CN101342194B - Traditional Chinese medicine preparation for treating median or late-stage malignant tumors, chronic hepatitis B, and preparation method thereof - Google Patents
Traditional Chinese medicine preparation for treating median or late-stage malignant tumors, chronic hepatitis B, and preparation method thereof Download PDFInfo
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Abstract
The present invention discloses a Chinese medicine for curing advanced cancers and chronic hbv hepatitis and a preparation method. The present invention is proportionally manufactured by a medicinal active component made of dry toad skin and a medicine-acceptable carrier; the medicine carrier contains sodium carboxymethylcellulose and starch. Compared with the prior dosage, the present invention with advanced process and high medicine content strengthens the curing effect, reduces the toxic side effect of the medicine and ensures safer and more convenient medicine taking for patients.
Description
Technical field
The present invention relates to a kind of Chinese medicine preparation for the treatment of middle and advanced stage tumor, chronic viral hepatitis B and preparation method thereof, belong to technical field of traditional Chinese medicine pharmacy.
Technical background
According to The World Health Organization's report, the past, global tumor invasion increased by 22% during the decade.No matter from morbidity (1,200,000) still dead (1,100,000), tumor is global topmost disease, and according to World Health Organization's scholarly forecast, tumor will become the new century mankind's first killer.
Hepatitis B is a kind of serious infectious disease that is caused by hepatitis B virus (HBV), and China has nearly 700,000,000 population infection cross hepatitis B virus, wherein has people more than 100,000,000 to carry virus throughout one's life, and more than 3,000 ten thousand people become the chronic viral hepatitis B patient.
Therefore, above-mentioned two kinds of diseases for many years always are the great difficult problem of medical educational circles joint research.
The water soluble ingredient indoles alkaloid of dry maxima skin has the immunity of adjusting, suppresses duplicating of HBV, DNA, has stronger antivirus action, and hepatitis B is had good therapeutical effect.Liposoluble constituent bufogenin class in the dry maxima skin has remarkable antitumor effect, there is big defective in prior art to the extraction of these two kinds of compositions at present: the cinobufacin sheet, Chinese patent (application number 200510005277.4) " cinobufacin (Cutis Bufonis) extract production process " all adopts aqueous extraction-alcohol precipitation technology 1. that liposoluble constituent bufogenin classes a large amount of in the dry maxima skin is not extracted.2. a large amount of water soluble ingredient indoles alkaloids is discarded.3. the cinobufacin sheet is a coated tablet, and dose is big, is difficult for being accepted by the patient.It adopts extraction process by water Chinese patent (application number 200510115451.0) " a kind of preparation method of cinobufotalin lyophilized powder ", makes that a large amount of liposoluble constituent bufogenin classes are discarded in the dry maxima skin, is unfortunate really.It adopts alcohol extraction process Chinese patent (application number 200410083994.4) " a kind of cinobufotalin lyophilized powder and preparation method thereof ", makes that a large amount of water soluble ingredient indoles alkaloids are discarded in the dry maxima skin, is unfortunate really.Chinese patent (200610167378.6) " total bufogenin extract, Preparation Method And The Use " with antitumor action, Chinese patent (200610096075.X) " Cutis Bufonis extract, its pharmaceutical preparation and preparation method thereof " is though improved indoles alkaloid respectively and the content of bufogenin class material, but it has used severe toxicity, carcinogenic reagent such as a large amount of methanol, chloroform, acetone in preparation process, its clinical adverse is many, and serious.
At the deficiencies in the prior art, we have invented a kind of treatment middle and advanced stage tumor, chronic viral hepatitis B Chinese medicine enteric coated capsule preparation, it be by dry maxima skin through being processed into active constituents of medicine and the medicine acceptable carrier through being processed into.After the alcohol extraction of this process using medicinal residues again water carry, respectively centrifugal, kept liposoluble constituent bufogenin and water soluble ingredient indoles alkaloid in the dry maxima skin to greatest extent, and effectively removed impurity.Enteric coated preparation of the present invention is compared with existing dosage form, has the technology advanced person, active constituents of medicine content height, and the bioavailability height, dose is little, has strengthened curative effect, has reduced toxicity, makes patient's safe ready more of taking medicine.
Summary of the invention
The purpose of this invention is to provide active constituent content height, stable curative effect, the treatment middle and advanced stage tumor that dose is little, toxic and side effects is little, the Chinese medicine enteric coated capsule of chronic viral hepatitis B.
