CN100574768C - A kind of anticancer pharmaceutical composition and its production and use - Google Patents
A kind of anticancer pharmaceutical composition and its production and use Download PDFInfo
- Publication number
- CN100574768C CN100574768C CN200610042221A CN200610042221A CN100574768C CN 100574768 C CN100574768 C CN 100574768C CN 200610042221 A CN200610042221 A CN 200610042221A CN 200610042221 A CN200610042221 A CN 200610042221A CN 100574768 C CN100574768 C CN 100574768C
- Authority
- CN
- China
- Prior art keywords
- injection
- poria
- norcantharidin
- ganoderma
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention belongs to medical technical field, disclose a kind of cantharidin or derivatives thereof or its analog and at least a composition and method of making the same and purposes with medicine of enhancing immunity of containing, the medicine that wherein has enhancing immunity is selected from: one or more in lentinan, Ganoderma, the Poria.This pharmaceutical composition is in the treatment that is used for the treatment of hepatocarcinoma, esophageal carcinoma, harmonization of the stomach carcinoma of gastric cardia, pulmonary carcinoma, malignant lymphoma etc. and low leukocyte counts, also can be used for hepatitis, liver cirrhosis, hepatitis b virus carrier, or can be used as before the cancer operation medication or be used for the medium aspect of combined chemotherapy disease and have synergistic function, and good stability, improve greatly than the effect of singly using norcantharidin with dosage, lentinan, Ganoderma, Poria, produced beyond thought effect.This pharmaceutical composition can be made clinically any or pharmaceutically acceptable dosage form with mixing acceptable accessories, is with a wide range of applications.
Description
1, technical field
The present invention relates to a kind of cantharidin or derivatives thereof or its analog and at least a composition and method of making the same and purposes of containing, belong to medical technical field with medicine of enhancing immunity.
2, background technology
Cancer is a class serious threat human life and healthy disease.Data show according to statistics, the annual newfound cancer patient of China is about about 1,000,000, and every year is seized about 6,000,000 people's life in the whole world, and 1,000 ten thousand people are placed dead edge, along with going from bad to worse of environment for human survival, the incidence rate of cancer is ascendant trend year by year.World Health Organization's prediction 21 century cancer will become human " first killer ".Modern medicine mainly is that the operative treatment cooperation is put, chemotherapy to treatment for cancer at present, though operation can be removed primary lesion, can not fundamentally stop the regeneration and the breeding of cancerous cell; Though put, chemotherapy can kill cancerous cell, simultaneously a large amount of normal tissue cells suffered damage, and brings out gastrointestinal reaction, bone marrow depression and Liver and kidney, impairment of cardiac function, makes patient's health weak more, be difficult to further treatment.And the Chinese traditional treatment cancer has long history, has formed the theoretical system and the treatment rule of own uniqueness.Work through vast medical worker has in recent years confirmed that the Chinese medicine cancer has outstanding effect, has particularly brought into play important effect to the rehabilitation behind the cancer operation and to the efficacy enhancing and toxicity reducing aspect of chemicotherapy.
Mylabris (Canthari) is the dry Scorpio of Meloidae insecticide south mylabris phalerata Mylabris phalerala Pallas or yellow black mylabris cichorii Mylabris cichoriiLinnaeus.Main product in Liaoning, area such as Henan, Guangxi, Anhui, Jiangsu, Hunan, Guizhou, be a kind of important insect drug.Modern pharmacy studies show that its main medicinal ingredient is a cantharidin.Clinically, cantharidin is demonstrating its unique curative effect aspect treatment cancer and some difficult miscellaneous diseases, but because of its toxicity has substantive damage to heart kidney organ, cantharidin is very limited on using.At present, along with the further investigation of people to cantharidin, synthesized multiple cantharidin derivative in succession, these chemical compounds reduce greatly than cantharidin toxicity, and pharmacological action is clearer and more definite.Existing each derivant of cantharidin has all been taken in national medicinal chemicals standard, norcantharidin records into the chemical drugs terrestrial reference and rises 1 24 pages of GBs, disodium cantharidinate records into the chemical drugs terrestrial reference and rises 1 239 pages of GBs, and N-methylcantharidimide records into the chemical drugs terrestrial reference and rises 6 47 pages of GBs.Modern pharmacology and clinical research show that all cantharidin or derivatives thereof or analog have stronger antitumor action, and body is not had tangible immunosuppressive action.Cantharidin or derivatives thereof or analog structural formula are as follows:
R=CH
3, be cantharidin R=OH, be the N-hydroxycantharidin disodium cantharidinate
R=H is norcantharidin R=CH
3, be N-methylcantharidimide
Lentinan (lentinan is called for short LNT) has many enterprises to produce in China at present, and lentinus edodes polysaccharide injecta and lentinan for injection listing are arranged.Lentinan has been medicinal chemicals at present, and listing producer has: Nanjing Kanghai Pharmaceutical Co., Ltd (the accurate word H10970108 of traditional Chinese medicines), Jinting Pharmaceutical Co., Ltd. (the accurate word H20030130 of traditional Chinese medicines), Meifeng Pharmaceutical Factory Fuzhou City (the accurate word H200300130 of traditional Chinese medicines) and Yiheng Pharmaceutical Co., Ltd., Nanjing (the accurate word H20055744 of traditional Chinese medicines) etc.Lentinan has to be regulated immunologic function and stimulates interferon formation and functions such as antitumor, antiviral, has replenishing QI to invigorate the spleen, and the effect that tonify deficiency is set upright is mainly used in the putting of chronic type b chronic persistent hepatitis and digestive tract tumor, chemotherapy adjuvant.
Ganoderma is Polyporaceae fungus Ganoderma lucidum (Leyss. Ex Fr.) Karst. Ganoderma lucidum (Ley-ss.ex Fr.) Karst. or Ganoderma Ganoderma sinense Zhao, the dry sporophore of Xu et Zhang.The property sweet, flat, GUIXIN, lung, liver, kidney channel.Have invigorating QI and tranquilization, the effect of relieving cough and asthma is mainly used in dizzy sleeplessness, shortness of breath and palpitation, cough due to consumptive disease.Ganoderma is widely known Chinese medicine, is commonly called as " Herba mesonae chinensis ".Beginning is stated from Shennong's Herbal, and " tonifying liver QI invigorating " " the hard muscles and bones " that be considered to can " the beneficial motive " " to pacify smart soul " classified as top grade.Compendium of Material Medica thinks that Ganoderma has " strengthening by means of tonics " " life lengthening " " sharp joint " effects such as " controlling deafness ".The complex chemical composition of Ganoderma, known polysaccharide (peptide) class, triterpenes, ucleosides, alkaloid, aminoacid and the trace element etc. of containing at present.Polysaccharide compound is one of contained main chemical compositions of Ganoderma, has proved that now the ganoderan class has antitumor action, immunoregulation effect, hypoglycemic activity, effect for reducing blood fat, antioxidation and anti-aging effects.Clinical trial confirms that also ganoderan can be used as tumor chemical therapy and radiocurable effective auxiliary therapeutic agent, alleviate because of operation and put, toxic and side effects that chemotherapy is brought, be the very ideal medical material of Biotherapeutics.The ganoderan kind is a lot, and water soluble polysaccharide, acidic polysaccharose and alkaline polysaccharide are arranged.
