolytic streptococcus clinical strains, and has a certain in vivo antibacterial effect.
The results of tests of bacterial cholecystitis and suppurative cholecystitis models, cholagogue spasmolysis, spleen strengthening, pain easing, anti-inflammatory, bacteriostasis and the like show that: the medicine group can improve the appearance of black or dark red gallbladder tissues with adhesion in part and black or dark red bile and the like of the gallbladder tissues of a bacterial cholecystitis model guinea pig, so that the weight of the guinea pig is increased; can improve the pathological symptoms that most gallbladder mucosa of model guinea pig has a large amount of folds or folds are widened above 1/2, the inherent membrane has a large amount of inflammatory cells and fibroblasts, the inherent layer is highly thickened or lengthened along with the folds of mucosa and is connected with each other to form a net, and has better therapeutic effect on guinea pig bacterial cholecystitis; the preparation can improve the characterization conditions of dull hair, slow movement, lodging of ears, diet reduction, stool reduction or loose stool, brownish yellow stool, unclean crissum and red urine of individual stool of a model rabbit with the suppurative cholecystitis, enables the weight increase to be recovered to be normal, basically improves the pathological symptoms of most gallbladder wall mucosa necrosis, a large amount of inflammatory cells and ulcer, basic fibrosis of submucosal tissues and adenomatous hyperplasia of the rabbit, and has better treatment effect on the suppurative cholecystitis of the rabbit. The drug group has obvious promotion effect on the secretion and growth of the bile flow of the rat; can promote the bile secretion of the mouse; can reduce the phenomena of impedance and tension increase of the common bile duct sphincter of the rabbit and bile secretion reduction after morphine hydrochloride injection, and shows that the medicine group has better functions of benefiting gallbladder and relieving spasm. The drug group can reduce the intestinal propulsion rate of mice; inhibit gastric emptying movement, and has certain spleen invigorating effect. The drug group can obviously inhibit the writhing reaction of mice caused by acetic acid; can obviously improve the heat resistance of the mouse and has better analgesic effect. The drug group can reduce the rat plantar swelling caused by the carrageen, has an inhibiting effect on the increase of the permeability of the capillary vessels in the abdominal cavity of the mouse caused by acetic acid, and has a certain anti-inflammatory effect. The drug group can reduce the death rate of mice infected by escherichia coli, hemolytic streptococcus standard strains and clinical strains, has the Minimum Inhibitory Concentration (MIC) of 0.48g/ml for escherichia coli and typhoid bacillus and the Minimum Bactericidal Concentration (MBC) of 0.95 g/ml and 0.48g/ml respectively, and has a certain in-vivo antibacterial effect.
The pharmacological research provides a certain theoretical basis for the clinical application of the drug group.
EXAMPLE 7 clinical study of pharmaceutical compositions
The study subjects group performed clinical studies by random grouping, positive drug (gallstone removal, anti-inflammatory cholagogic tablet) control, and single blind observation. The test medicine group contains 0.85g of crude drugs per tablet. The reference medicine, danshitong, is produced by the pharmaceutical factory of Guangdong Shantou, and the anti-inflammatory and cholagogic tablet is produced by the pharmaceutical factory of Guangzhou Xingcheng. In 368 cases of the treatment results group, 301 cases were clinically controlled, 37 cases were significantly effective, 24 cases were effective, and 6 cases were ineffective. In 72 cases of the Danshitong group, there were 33 cases of clinical control, 19 cases of significant effect, 11 cases of effect and 9 cases of no effect. 81 cases of anti-inflammatory and cholagogic tablet groups, 30 cases of clinical control, 22 cases of effective treatment, 16 cases of effective treatment and 13 cases of ineffective treatment. Through statistical treatment, x2 is 106.65, less than 0.05, Ridit analysis shows that the curative effect of the treatment group is excellent, and there is no difference between the cholelithiasis treating and inflammation diminishing cholagogic tablets. Adverse reactions of the drugs and abnormal changes of safety indexes are not observed in the test process.
Clinical observation results show that the product is suitable for patients with chronic cholecystitis liver and gallbladder disharmony and damp-heat retention syndrome, such as epigastric or hypochondriac distending pain, right shoulder and back pain, abdominal distension and poor appetite, bitter taste in mouth, greasy tongue coating and the like, can quickly relieve clinical symptoms of chronic cholecystitis hypochondriac pain, epigastric pain, abdominal distension, anorexia and the like, can basically control clinical symptoms after being taken for one week to one month, and has the effective rate of over 90 percent. The patients with chronic cholecystitis complicated with cholelithiasis are treated for three months, and calculus imaging examination of a considerable part of the patients is improved. In the clinical application process, no obvious adverse reaction is seen.