Another purpose of the present invention provides the preparation method of Chinese medicine enteric coated capsule of a kind of technology advanced person's treatment middle and advanced stage tumor, chronic viral hepatitis B.
For achieving the above object, the technical solution used in the present invention is:
Get 3500 of dry maxima skins, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
Theory of Chinese medical science is thought:
Emphasize endogenous cause of ill for the extremely that the cause of disease traditional Chinese medical science of tumor has, positive QI-insufficiency then has the exopathogen invasion and attack." people of all spleen kidney deficiencies and debilitating disorder has the disease of gathering more ", and " long-pending one-tenth also, positive QI-insufficiency, then pathogen is crouched it, ".The cause of mentioning abscess in the existing medical book Miraculous Pivot the earliest of China is because " pathogen occupies therebetween "." interior warp " said: " the diaphragm plug closes exhausted, and is obstructed up and down ... that then disease due to intense worry also " is for choking every the cause of disease of (esophageal carcinoma).Chen Shigong work " Waike Zhengzong, Orthodox Manual of External Diseases " carries: and " carcinoma of lip ... because of food is fried in shallow oil stir-fry, surfeit are processed and are doublely pondered over sudden and violent urgency, and expectorant is capable with fire, stay and annotate in lip, and just knot is like bean, gradually big if Bombyx bombycis, and prominent swollen hard, very the person has a pain ... ".Record in the Shen Douyuan work " surgery opens profound ": " first time-out is cold and heat pain not, and atropurpureus is broken, and the inside is earlier from black mashed, 20 years old later on accidentally the long-pending heat of sexual life gives birth to, on 40 years old, the anemia weakness of QI, savoury is too much gives birth to, perfect one or two, skin is deceived person's refractory and be will certainly die.”。Errors in Medicine Corrected is sayed it " tripe fu jie piece, blood that must be tangible ".Be how enclosed mass tangible in the abdomen swells thing by due to the blood stasis.
For treatment, " defend Ji treasured book " also introduce use oral medicinal herb external " should descend big Hippopus hippopus (Linnaeus) to loose and get it, obey evacuation of pus then, the Tuoli that relieves internal heat, interior benefit etc. loose, after breaking the Moschus patch it." " Shanxi book " be loaded with " first Supreme Being's order has big tumor disease, make doctor cut it." this is the record the earliest of using the operative treatment tumor in motherland's medical literature.
In the successive dynasties document, we can also see that motherland's medical science attaches great importance to the prevention of tumor and early discovery, early treatment.As saying that " acid regurgitation, little disease also in " card is controlled to converge and mended ".So, can be of a specified duration.Or neglect it with little disease, this does not know, and it is dysphagic, regurgitation gradually also." illustrate that ancient medicine clearly realizes that clinically, the chronic stimulation disease of some stomach, such as chronic gastropathy, gastric ulcer, as not finding early, treatment in time, the possibility that canceration is then arranged of long duration.In " skin infection experience pandect " breast carcinoma is said especially: " if broken can treatment, broken refractory ", " Zhi Desheng early, then internal ulceration meat is mashed late sees the five internal organs and dead." emphasized the early discovery and the early treatment of tumor, be the key of success and failure.
Bufo siccus is of long duration as the Drug therapy disease, its property theory record, and head sees first pharmacology monograph Shennong's Herbal of China: " Rana limnocharis, acrid in the mouth, cold, main pathogen, broken malicious hard blood, carbuncle, the erosion of vulva, that obeys does not fever ".The name of " Bufo siccus ", head sees " Mingyi Bielu ", and TAO Hong-Jing is annotated cloud, Rana limnocharis " Bufo siccus ".Cutis Bufonis is used as medicine separately, and the beginning sees " herbal classic is met former ": " Cutis Bufonis, hot, cool, little poison ".This agrostology monumental work in the present age " China's book on Chinese herbal medicine " record road: Bufo siccus " acrid in the mouth, cool in nature, poisonous.GUIXIN, liver, spleen, lung meridian ", can " detoxicating and resolving stagnation of pathogens, removing food stagnancy diuretic, destroying parasites for curing malnutrition.Cure mainly carbuncle, furuncle, carbuncle on the back, scrofula, malignant boil, the abdominal mass hypochondriac lump, tympanites, edema, infantile malnutrition, tetanus, chronic cough and asthma ", and further point out " Bufo siccus also is applied to oncotherapy, and gastric cancer, the esophageal carcinoma, bladder cancer, hepatocarcinoma, leukemia are had certain curative effect ".