Poria is the dry sclerotia of Polyporaceae fungus Poria Poria coco (Schw.) Wolf.Sweet in the mouth, light, property is flat; GUIXIN, lung, spleen, kidney channel; Has promoting diuresis to eliminate damp pathogen, the effect of spleen invigorating mind calming.Studies show that in recent years, Poria have positive antitumor action, and its antineoplastic main active is a pachyman.Pachyman plays an active part in the antineoplastic immunne response, promote the lymphocytic proliferation and differentiation of T, strengthen the macrophage vigor, improve the killing activity of immunologically competent cell, correct neuroendocrine disturbance, enhancing is to the toleration of chemotherapy, allaying tiredness is corrected protein synthesis, reduces hemorrhage infection, suppress the focus development, worsen, prolong the time-to-live.
Utilize one or more the interaction in cantharidin or derivatives thereof or its analog and Ganoderma, lentinan, the Poria at present, composition of prescription is used to prepare the medicine of anticancer aspect, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, better treat cancer, improve patient's quality of life, the invention provides a kind of new pharmaceutical composition and preparation method thereof, said composition contains cantharidin or derivatives thereof or its analog of effective dose, with at least a medicine with enhancing immunity, the medicine that wherein has enhancing immunity is selected from: one or more in lentinan, Ganoderma, the Poria.
Aforementioned pharmaceutical compositions, the parts by weight of its crude drug are: 0.02～5000 part of cantharidin or derivatives thereof or its analog, medicine with enhancing immunity is different and different according to medicine, for lentinan is 1～20 part, for Ganoderma is 500～20000 parts, is 2000～50000 parts for Poria.
Aforementioned pharmaceutical compositions, the parts by weight of its crude drug are preferably: 0.05～2000 part of cantharidin or derivatives thereof or its analog, medicine with enhancing immunity is different and different according to medicine, for lentinan is 2～8 parts, for Ganoderma is 2000～10000 parts, is 5000～20000 parts for Poria.
Aforementioned pharmaceutical compositions, the parts by weight of its crude drug are more preferably: 0.1～1000 part of cantharidin or derivatives thereof or its analog, and the medicine with enhancing immunity is different and different according to medicine, is 4 parts for lentinan, for Ganoderma is 4000 parts, is 10000 parts for Poria.
Aforementioned pharmaceutical compositions, its crude drug are formed and parts by weight are particularly preferred is: 10 parts of norcantharidin add in the following bulk drugs one or more: 4 parts of lentinan, 4000 parts of Ganodermas, 10000 parts in Poria.Both can be made by 2 kinds of crude drug: 4 parts of 10 parts of norcantharidin and lentinan perhaps are 4000 parts of 10 parts of norcantharidin and Ganodermas, perhaps are 10000 parts in 10 parts of norcantharidin and Poria; Also can make by 3 kinds or 4 kinds of crude drug.
Preparation of drug combination method of the present invention is, described Ganoderma, Poria can prepare extract with The suitable solvent and method, wherein the main effective ingredient of Ganoderma extract and Poria extract is polysaccharide, cantharidin or derivatives thereof or its analog again with Ganoderma extract, Poria extract, lentinan in one or more and mixing acceptable accessories make arbitrary preparation.
Cantharidin or derivatives thereof or its analog are norcantharidin, disodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, acrylic cantharidimide etc., preferred norcantharidin.Therefore lentinan can directly be bought from market because of domestic existing listing medicinal chemicals.Ganoderma and Poria are Chinese crude drug, feed intake after must extracting, below be the extraction process of the two:
Above-mentioned Ganoderma can obtain Ganoderma extract through extracting processing with The suitable solvent, extract solvent preferred water or ethanol, extracting method can be infusion process, percolation, decocting method, reflux extraction or continuous extraction, the effective ingredient of extract is a ganoderan, its polyoses content preferably is not less than 30%, preferably is not less than 50%.
The invention provides the extraction process of Ganoderma, but be not limited only to following technology, specific as follows:
Get the Ganoderma medical material, be ground into coarse grain, add the moistening of 3 times of amounts of water and spend the night, decoct next day three times, added 12 times of amounts of water for the first time in 3 hours, added 10 times of amounts of water for the second time in 2 hours, added 10 times of amounts of water in 1 hour for the third time, collecting decoction filters, it is 1.10～1.15 that filtrate is concentrated into relative density, puts coldly, adds ethanol and makes that to contain alcohol amount be 80%, stir evenly, placed 24 hours, filter at 4 ℃, collect filter cake, add suitable quantity of water and make dissolving, filter, add ethanol and make that to contain alcohol amount be 85%, stir evenly, placed 24 hours, filter at 4 ℃, collect filter cake, add proper amount of acetone, washing with alcohol, sucking filtration, precipitation adds suitable quantity of water makes dissolving, ultrafiltration, collect molecular weight 5000～50000 daltonian parts, cold drying, promptly.Content by ganoderan in the Ganoderma extract of this prepared is not less than 50%, and yield is 0.5～3%.
Except that adopting said method, also can obtain by the following method, but be not limited only to following method:
Method one: get the Ganoderma medical material, be ground into coarse grain, decoct with water three times, added 12 times of amounts of water in 3 hours for the first time, second and third time added 10 times of amounts of water, collecting decoction in 2 hours, filter, it is 1.03～1.08 that filtrate is concentrated into relative density, puts cold, add ethanol and make that to contain alcohol amount be 65%, stir evenly, placed 24 hours at 4 ℃, filter, filtrate recycling ethanol filters to there not being the alcohol flavor, add ethanol and make that to contain alcohol amount be 80%, stir evenly, placed 24 hours, filter at 4 ℃, collect filter cake, add suitable quantity of water and make dissolving, placed 48 hours, filter and collect filter cake at 4 ℃, vacuum drying, promptly.Content by polysaccharide in the Ganoderma extract of this prepared is not less than 30%, and yield is 5～8%.