Claims (9)
1. A pharmaceutical composition for treating chronic cholecystitis is characterized by being mainly prepared from the following traditional Chinese medicine raw materials in parts by weight: 10-15 parts of white paeony root, 8-12 parts of corydalis tuber, 8-12 parts of angelica, 8-12 parts of bighead atractylodes rhizome, 10-15 parts of oriental wormwood, 8-12 parts of szechwan chinaberry fruit, 6-11 parts of cluster mallow fruit, 10-15 parts of poria cocos, 6-11 parts of rhizoma alismatis, 6-11 parts of cape jasmine fruit, 6-11 parts of calcined concha arcae, 6-11 parts of endothelium corneum gigeriae galli and 3-6 parts of liquorice.
2. The pharmaceutical composition for treating chronic cholecystitis as claimed in claim 1, wherein the weight parts of the traditional Chinese medicine raw materials are as follows: 14 parts of white paeony root, 12 parts of corydalis tuber, 12 parts of angelica, 12 parts of bighead atractylodes rhizome, 15 parts of oriental wormwood, 12 parts of szechwan chinaberry fruit, 10 parts of cluster mallow fruit, 15 parts of tuckahoe, 11 parts of rhizoma alismatis, 11 parts of cape jasmine fruit, 11 parts of calcined concha arcae, 11 parts of endothelium corneum gigeriae galli and 6 parts of liquorice.
3. A process for preparing a pharmaceutical composition according to any one of claims 1 to 2, comprising the steps of:
(1) crushing the chicken's gizzard-membrane into fine powder for later use according to the weight parts;
(2) mixing the angelica, the bighead atractylodes rhizome and the oriental wormwood in parts by weight, and distilling the mixture for 4 to 6 hours by using 6 to 10 times of water to obtain volatile oil; clathrating with beta-CD to obtain beta-CD clathrate, and collecting the residue;
(3) mixing rhizoma corydalis and fructus gardeniae according to the weight parts, adding 60-80% ethanol in an amount which is 4-8 times that of the mixture, performing reflux extraction for 2 times, and combining ethanol extract for later use, wherein each time lasts for 1-3 hours; optionally further concentrating the ethanol extractive solution under reduced pressure to obtain ethanol extract; the dregs after the ethanol extraction are reserved for standby;
(4) decocting calcined concha arcae in 8-12 times of water for 30-60 minutes according to the weight part, mixing with the white paeony root, the szechwan chinaberry fruit, the cluster mallow fruit, the poria cocos, the rhizoma alismatis and the liquorice in the weight part, and adding 6-10 times of water for decocting for 1-2.5 hours;
(5) mixing the mixture decocted in the step (4) with the dregs extracted in the step (2) and the step (3), and decocting for 1-2.5 hours by using 6-10 times of water;
(6) filtering the extracting solution obtained after the decoction in the steps (4) and (5), combining, centrifuging and reserving the centrifugate for later use; the centrifugate can be further concentrated into extract under reduced pressure;
(7) mixing the ethanol extract in the step (3) and the centrifugate in the step (6), concentrating under reduced pressure to obtain an extract, adding the fine powder of the endothelium corneum gigeriae galli obtained in the step (1), mixing, drying, and crushing into fine powder to obtain the active ingredient of the medicament; or,
and (3) mixing the alcohol extract obtained in the step (3) and the extract obtained in the step (6), adding the fine powder of the endothelium corneum gigeriae galli obtained in the step (1), mixing, drying, crushing into fine powder, adding the beta-CD inclusion compound, and uniformly mixing to obtain the active ingredient of the medicament.
4. The method for preparing a pharmaceutical composition according to claim 3, wherein the pharmaceutically active ingredient of step (7) is mixed with excipients or adjuvants to make any one of the usual dosage forms.
5. The process for preparing a pharmaceutical composition according to claim 4, wherein the dosage forms are tablets, capsules and pills.
6. The method for preparing a pharmaceutical composition according to claim 3, wherein the ethanol reflux extraction time in step (3) is 1.5 to 2.5 hours.
7. The process for preparing a pharmaceutical composition according to claim 3, wherein the time for the second water decoction in step (4) is 1.5 to 2.5 hours.
8. The process for preparing a pharmaceutical composition according to claim 3, wherein the water decoction time in the step (5) is 1.5 to 2.5 hours.
9. Use of a pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament for the cholagogic, spasmolytic, spleen-invigorating, analgesic, anti-inflammatory or bacteriostatic treatment.
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