For tumor, the common typing of the traditional Chinese medical science is as follows:
(1) syndrome of qi stagnation and blood stasis is controlled
[clinical manifestation] breast side of body feeling of distension and oppression, irascible temperament, the side of body mass in the abdomen occurs down, the twinge tenderness, localized pain is gone into the Night Watch play, can lay one's hand on and swollen thing enclosed mass the black purple of onyx, dark tongue quality or see purpura, petechia, hesitant pulse etc.
(2) phlegm-damp cohesion card is controlled
[clinical manifestation] phlegm-damp stagnates at lung, as seen breathes with cough and coughs up phlegm; Stagnation of phlegm is in the heart, and painstaking effort are not smooth, visible chest distress and palpitation symptoms, mental confusion due to phlegm, then visible coma, dementia; The heart disturbed by phlegm-fire is then sent out to demented; Expectorant is stopped at stomach, stomach-QI being unable to descend normally, visible nausea and vomiting, gastral cavilty feeling of fullness; Expectorant then can cause the scrofula sucutaneous nodule meridians muscles and bones, swollen thing enclosed mass, numb limbs and tense tendons or hemiplegia; Violate in head on expectorant is turbid, then cause dizzy, confused emitting; The mental disorder throat that condenses then blocks in the pharynx, gulp down not down, that tells does not go out, or foam at the mouth mucus sputum.Assertive evidence is more common in esophageal carcinoma, pulmonary carcinoma companion ascites pleural fluid.
(3) vehement card is controlled in the pyretic toxicity
[clinical manifestation] heating, flushing conjunctival congestion, thirst and liking drink, the dry pharynx dryness of the tongue, vexed insomnia, dry cough is losed heart, and expectorant is few and thick, or sputum mixed with blood, constipation, oliguria with reddish urine, or low grade fever night sweat, flushed cheeks, dizziness and tinnitus, hematemesis and epistaxis, red tongue, rapid pulse.
(4) the insufficiency of vital energy and blood card is controlled
[clinical manifestation] has a dizzy spell, deficiency of QI with disinclination to talk, weak spontaneous perspiration, pale white complexion or sallow, palpitation and insomnia, light red tongue and tender, thready and weak pulse etc.
(5) syndrome of blood stasis due to qi deficiency is controlled
[clinical manifestation] pale white complexion or dark stagnate, body is tired weak, deficiency of QI with disinclination to talk, pain is as thorn (being common in breast side of body position), pain in fixed position, tenderness, light red tongue is dark or purpura, deep and hesitant pulse arranged.
(6) syndrome of hyperactivity of fire due to deficiency of YIN is controlled
[clinical manifestation] hectic fever in the afternoon, or night heating, the heating no desire to wear clothes, the heating of brothers' heart, or osteopyrexia and fever, vexed, sleep dreaminess, flushed cheeks, night sweat, dry mouth and throat, constipation with dry stool, oliguria yellow skin, body of the tongue extra dry red wine or crackle is arranged, no fur or few tongue, thready and rapid pulse less.
(7) syndrome of water over-flowing due to YANG-insufficiency is controlled
[clinical manifestation] general edema, waist is following for very, by depression do not rise, even the abdominal part distension, the cardiopalmus cough with asthma, soreness of the waist and knees and the pain, aversion to cold and cold limbs is attached most importance to lower limb, the vertigo, lethargy, dysuria, nocturia is more, pale complexion or dark, light red tongue is fat, tongue is white, deep-thready pulse, or the stool chronic diarrhea is more than, die-hard, have loose bowels just before dawn.
Dry maxima skin has the refreshment of having one's ideas straightened out, pain relieving, antidotal effect.Be used for malignant boil, scrofula, laryngopharynx swelling and pain and various toothache.This product is poisonous, and good counteracting toxic substances reducing swelling and alleviating pain effect is arranged, and external, for oral administration good effect is arranged all.The cinobufacin main component is a dry maxima skin, wherein contains bufadienolide, lipid material in the toadpoison.Have heat-clearing and toxic substances removing, reducing swelling and alleviating pain, blood circulation promoting and blood stasis dispelling, the effect of hard masses softening and resolving is used for advanced malignant tumor, and is evident in efficacy to digestive system tumor especially.