Method two: get the Ganoderma medical material, be ground into coarse grain, add the moistening of 3 times of amounts of water and spend the night, decoct secondary next day, added 12 times of amounts of water for the first time in 3 hours, added 10 times of amounts of water for the second time in 2 hours, collecting decoction filters, and it is 1.02～1.06 that filtrate is concentrated into relative density, put coldly, add ethanol and make that to contain alcohol amount be 70%, stir evenly, placed 24 hours at 4 ℃, filter, collect filter cake, add suitable quantity of water and make dissolving, filter, add ethanol and make that to contain alcohol amount be 85%, stir evenly, placed 24 hours at 4 ℃, filter, collect filter cake, add suitable quantity of water and make dissolving, placed 48 hours at 4 ℃, filter and collect filter cake, vacuum drying, promptly.Content by ganoderan in the Ganoderma extract of this prepared is not less than 40%, and yield is 3～6%.
Above-mentioned Poria can obtain Poria extract through extracting processing with The suitable solvent, and the effective ingredient of extract is a pachyman, and its polyoses content preferably is not less than 30%, preferably is not less than 50%.
The invention provides the extraction process of Poria, but be not limited only to following technology, specific as follows:
Get Poria, be ground into fine powder, add 0.5mol/L sodium hydroxide solution extraction secondary, stir, 4 hours for the first time, add 8 times of amounts of solvent, 3 hours for the second time, add 6 times of amounts of solvent, low temperature stirs, sucking filtration, merging filtrate, with the neutralization of 10% acetic acid, cold preservation 12 hours is filtered.To precipitate water, acetone, ether washing successively, drying, promptly.Poria extract yield by this prepared is 8%～10%, and the content of pachyman is not less than 50% in the extract.
Pharmaceutical composition of the present invention is except that available method for preparing obtains, also the medical material in the crude drug directly can be replaced feeding intake with extract, promptly can be by cantharidin or derivatives thereof or its analog, and in the lentinan, Ganoderma extract, Poria extract three one or more feed intake and make.Cantharidin derivative wherein is norcantharidin, disodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, acrylic cantharidimide etc., preferred norcantharidin; Lentinan wherein should meet national chemical drugs crude drug standard; Ganoderma polyoses content is not less than 30% in the Ganoderma extract wherein, preferably is not less than 50%; Pachyman content is not less than 30% in the Poria extract wherein, preferably is not less than 50%.Calculate with respect to the yield of medical material according to extract, the parts by weight of pharmaceutical composition of the present invention are: 0.02～5000 part of cantharidin or derivatives thereof or its analog, with be selected from following bulk drugs: 1～20 part of lentinan, 2～600 parts of Ganoderma extracts, 160～5000 parts of Poria extracts.
The aforementioned pharmaceutical compositions parts by weight are preferably: 0.05～2000 part of cantharidin or derivatives thereof or its analog and be selected from following bulk drugs: 2～8 parts of lentinan, 10～300 parts of Ganoderma extracts, 400～2000 parts of Poria extracts.
The aforementioned pharmaceutical compositions parts by weight are more preferably: 0.1～1000 part of cantharidin or derivatives thereof or its analog and be selected from following bulk drugs: 4 parts of lentinan, 20～120 parts of Ganoderma extracts, 800～1000 parts of Poria extracts.
Aforementioned pharmaceutical compositions, its parts by weight are particularly preferred to be: the compositions that 0.1～1000 part of cantharidin or derivatives thereof or its analog and lentinan are 4 parts; Perhaps be: the compositions that 0.1～1000 part of cantharidin or derivatives thereof or its analog and Ganoderma extract are 20～120 parts; Perhaps be: the compositions that 0.1～1000 part of cantharidin or derivatives thereof or its analog and Poria extract are 800～1000 parts.
More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.If with the gram is unit, can make the preparation of 100～10000 consumptions, as injection, can be made into 100～10000,1～10 of each consumption as tablet, can be made into 100～10000, takes 1～10 at every turn.
The ratio of above weight proportion obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
Pharmaceutical composition of the present invention can be used for the treatment of hepatocarcinoma, esophageal carcinoma, harmonization of the stomach carcinoma of gastric cardia, pulmonary carcinoma, malignant lymphoma etc. and low leukocyte counts, also can be used for hepatitis, liver cirrhosis, hepatitis b virus carrier, or can be used as the preceding medication of cancer operation or be used for combined chemotherapy.
Pharmaceutical composition of the present invention can add one or more pharmaceutically acceptable carriers, with oral, snuffing is gone into or the mode of parenteral is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, soft capsule, dispersible tablet, oral liquid, granule, chewable tablet, oral cavity disintegration tablet, drop pill, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, make liquid preparation such as water or oil-suspending agent or other liquid preparation such as syrup etc.; When being used for parenteral, can be made into solution, water or the oil-suspending agent etc. of injection, as liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion etc.The preferred dosage form of this compositions is oral formulations or injection, as sheet, capsule, granule, powder pin, liquid drugs injection, transfusion etc.
Pharmaceutical composition of the present invention can adopt the conventional method production in the existing pharmaceutical field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.
Pharmaceutical composition of the present invention is when making oral formulations, and selectable filler has: starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Selectable binding agent has: sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Selectable disintegrating agent has: dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Selectable lubricant has: magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
Pharmaceutical composition of the present invention in order to increase its dissolubility, can add solubilizing agents such as polyoxyethylene sorbitan monoleate when making injection.Can add the isoosmotic adjusting agent that is used to regulate osmotic pressure in the transfusion, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol and dextran etc., preferred sodium chloride or glucose.Can add excipient in the powder pin, for example, mannitol, glucose etc.
The present composition has the following advantages:
(1) provide first a kind of cantharidin or derivatives thereof or its analog especially norcantharidin and at least a compatibility of drugs with enhancing immunity be used for the pharmaceutical composition of anti-tumor aspect, satisfied urgent clinical needs;
(2) interaction and the composition of prescription to pharmaceutical composition of the present invention carried out pharmaceutical research, found that compositions is to mice S
180Growth of tumor has significant inhibitory effect, and tumour inhibiting rate all can reach more than 50%, but significant prolongation ehrlich ascites carcinoma U
14The existence natural law of mice, increase in life span also significantly increase, and both can significantly strengthen the effect of radiotherapy, also can significantly strengthen the curative effect of chemotherapy, and can significantly alleviate the toxicity of chemotherapy, the liver tumor growth of deficiency of vital energy shape rat is also had significant inhibitory effect, but and the survival natural law of significant prolongation rat; And compare with norcantharidin, lentinan, Ganoderma, Poria with single, be applied to antitumor behind the compatibility, evident in efficacy, consequently those skilled in the art institute is beyond thought;
(3) the present invention can directly feed intake with raw material or extract, and preparation technology is simple, can make between the different batches medicine mass discrepancy little, and drug quality is more uniform and stable;
(4) stability experiment that carries out shows that the every index of medicine composition injection of the present invention is all more stable, has guaranteed safety of clinical administration;
(5) present composition drug combination determined curative effect, and reduced relative dosage, be with a wide range of applications.