At the deficiencies in the prior art, we have invented a kind of treatment middle and advanced stage tumor, chronic viral hepatitis B Chinese medicine enteric coated capsule preparation, it be by dry maxima skin through being processed into active constituents of medicine and the medicine acceptable carrier through being processed into.After the alcohol extraction of this process using medicinal residues again water carry, respectively centrifugal, kept liposoluble constituent bufogenin class and water soluble ingredient indoles alkaloid in the dry maxima skin to greatest extent, and effectively removed impurity.Enteric coated preparation of the present invention is compared with existing dosage form, has the technology advanced person, active constituents of medicine content height, and the bioavailability height, dose is little, has strengthened curative effect, has reduced toxicity, makes patient's safe ready more of taking medicine.
The existing cinobufacin sheet of enteric coated capsule contrast with the present invention's preparation illustrates its main pharmacodynamics below:
The experiment medicine:
Enteric coated capsule of the present invention is the medicine of the embodiment of the invention 1 method preparation.
The cinobufacin sheet is to buy on the market.
One, antitumor action
1, to the influence of mouse transplanted sarcoma 180 (S-180) solid type
60 of kunming mices, male and female half and half, body weight 18～22g, every the right axillary fossa subcutaneous vaccination of mice 1:4S-180 cell suspension 0.2ml is divided into 6 groups next day, 10 every group at random.Matched group is irritated the isopyknic normal saline of stomach; Cinobufacin sheet group gastric infusion 6g medical material/kg; Enteric coated capsule group gastric infusion 1.5,3 of the present invention, 6g medical material/kg; The positive matched group of cyclophosphamide.The next day subcutaneous injection cyclophosphamide 0.03g/kg.Gastric infusion is 14 days continuously, once a day.Next day after administration finishes, put to death mice, strip the tumor piece, weigh, calculate its tumor control rate.See Table 1
The influence of table 1 pair mice transplantability S-180 solid type (x ± s)
Compare * * P＜0.01 with matched group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: growth has the obvious suppression effect to mouse transplanted sarcoma 180 solid types for enteric coated capsule group of the present invention, cinobufacin sheet group and cyclophosphamide group, has compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention, cinobufacin sheet group are strong to mouse transplanted sarcoma 180 solid type growth inhibited effects, and antitumor action strengthens.
2, to the influence of mouse bearing liver cancer (Hep) solid type
60 of kunming mices, male and female half and half, body weight 18～22g, every the right axillary fossa subcutaneous vaccination of mice 1:4Hep cell suspension 0.2ml is divided into 6 groups next day, 10 every group at random.Matched group is irritated the isopyknic normal saline of stomach; Cinobufacin sheet group gastric infusion 6g medical material/kg; Enteric coated capsule group of the present invention is gastric infusion 1.5,3,6g medical material/kg respectively; The positive matched group of cyclophosphamide.The next day subcutaneous injection cyclophosphamide 0.03g/kg.Gastric infusion is 14 days continuously, once a day.Next day after administration finishes, put to death mice, strip the tumor piece, weigh, calculate its tumor control rate.See Table 2
The influence of table 2 pair mice transplantability HEP solid type (x ± s)
Compare * * P＜0.01 with matched group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: growth has the obvious suppression effect to the mouse bearing liver cancer solid type for enteric coated capsule group of the present invention, cinobufacin sheet group and cyclophosphamide group, has compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention is stronger to the effect of mouse bearing liver cancer solid type growth inhibited than cinobufacin sheet group, and antitumor action strengthens.
Two, to the influence of immune function
1, to the influence of mononuclear cell phagocytic function
50 of kunming mices, body weight 18～22g, male and female half and half are divided into 5 groups at random, 10 every group.Matched group is irritated stomach to the normal saline with volume; Cinobufacin sheet group gastric infusion 6g medical material/kg; Enteric coated capsule group of the present invention is gastric infusion 1.5,3,6g medical material/kg respectively.Continuous gastric infusion 7d, once a day, 1h after the last administration, only (dilute 6 times) in mouse tail vein injection india ink 0.1ml/ with normal saline, 2min, 20min after injection, get blood 20ml with the eye socket vein respectively, add in the 4ml0.1% sodium carbonate liquid 752 type spectrophotometer 680nm place colorimetrics.Take by weighing the mice body weight then, put to death mice, take by weighing Mouse Liver, spleen weight, calculate phagocytic index.See Table 3
The influence of table 3 pair mouse monokaryon cytophagy (x ± s)
Compare * * P＜0.01 with matched group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: enteric coated capsule group of the present invention and cinobufacin sheet group have tangible potentiation to monocytic phagocytic function, have compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention obviously strengthens monocytic phagocytic function than cinobufacin sheet group.