Below routine by experiment beneficial effect of further setting forth medicine of the present invention.In the following experimental example: the compositions of cantharidin or derivatives thereof or its analog, Ganoderma hereinafter to be referred as
The BL compositionsThe compositions of cantharidin or derivatives thereof or its analog, lentinan hereinafter to be referred as
BX CompositionsThe compositions of cantharidin or derivatives thereof or its analog, Poria hereinafter to be referred as
The BF compositionsGanoderan and pachyman used in the following experimental example are taken from embodiment 1 and embodiment 2 respectively.
Test routine 1BL, BX, BF compositions to mice S
180
The tumor growth inhibitory action
Test sample: matched group: normal saline, commercial;
Norcantharidin group: Injectio natarii norcantharidatis injection, specification 2ml:10mg
Ganoderma group: ganoderan injection, self-control, 2ml: be equivalent to Ganoderma medical material 4g;
Lentinan group: lentinus edodes polysaccharide injecta, self-control, 2ml:4mg;
Poria group: pachyman injection, self-control, 5ml: be equivalent to Poria 10g;
BL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BX injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BF injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 4) is divided into basic, normal, high three dosage groups.
Animal subject: 140 of healthy mices, body weight 16～20g, male and female half and half, 10 every group.
Tumor strain: mice S
180Sarcoma
Test method: get and inoculate the mice S that goes down to posterity
180Tumor adds normal saline in homogenizer, make mice S
180The tumor homogenate, again with normal saline 1: 3 dilution, getting 0.2ml then, to inject oxter, a mice left side subcutaneous, weighed in 24 hours, mice gastric infusion every day once, administration volume identical (0.5ml/ is only), totally 7 days.Next day is put to death mice in drug withdrawal, and the subcutaneous tumors piece is peeled off in the also carefulness of weighing, and takes by weighing tumor in the EM50 electronic balance and weighs, and calculate tumour inhibiting rate.
Table 1BL, BX, BF composite injection are to mice S
180The tumor growth inhibitory action (x ± s, n=10)
Compare with the normal saline matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the norcantharidin group,
aP＜0.01,
eP＜0.05; Compare with the Ganoderma group,
bP＜0.01; Compare with the lentinan group,
cP＜0.01; Compare with the Poria group,
dP＜0.01.
Result of the test and conclusion: result of the test sees Table 1.
(1) compare with the normal saline matched group, Ganoderma group, lentinan group and Poria group all can obviously suppress mice S
180The growth of sarcoma (p＜0.05); Norcantharidin group and BL, BX, BF injection low dose group all can significantly suppress mice S
180The growth of sarcoma (p＜0.01); BL, BX, the middle and high dosage group of BF injection all can extremely significantly suppress mice S
180The growth of sarcoma (p＜0.001).
(2) compare with the norcantharidin group, BL, BX, BF injection low dose group all can obviously suppress mice S
180The growth of sarcoma (p＜0.05), tumour inhibiting rate significantly increases (p＜0.05); BL, BX, the middle and high dosage group of BF injection all can significantly suppress mice S
180The growth of sarcoma (p＜0.01), tumour inhibiting rate significantly increases (p＜0.01).
(3) compare with the Ganoderma group, BL, BX, the basic, normal, high dosage group of BF injection all can significantly suppress mice S
180The growth of sarcoma (p＜0.01), tumour inhibiting rate significantly increases (p＜0.01).
(4) compare with the lentinan group, BL, BX, the basic, normal, high dosage group of BF injection all can significantly suppress mice S
180The growth of sarcoma (p＜0.01), tumour inhibiting rate significantly increases (p＜0.01).
(5) compare with the Poria group, BL, BX, the basic, normal, high dosage group of BF injection all can significantly suppress mice S
180The growth of sarcoma (p＜0.01), tumour inhibiting rate significantly increases (p＜0.01).
Result of the test shows, compares with norcantharidin, Ganoderma, lentinan, Poria with single, and any compatibility in norcantharidin and Ganoderma, lentinan and the Poria is used, and all can significantly suppress mice S
180The growth of sarcoma is significantly increased the tumour inhibiting rate of mice, and tumour inhibiting rate all reaches more than 50%, and effect is relevant with dosage, and effect is best during high dose.Prompting, norcantharidin and Ganoderma, lentinan and Poria associating compatibility have the effect of Synergistic when using.
Test the influence of routine 2BL, BX, BF compositions to ehrlich ascites carcinoma U14 mice increase in life span
Test sample: matched group: normal saline, commercial;
Norcantharidin group: Injectio natarii norcantharidatis injection, specification 2ml:10mg;
BL injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 1 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BX injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 2 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BF injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 3 among the embodiment 4) is divided into basic, normal, high three dosage groups.
Animal subject: healthy mice, 110, body weight 20～25g, the male and female dual-purpose is divided into 11 groups at random, 10 every group.
Tumor strain: mouse ascites cancer U
14
Test method: mouse peritoneal inoculation ehrlich ascites carcinoma U
14Tumor strain bacteria suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.5ml/ are only).Inoculate next day, the mice random packet is weighed in, and presses table 2 intraperitoneal injection, every day 1 time, continuous 10 days.After this observe the death time of mice, the result represents [increase in life span=(test group The average survival time natural law-matched group The average survival time natural law)/matched group The average survival time natural law * 100%] with average survival natural law and increase in life span.
Table 2BL, BX, BF composite injection are to ehrlich ascites carcinoma U
14The influence of mice increase in life span (x ± s, n=10)
Compare with the normal saline matched group
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the norcantharidin group,
aP＜0.05,
bP＜0.01.
Result of the test and conclusion: the results are shown in Table 2.
(1) compare with the normal saline matched group, norcantharidin group and BL, BX, BF injection low dose group all can obviously prolong the existence natural law (p＜0.05) of mice; But dosage group significant prolongation ehrlich ascites carcinoma U in BL, BX, the BF injection
14The existence natural law of mice (p＜0.01); But BL, BX, BF injection high dose group utmost point significant prolongation ehrlich ascites carcinoma U
14The existence natural law of mice (p＜0.001).