2, the influence that hemolysin is generated
60 of kunming mices, male and female half and half, body weight 18～22g is divided into 5 groups at random, 12 every group.Matched group is irritated the isopyknic normal saline of stomach; Cinobufacin sheet group gastric infusion 6g medical material/kg; Enteric coated capsule group of the present invention is gastric infusion 1.5,3,6g medical material/kg respectively.Successive administration 7d, once a day, first day every Mus lumbar injection 5% chicken red blood cell suspension 0.2ml carries out immunity in administration.Immunity back 7d, 1h after the last administration plucks eyeball and gets blood, and is centrifugal, gets serum and dilutes 100 times with normal saline.Getting serum 1ml mixes with 5% chicken red blood cell suspension 0.5ml, in 0 ℃ of refrigerator, add 10% complement 0.5ml, in 37 ℃ of calorstats, be incubated 30min, cessation reaction in 0 ℃ of refrigerator, centrifugal, get supernatant 1ml and 3ml Dou Shi reagent reacting,, survey absorbance in 752 type spectrophotometer 560nm place colorimetrics.Calculate hemolysin content.See Table 4
The influence that table 4 pair hemolysin generates (x ± s)
Compare * * P＜0.01 with matched group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: enteric coated capsule group of the present invention and cinobufacin sheet group have the effect of remarkable increase hemolysin content, have compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention is stronger than the effect that cinobufacin sheet group increases hemolysin content.
Three, the effect of resistance of hepatitis B
1, the influence of the damage of the liver function that carbon tetrachloride is caused
SD is 60 of rat, male and female half and half, and body weight 150～180g is divided into 6 groups at random, 10 every group.Blank group and carbon tetrachloride poisoning matched group are irritated the isopyknic normal saline of stomach; Cinobufacin sheet group gastric infusion 3.2g medical material/kg; Enteric coated capsule group of the present invention is gastric infusion 0.8,1.6,3.2g medical material/kg respectively.Successive administration 10d, once a day, 10d irritates stomach 15% carbon tetrachloride Oleum Sesami liquid 0.2ml/100mg (except the blank).Put to death mice behind the 24h, it is centrifugal to get blood, gets serum is measured serum paddy third Cyklokapren (SGPT) and glutamic oxaloacetic transaminase, GOT (SGOT) by reitman-frankel method activity.See Table 5
Table 5 couple carbon tetrachloride poisoning mice SGPT, the active influence of SGOT (x ± s)
Compare * * P＜0.01 with the carbon tetrachloride poisoning group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: enteric coated capsule group of the present invention and cinobufacin sheet group can obviously suppress the rising that carbon tetrachloride causes rat blood serum SGPT and SGOT, and hepatic injury is had the effect of obvious protection, have compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention causes that to carbon tetrachloride rat blood serum SGPT and SGOT rising inhibitory action strengthen, and strengthen the liver injury protection effect than cinobufacin sheet group.
2, promote the effect of bile secretion
SD is 50 of rat, male and female half and half, and body weight 150～180g, fasting (can't help water) 12h divides 5 groups at random, 10 every group.Matched group is given isopyknic normal saline; Cinobufacin sheet group administration 3.2g medical material/kg; Enteric coated capsule group of the present invention administration 0.8,1.6 respectively, 3.2g medical material/kg.Cut open the belly under the 3% pentobarbital 30mg/kg intraperitoneal injection of anesthesia, insert an internal diameter 2mm plastic flexible pipe to collect bile, cut off paries anterior gastricus, in duodenum, insert an internal diameter 2mm flexible pipe in order to administration at nearly pylorus place at left and right sides common hepatic duct.Treat that bile flow experimentizes after stable, observe the biliary flow of administration front and back 30min.See Table 6
The excretory influence of table 6 pair rat bile (x ± s)
Compare * * P＜0.01 with matched group; With cinobufacin sheet group than △ P＜0.05, #P 0.05.
The result: enteric coated capsule group of the present invention and cinobufacin sheet group can obviously increase biliary secretion, have compared utmost point significant difference with matched group.Enteric coated capsule group of the present invention promotes the bile secretion effect to strengthen than cinobufacin sheet group.
3, to the medicine inhibition test of duck hepatitis-B animal model
Adopt vertical transmission infected duck hepatitis B virus (DHBV), the positive sheldrake of DHBV-DNA detection sets up 6 groups separately, and each group is 12 December sheldrakes of selecting at random in age, cinobufacin sheet group administration 4g medical material/kg; Enteric coated capsule group of the present invention administration 1,2 respectively, 4g medical material/kg; Positive controls (acycloguanosine 0.4g/kg), oral administration, 3 times weekly, the next day administration, continuous 12 weeks; The oral lactasinum tablet of negative control group, 1 slice/time, continuous 12 weeks.Below respectively organize sheldrake the 2nd all venous blood collections after the 4th week, the 8th week, the 12nd week and the drug withdrawal before administration, after the administration respectively, do the DHBV one DNA dot blot hybridization test of serum.See Table 7
The influence of table 7 pair sheldrake serum DHBV-dna content
++ ++ being equivalent to DHBV-dna content is 100pg; +++be 50pg; ++ be 25pg; + be 10pg
The result: enteric coated capsule group of the present invention and cinobufacin sheet group have in various degree reduction to the content of sheldrake serum DHBV-DNA, can suppress duplicating of DHBV-DNA, significant difference is arranged before and after administration, has function of resisting hepatitis B virus, during 12 weeks, enteric coated capsule group negative conversion rate of the present invention is respectively 66.7%, 58.3%, 50% in medication; Cinobufacin sheet group negative conversion rate is 50%.Enteric coated capsule group of the present invention is stronger than cinobufacin sheet group function of resisting hepatitis B virus.
Conclusion: enteric coated capsule group of the present invention and cinobufacin sheet group have the obvious suppression effect to growth of mouse transplanted sarcoma 180 solid types and the growth of mouse bearing liver cancer solid type; Monocytic phagocytic function had tangible potentiation; Effect with remarkable increase hemolysin content; Obviously suppress the rising that carbon tetrachloride causes rat blood serum SGPT and SGOT, hepatic injury is had the effect of obvious protection; Can obviously increase biliary secretion; The content of sheldrake serum DHBV-DNA there is in various degree reduction, can suppresses duplicating of DHBV-DNA, have function of resisting hepatitis B virus.As seen, enteric coated capsule of the present invention improves the immunity of body than cinobufacin sheet antitumor, and pharmacological actions such as resistance of hepatitis B are strong.
Enteric coated capsule of the present invention is through long term toxicity test, the result shows: the present invention has carried out to rat that basic, normal, high three dosage are respectively 8,16,32g/kg/d, be equivalent to 19.0,38.1,76.2 times of clinical plan consumption, cycle is the long term toxicity test in 12 weeks, day by day observe the general situation of animal after the administration, weigh weekly once, after 12 weeks of administration, each group is all put to death 12 rat, remains the rat drug withdrawal in addition and recovers to put to death after 2 weeks.After 12 weeks of administration, enteric coated capsule of the present invention is to the general situation of animal, and hematology, blood biochemical are learned, electrocardiogram does not all have tangible influence, the yet no abnormal pathological change of system's dissection, organ coefficient and histopathological examination.2 weeks of drug withdrawal are not seen obvious change yet.So in the cycle long term toxicity test in 12 weeks of rat, do not find overt toxicity reaction and delayed toxicity reaction.As seen, the following rat oral administration of 32g/kg/d is a safe dosage.
Enteric coated capsule of the present invention is through acute toxicity testing, and the result shows: with enteric coated capsule Cmax of the present invention, maximum volume gastric infusion, successive administration is 3 times in 24h, each 3h at interval, and accumulation medicine total amount reaches 125g/kg, is equivalent to 298 times of clinical plan consumption.Mice is movable normal after matched group and the enteric coated capsule group of the present invention administration, animal skin gloss, and mouth and nose do not have secretions, do not have diarrhoea and take place.There is not 1 dead mouse.Weigh behind the administration 7d, 8d puts to death every mice perusal heart of back dissection, liver, spleen, lung, kidney, brain, thymus, adrenal gland, ovary, uterus, stomach, intestinal etc. and does not all find color and paramophia.Show that enteric coated capsule of the present invention does not have acute toxic reaction.