(2) compare with the norcantharidin group, BL, BX, BF injection low dose group all can obviously prolong ehrlich ascites carcinoma U
14The existence natural law of mice (p＜0.05), increase in life span also obviously increase (p＜0.05); But BL, BX, the middle and high dosage group of BF injection significant prolongation ehrlich ascites carcinoma U
14The existence natural law of mice (p＜0.01), increase in life span also significantly increase (p＜0.01).
Result of the test shows, compares with norcantharidin with single, and the compositions that norcantharidin and Ganoderma, lentinan, Fu form all can prolong ehrlich ascites carcinoma U
14The existence natural law of mice, increase in life span also increases; And action effect is relevant with dosage, and effect is best during high dose.Prompting, norcantharidin and Ganoderma, lentinan and Poria associating compatibility have the effect of Synergistic when using.
Test the potentiation of routine 3BL, BX, BF compositions to radiotherapy
Test sample: matched group: normal saline, commercial;
BL injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 1 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BX injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 2 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BF injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 3 among the embodiment 4) is divided into basic, normal, high three dosage groups.
Animal subject: healthy mice, 110, body weight 20～25g, the male and female dual-purpose is divided into 11 groups at random, 10 every group.
Tumor strain: mice S
180Sarcoma.
Test method: every mice left fore oxter subcutaneous vaccination S
180Tumor strain cell suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.2ml/ are only), weigh in during 24h.Inoculate next day, random packet, except that the blank group, all the other each groups are the 3rd day, the 6th day usefulness after inoculation all
60Co total irradiation, exposure dose are 0.05Gy/min.Inoculate next day, mice is pressed table 3 intraperitoneal injection, every day 1 time, continuous 10 days.Weigh in every day, observes the mice with tumor body weight change.24h after the last administration, weigh in, put to death animal, peel off the subcutaneous tumors piece, take by weighing the tumor body weight, calculate tumor control rate and potentiation rate [potentiation rate=(the average tumor of average tumor weight-radiotherapy of combination radiotherapy group and composite injection therapeutic alliance group is heavy)/average tumor of combination radiotherapy group heavy * 100%].
Table 3 present composition to the potentiation of radiotherapy (x ± s, n=10)
Compare with the blank group,
*P＜0.01,
*P＜0.001; With
60Co irradiation group is compared,
aP＜0.05,
bP＜0.01.
Result of the test and conclusion result of the test see Table 3.
(1) compare with the blank group,
60Co irradiation group is to mice S
180Sarcoma has significant inhibitory effect (p＜0.01);
60Co irradiation and BL, BX, the therapeutic alliance of BF injection are to mice S
180Sarcoma has utmost point significant inhibitory effect (p＜0.001).
(2) with
60Co irradiation group is compared,
60Co irradiation and low dosage BL, BX, the therapeutic alliance of BF injection are to mice S
180The inhibitory action of sarcoma obviously strengthens (p＜0.05), and tumour inhibiting rate obviously increases (p＜0.05);
60Co irradiation and middle and high dosage BL, BX, the therapeutic alliance of BF injection are to mice S
180The inhibitory action of sarcoma significantly strengthens (p＜0.01), and tumour inhibiting rate significantly increases (p＜0.01).
Result of the test shows that BL, BX, BF injection can significantly strengthen
60The radiotherapy effect of Co irradiation, prompting, norcantharidin and Ganoderma, lentinan, Poria drug combination have the effect that strengthens radiotherapy effect.
Test routine 4BL, BX, BF compositions potentiation and Attenuation to chemotherapy (Cy)
Test sample: matched group: normal saline, commercial;
Cyclophosphamide for injection: commercial, 100mg, Hualian Pharmaceutical Co., Ltd., Shanghai;
Norcantharidin group: Injectio natarii norcantharidatis injection, specification 2ml:10mg;
BL injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 1 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BX injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 2 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BF injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 3 among the embodiment 4), get two during use, be divided into basic, normal, high three dosage groups.
Animal subject: healthy mice, 110, body weight 20～25g, the male and female dual-purpose is divided into 11 groups at random, 10 every group.
Tumor strain: mice S
180Sarcoma.
Test method: every mice left fore oxter subcutaneous vaccination S
180Tumor strain cell suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.2ml/ are only).The inoculation next day, the mice random packet is weighed in, and presses table 4 dosage intraperitoneal injection, the next day 1 time, continuous 10 days.Weigh in every day, observes the mice with tumor body weight change.24h after the last administration, weigh in, put to death animal, peel off the subcutaneous tumors piece, take by weighing the tumor body weight, calculate tumor control rate and potentiation rate [potentiation rate=(the average tumor weight-chemotherapy of chemotherapy group and BL, BX, the average tumor of BF injection drug combination group weigh)/average tumor of chemotherapy group heavy * 100%]; Anatomical isolation thymus, spleen and target organ are weighed and are calculated organ index.
Table 4BL, BX, BF compositions to the potentiation of chemotherapy and Attenuation (x ± s, n=10)
Compare with the blank group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the Cyclophosphamide for injection group,
aP＜0.05,
bP＜0.01.
Result of the test and conclusion: result of the test sees Table 4.
(1) to the potentiation of radiotherapy:
Compare with the blank group, the Cyclophosphamide for injection group is to mice S
180Sarcoma has obvious suppression effect (p＜0.05); Cyclophosphamide and BL, BX, BF drug combination low dose group are to mice S
180Sarcoma has significant inhibitory effect (p＜0.01); Cyclophosphamide and BL, BX, the middle and high dosage group of BF drug combination are to mice S
180Sarcoma has utmost point significant inhibitory effect (p＜0.001).
Compare with the Cyclophosphamide for injection group, cyclophosphamide and BL, BX, BF drug combination low dose group are to mice S
180Sarcoma has obvious suppression effect (p＜0.05), and tumour inhibiting rate obviously increases (p＜0.05); Cyclophosphamide and BL, BX, the middle and high dosage group of BF drug combination are to mice S
180Sarcoma has significant inhibitory effect (p＜0.01), and tumour inhibiting rate also significantly increases (p＜0.01).
(2) to the Attenuation of chemotherapy:
Compare with the blank group, during the independent medication of Cyclophosphamide for injection, the peripheral leukocytes number of mice, thymus index, spleen index all extremely significantly reduce (p＜0.01); Compare with the Cyclophosphamide for injection group, cyclophosphamide and BL, BX, the basic, normal, high dosage group of BF drug combination can obviously suppress peripheral leukocytes number, the thymus index of mice, the reduction (p＜0.01) of spleen index.
Result of the test shows, when cyclophosphamide and BL, BX, BF compositions drug combination, can significantly strengthen the curative effect of chemotherapy, and can alleviate the toxicity of chemotherapy.
Test routine 5BL, BX, BF compositions to qi-deficiency type rats'liver tumor inhibition effect
Test sample: matched group: normal saline, commercial;
Norcantharidin group: Injectio natarii norcantharidatis injection, specification 2ml:10mg;
BL injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 1 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BX injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 2 among the embodiment 4) is divided into basic, normal, high three dosage groups;
BF injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 3 among the embodiment 4) is divided into basic, normal, high three dosage groups.
Animal subject: 110 of rats, body weight 150～180g, makes model of qi-asthenia by 10 every group.
Test method: get rat and do inoculation in the liver of W256, inoculate after 7 days, press the dosage intraperitoneal injection of anesthesia of 35mg/kg with pentobarbital sodium, fixing, cutting open the belly exposes liver, and tumor surface maximum diameter (a) and path (b) are pressed (a * b on the measurement liver
2)/2=V (gross tumor volume).Separate stomach, arteria duodenalis, common hepatic artery and proper hepatic artery, ligation stomach, arteria duodenalis are long-range, with silver brain clip blocking-up common hepatic artery, in sending into proper hepatic artery again at stomach, arteria duodenalis upper cut and after inserting external diameter 0.3mm conduit under the operating loupe, inject respectively by the test grouping then and be subjected to the reagent thing, postoperative tube drawing ligation stomach, arteria duodenalis, decontrol the common hepatic artery silver brain clip, sew up the incision again, place animal housing to wait to revive rat, continue breeding observing, performed the operation back 8 days, detect gross tumor volume by last method.And carry out the survival natural law of experimental observation rat as stated above again.
Result of the test and conclusion: test result sees Table 5.
(1) compare with the normal saline matched group, gross tumor volume significantly reduces after the administration of norcantharidin group, and volume change enlarges markedly (p＜0.01); The survival natural law of rat obviously prolongs (p＜0.05).Gross tumor volume extremely significantly reduces after BL, BX, the administration of BF composite injection, and the volume change utmost point enlarges markedly (p＜0.001); BL, BX, BF composite injection low dose group survival of rats natural law significant prolongation (p＜0.01), BL, BX, the middle and high dosage group of BF composite injection survival of rats natural law utmost point significant prolongation (p＜0.001).
(2) compare with the norcantharidin group, gross tumor volume obviously reduces after BL, BX, the administration of BF composite injection low dose group, and volume change obviously increases (p＜0.05), and the survival of rats natural law obviously prolongs (p＜0.05); Gross tumor volume significantly reduces after BL, BX, the administration of the middle and high dosage group of BF composite injection, and volume change enlarges markedly (p＜0.01), survival of rats natural law significant prolongation (p＜0.01).
Result of the test shows that the rats'liver gross tumor volume reduces behind norcantharidin and Ganoderma, lentinan, the Poria combination drug, and volume change increases, and the existence natural law of rat prolongs, prompting, and BL, BX, BF compositions have the effect of Synergistic.
Table 5BL, BX, BF compositions to the influence of rats'liver tumor and survival natural law (x ± s, n=10)
Compare with the normal saline matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the norcantharidin group;
#P＜0.05,
##P＜0.01.
Test routine 6BL, BX, the experiment of BF composition stable
Test sample: BL injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 1 among the embodiment 4);
BX injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 2 among the embodiment 4);
BF injection group: self-control (prescription and preparation method are referring to the preparation of aqueous injection prescription 3 among the embodiment 4).
Investigation project: character, content, related substance.
Long-time stability experimental technique and result: each compositions of this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, and experimental result shows that the long-term placement of pharmaceutical composition of the present invention is basicly stable.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Ganoderma extract in following examples 3～9, Poria extract come from second batch among embodiment 1 and the embodiment 2.
The preparation of embodiment 1 Ganoderma extract
Get the Ganoderma medical material, be ground into coarse grain, add the moistening of 3 times of amounts of water and spend the night, decoct next day three times, added 12 times of amounts of water for the first time in 3 hours, added 10 times of amounts of water for the second time in 2 hours, added 10 times of amounts of water in 1 hour for the third time, collecting decoction filters, it is 1.10～1.15 that filtrate is concentrated into relative density, puts coldly, adds ethanol and makes that to contain alcohol amount be 80%, stir evenly, placed 24 hours, filter at 4 ℃, collect filter cake, add suitable quantity of water and make dissolving, filter, add ethanol and make that to contain alcohol amount be 85%, stir evenly, placed 24 hours, filter at 4 ℃, collect filter cake, add proper amount of acetone, washing with alcohol, sucking filtration, precipitation adds suitable quantity of water makes dissolving, ultrafiltration, collect molecular weight 5000～50000 daltonian parts, cold drying, promptly.Content by ganoderan in the Ganoderma extract of this prepared is not less than 50%, and yield is 0.5～3%.
Prepare three batches of extracts respectively, extract yield and content see Table 6.
Table 6 three batches of Ganoderma extract determination of polysaccharide result and yield
The assay of ganoderan
It is an amount of that the preparation precision of reference substance solution takes by weighing 105 ℃ of glucose reference substances that are dried to constant weight, adds water and make the solution that every 1ml contains 0.1mg, promptly.
Accurate respectively reference substance solution 0.2ml, 0.4ml, 0.6ml, 0.8ml, 1.0ml, the 1.2ml of drawing of the preparation of standard curve, put in the 10ml tool plug test tube, add water to 2.0ml, (precision takes by weighing anthrone 0.1g to accurate adding sulphuric acid anthrone solution, add 80% sulfuric acid solution 100ml and make dissolving, shake up) 6ml, shake up, put in the water-bath and heated 15 minutes, take out, put into water-bath cooling 15 minutes, with the corresponding solvent is blank, measures absorbance under 625nm, is vertical coordinate with the absorbance, concentration is abscissa, the drawing standard curve.
This product 20mg is got in the preparation of need testing solution, puts in the 50ml measuring bottle, is dissolved in water, and is diluted to scale, shakes up promptly.
The accurate need testing solution 2ml that draws of algoscopy puts in the 10ml tool test tube, and assay method under the sighting target directrix curve is measured absorbance in accordance with the law, from the weight that standard curve is read the glucose of need testing solution, calculates, promptly.