Clinical trial:
Enteric coated capsule of the present invention is through clinical observation patient 293 examples, outpatient's 131 examples wherein, inpatient's 162 examples.Wherein treat pulmonary carcinoma 76 examples, the esophageal carcinoma 85 examples, cervical cancer 64 examples, chronic hepatitis B 73 examples.This product is oral, one time 2,3～4 times on the one.Enteric coated capsule centering of the present invention, late tumor, the patient's of chronic hepatitis b disease clinical observation, the result shows: enteric coated capsule total effective rate of the present invention is 85.6%, its clinical efficacy is satisfied.After the patient uses this product, clinical symptoms can be improved at short notice, patient's clinical sign can be eliminated within a certain period of time, the detoxifcation of this product is described, detumescence, the exact efficacy of pain relieving, and in the clinical observation process, do not find that the patient has untoward reaction and anaphylaxis, this product safety, effective is described.
The specific embodiment of the invention:
The embodiment of the invention 1:
Get dry maxima skin 3500g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
The embodiment of the invention 2:
Get dry maxima skin 2500g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
The embodiment of the invention 3:
Get dry maxima skin 3000g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
The embodiment of the invention 4:
Get dry maxima skin 4000g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
The embodiment of the invention 5:
Get dry maxima skin 4500g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose, starch mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
Claims (2)
1. Chinese medicine preparation for the treatment of middle and advanced stage tumor, chronic viral hepatitis B is characterized in that it is the enteric coated capsule of being made through following preparation method by dry maxima skin and sodium carboxymethyl cellulose, starch:
Get dry maxima skin 2500g-4500g, shred, clean, add the alcohol reflux secondary, refluxed 1 hour for the first time, refluxed 30 minutes for the second time, merge extractive liquid, filters, medicinal residues are standby, and filtrate is got supernatant recovery ethanol to there not being the alcohol flavor with the centrifugal 30min of 3500～4500r/min rotating speed, and it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, decocted 1 hour for the first time, decocted 45 minutes for the second time, merging decocted, and filtrate is with the centrifugal 30min of 3500～4500r/min rotating speed, get supernatant concentration to clear paste, merge with above-mentioned clear paste, be spray dried to fine powder, promptly get active constituents of medicine, again with sodium carboxymethyl cellulose 50g, starch 150g mixing, make granule, the enteric coated capsule of packing into, promptly.
2. according to claim 1, it is characterized in that the concrete preparation method of this enteric coated capsule is as follows:
Get dry maxima skin 3500g, shred, clean, add 85% alcohol reflux secondary, add 6 times of amount ethanol for the first time, soaked 2 hours earlier, reflux, extract, is 1 hour again, adds 4 times of amount ethanol for the second time, reflux, extract, 30 minutes, merge extractive liquid,, filter, medicinal residues are standby, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant recovery ethanol to there not being the alcohol flavor, it is standby to get clear paste; Get the alcohol extraction medicinal residues, decoct with water secondary, add 8 times of water gagings for the first time, decocted 1 hour, and added 6 times of water gagings for the second time, decocted 45 minutes, collecting decoction filters, and filtrate is with the centrifugal 30min of 4000r/min rotating speed, get supernatant concentration to relative density and be 1.08～1.12 clear paste, merge, be spray dried to fine powder with above-mentioned clear paste, promptly get active constituents of medicine, with sodium carboxymethyl cellulose 50g, starch 150g mixing, make granule again, the enteric coated capsule of packing into promptly gets enteric coated capsule of the present invention.
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| CN102670656B (en) * | 2012-05-18 | 2013-05-29 | 陕西东泰制药有限公司 | Chinese medicinal enteric capsules for treating medium-term and advanced tumors and chronic hepatitis B and preparation method for capsules |
| CN102813681A (en) * | 2012-08-27 | 2012-12-12 | 刘春红 | Preparation method of Cordyceps-toad skin composition |
| CN105582023B (en) * | 2015-05-25 | 2019-10-25 | 浙江中医药大学 | A kind of preparation method of toad cake extract and its sustained release pellet |
| CN105055455B (en) * | 2015-08-06 | 2017-07-28 | 陕西东泰制药有限公司 | It is a kind of to be used for Advanced cancers, Chinese medicinal enteric capsule of chronic hepatitis B and preparation method thereof |
| CN105147920B (en) * | 2015-09-21 | 2020-02-14 | 贵阳中医学院 | Medicine for treating tumor and preparation method thereof |
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