The discriminating of Ganoderma extract
Get this product 50mg, add ethanol 25ml, reflux 30 minutes filters, and filtrate evaporate to dryness, residue add methanol 2ml makes dissolving, as need testing solution.Other gets Ganoderma control medicinal material 2g, shines medical material solution in pairs with legal system.According to the thin layer chromatography test, draw above-mentioned two kinds of each 5ul of solution, put respectively on same silica gel G plate, upper solution with petroleum ether (60～90 ℃)-Ethyl formate-formic acid (15: 5: 1) is developing solvent, launches, and takes out, dry, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
The preparation of embodiment 2 Poria extracts
Get Poria, be ground into fine powder, add 0.5mol/L sodium hydroxide solution extraction secondary, stir, 4 hours for the first time, add 8 times of amounts of solvent, 3 hours for the second time, add 6 times of amounts of solvent, low temperature stirs, sucking filtration, merging filtrate, with the neutralization of 10% acetic acid, cold preservation 12 hours is filtered.To precipitate water, acetone, ether washing successively, drying, promptly.
The discriminating of Poria extract
(1) get Poria extract powder 1g, add acetone 10ml, reflux 10 minutes filters, and filtrate evaporate to dryness, residue add glacial acetic acid 1ml makes dissolving, is adding 1 in sulphuric acid, shows pale red, after become brown.
(2) it is a small amount of to get the Poria extract powder, adds 1 of potassium iodide test solution, shows peony.
Above-mentioned three batches of Poria extracts are differentiated, all met the requirements.
The assay of Poria extract
The glucose 10mg that the preparation precision of standard glucose solution takes by weighing 105 ℃ of dry constant weights puts in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up.
Glucose standard solution 0.1,0.2,0.3,0.4,0.5,0.6 is accurately measured in the standard curve drafting, 0.7ml puts in the dry test-tube, adds water respectively and makes into 2ml, adds 5% phenol solution 1ml more respectively, shake up, add concentrated sulphuric acid 5.0ml then, fully shake up, placed 5 minutes, heating was taken out in 20 minutes in 60 ℃ of water-baths, was cooled to room temperature rapidly, made blank simultaneously, at 490nm wavelength place, measure its absorption maximum degree, the drawing standard curve, promptly.
The algoscopy precision takes by weighing the Poria extract 40mg of 70 ℃ of dry constant weights, be dissolved in water and standardize solution in the 50ml volumetric flask, shake up, standby, accurately measure 0.1ml, add water to 2ml, survey its trap value by the same method of bioassay standard curve, calculate, promptly.
Make three batches of Poria extracts according to above-mentioned technology, yield and assay the results are shown in Table 7.
The assay result and the yield of three batches of Poria extracts of table 7
The preparation of embodiment 3BL, BX, BF composition powder injection
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 100g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
2, concrete steps:
1) container of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) it is an amount of norcantharidin, sodium hydroxide to be added the injection water, and heated and stirred makes dissolving, and Ganoderma extract (or lentinan or Poria extract) adds a small amount of water for injection, adds the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add sterile water for injection to 3000ml.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4BL, BX, BF compositions aqueous injection
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
2, concrete steps:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) it is an amount of norcantharidin, sodium hydroxide to be added the injection water, and heated and stirred makes dissolving, and Ganoderma extract (or lentinan or Poria extract) adds a small amount of water for injection, adds the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add water for injection to 5000ml.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45 μ m.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) with the solution sealing by fusing in glass ampule.
8) 100 ℃ of flowing steam sterilizations are 30 minutes.
9) while hot sample being put into 0.01% methylene blue solution hunts leak.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5BL, BX, the transfusion of BF compositions sodium chloride
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 100g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
2, concrete steps:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) it is an amount of norcantharidin, sodium hydroxide to be added water for injection, and heated and stirred makes dissolving, and Ganoderma extract (or lentinan or Poria extract) adds a small amount of water for injection, adds the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.With sodium chloride with an amount of water for injection dissolving fully, merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45 μ m.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in the infusion bottle of 100ml.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6BL, BX, BF compositions glucose infusion liquid
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 50g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Sodium hydroxide 5g
Polyoxyethylene sorbitan monoleate 100g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) it is an amount of norcantharidin, sodium hydroxide to be added water for injection, and heated and stirred makes dissolving, and Ganoderma extract (or lentinan or Poria extract) adds a small amount of water for injection, adds the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, benefit adds to the full amount of water for injection.Glucose is complete with the water for injection dissolving of dosing amount 40%, heated and boiled 15 minutes.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45 μ m.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in the infusion bottle of 100ml.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7BL, BX, BF composition tablet
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, concrete steps:
1) norcantharidin, Ganoderma extract, lentinan, Poria extract are pulverized, it is standby to cross 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) water-soluble 2% the aqueous solution made of hypromellose is standby.
4) norcantharidin, Ganoderma extract (or lentinan or Poria extract), starch, microcrystalline Cellulose mix homogeneously, the 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
10) the sheet weight sheet of determining according to chemical examination.
11) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8BL, BX, composition capsule
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Starch 40.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Prepare 1000 altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Starch 40.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Prepare 1000 altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Starch 40.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Prepare 1000 altogether
2, concrete steps:
1) it is standby norcantharidin, Ganoderma extract, lentinan, Poria extract to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with norcantharidin, Ganoderma extract (or lentinan or Poria extract), starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9BL, BX, BF composition granule
1, prescription:
Prescription 1:BL compositions
Norcantharidin 10g
Ganoderma extract 57.2g (being equivalent to crude drug 4kg)
Icing Sugar 970.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Prescription 2:BX compositions
Norcantharidin 10g
Lentinan 4g
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Prescription 3:BF compositions
Norcantharidin 5g
Poria extract 416g (being equivalent to crude drug 5kg)
Icing Sugar 600.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
2, concrete steps:
1) it is standby norcantharidin, Ganoderma extract, lentinan, Poria extract, sucrose to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that norcantharidin, Ganoderma extract (lentinan or Poria extract) and Icing Sugar are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material.
5) 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) granule is crossed 18 mesh sieve granulate.
8) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
9) packing, finished product is examined entirely, the packing warehouse-in.
Claims (5)
1. an anticancer pharmaceutical composition is characterized in that, the crude drug of said composition is 10 parts norcantharidin and 10000 parts Poria by weight.
2. the preparation method of an anticancer pharmaceutical composition, it is characterized in that, parts by weight are that 10000 parts Poria prepares extract with The suitable solvent and method, be that 10 parts of norcantharidin and mixing acceptable accessories are made clinically any or pharmaceutically acceptable preparation with parts by weight again, wherein the main effective ingredient of Poria extract is a polysaccharide.
3. preparation method as claimed in claim 2 is characterized in that the content of effective ingredient pachyman is not less than 30% in the Poria extract.
4. an anticancer pharmaceutical composition is characterized in that, the crude drug of said composition is 416 parts of 5 parts of norcantharidin and Poria extracts by weight, and wherein the content of effective ingredient pachyman is not less than 30% in the Poria extract.
5. the preparation method of an anticancer pharmaceutical composition, it is characterized in that, parts by weight are that 5 parts of norcantharidin and 416 parts of Poria extracts and mixing acceptable accessories are made arbitrary preparation, and the content of effective ingredient pachyman is not less than 30% in the Poria extract.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610042221A CN100574768C (en) | 2006-01-24 | 2006-01-24 | A kind of anticancer pharmaceutical composition and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610042221A CN100574768C (en) | 2006-01-24 | 2006-01-24 | A kind of anticancer pharmaceutical composition and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101007026A CN101007026A (en) | 2007-08-01 |
| CN100574768C true CN100574768C (en) | 2009-12-30 |
Family
ID=38695836
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200610042221A Expired - Fee Related CN100574768C (en) | 2006-01-24 | 2006-01-24 | A kind of anticancer pharmaceutical composition and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100574768C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716340A (en) * | 2012-07-06 | 2012-10-10 | 许瑞琴 | Traditional Chinese medicine used for treating esophageal cancer |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716465B (en) * | 2012-06-18 | 2014-01-15 | 贵州金桥药业有限公司 | Pharmaceutical composite for treating tumor and preparation method of pharmaceutical composite |
| CN102784162A (en) * | 2012-08-03 | 2012-11-21 | 天津红日药业股份有限公司 | Edible fungi compound polysaccharides health care treatment preparation |
| CN103860580B (en) * | 2014-03-27 | 2017-11-28 | 华夏先葆(北京)中药研究院有限公司 | It is a kind of have strengthen the body resistance to consolidate the constitution, the composite fungi amylose preparation of strengthening the spleen and stomach, strengthen immunity function |
| CN105561215A (en) * | 2016-03-03 | 2016-05-11 | 湖北省中医院 | Poria cocos-lucid ganoderma-rhizoma curcumae longae compound preparation |
| CN106248618A (en) * | 2016-07-21 | 2016-12-21 | 中国科学院合肥物质科学研究院 | A kind of ganoderan quantitative approach based on NIR spectra technology |
-
2006
- 2006-01-24 CN CN200610042221A patent/CN100574768C/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| 抗癌中药及其制剂研究进展. 程书权.中国医药报. 2002 |
| 抗癌中药及其制剂研究进展. 程书权.中国医药报. 2002 * |
| 防治恶性肿瘤的天然药物. j贾敏如.成都中医药大学学报，第25卷第2期. 2002 |
| 防治恶性肿瘤的天然药物. 贾敏如.成都中医药大学学报，第25卷第2期. 2002 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716340A (en) * | 2012-07-06 | 2012-10-10 | 许瑞琴 | Traditional Chinese medicine used for treating esophageal cancer |
| CN102716340B (en) * | 2012-07-06 | 2014-05-28 | 许瑞琴 | Traditional Chinese medicine used for treating esophageal cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101007026A (en) | 2007-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100548323C (en) | A kind of pharmaceutical composition of making by Herb Gynostemmae Pentaphylli, Radix Panacis Quinquefolii and the Radix Astragali | |
| CN100574768C (en) | A kind of anticancer pharmaceutical composition and its production and use | |
| CN103394045B (en) | Chinese medicine composition and preparation method and application thereof | |
| CN1985864B (en) | Medicine composition prepared mainly from glycyrrhizic acid or its salt, ginseng and glossy ganoderma | |
| CN1923241B (en) | Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use | |
| CN104013636A (en) | Anti-tumor pharmaceutical use of pentacyclic triterpene saponin compounds of szechuan melandium root | |
| CN1977885B (en) | Antihepatitis medicinal composition | |
| CN100534493C (en) | Novel antineoplastic compound medicine | |
| CN1961898B (en) | An antitumor compound pharmaceutical composition with barbed stullcap and preparation process thereof | |
| CN101623437B (en) | Pulse-activating preparation for injection and preparation method thereof | |
| CN1985873B (en) | Medicine composition of glycyrrhizic acid or its salt, ginseng and astragalus root | |
| CN101011543B (en) | Antineoplastic medicine composition | |
| CN100482266C (en) | Medical composite prepared by sarcandra and oldenlandia | |
| CN1977886B (en) | Medicinal composition of oxymatrine, ganoderma lucidum and astragalus | |
| CN100493522C (en) | Medicinal composition of oxymatrine and polysaccharide | |
| CN1954838B (en) | Medical composite of antineoplastic | |
| CN1954839B (en) | Medical composition prepared by caulis Marsdeniae Tenacissimae, ginseng and astragalus root | |
| CN1961894B (en) | A novel compound pharmaceutical composition, preparation method and use thereof | |
| CN101073611B (en) | Medicinal composition for preventing tumor | |
| CN102349956B (en) | Compound extract for moisturizeing pathogenic dryness and relieving itching and preparation thereof | |
| CN1969937B (en) | Pharmaceutical composition for treating hepatitis | |
| CN1970001B (en) | Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis | |
| CN101049336B (en) | New composition of medication for anti cancer | |
| CN1977888B (en) | Medicinal composition of baicalin, ganoderma lucidum and salvia miltrorrhiza | |
| CN1961895B (en) | A novel anticancer pharmaceutical composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: XUAN ZHU SHANDONG MEDICINE TECHNOLOGY CO. Free format text: FORMER OWNER: HUANG ZHENHUA Effective date: 20080516 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20080516 Address after: Post encoding No. 2518 block A, Tianchen Avenue Ji'nan High-tech Development Zone in Shandong Province: 250101 Applicant after: Shandong Xuanzhu Medical Technology Co., Ltd. Address before: Post encoding No. 2518 block A, Dongchen street, Ji'nan high tech Development Zone in Shandong Province: 250101 Applicant before: Huang Zhenhua |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: HAIAN SUSHI TECHNOLOGY TRANSFORMATION CENTER CO., Free format text: FORMER OWNER: SHANDONG XUANZHU MEDICAL TECHNOLOGY CO., LTD. Effective date: 20131008 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 250101 JINAN, SHANDONG PROVINCE TO: 226601 NANTONG, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20131008 Address after: 226601 No. 8 Yingbin Road, software park, Haian County, Jiangsu Province Patentee after: Haian Su Fu Technology Transfer Center Co., Ltd. Address before: Tianchen Avenue in Ji'nan high tech Development Zone of Shandong province 250101 City No. 2518 block A Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20091230 Termination date: 20170124 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |