CN1969922B - Compound pharmaceutical composition and preparation process thereof - Google Patents
Compound pharmaceutical composition and preparation process thereof Download PDFInfo
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- CN1969922B CN1969922B CN2005101045551A CN200510104555A CN1969922B CN 1969922 B CN1969922 B CN 1969922B CN 2005101045551 A CN2005101045551 A CN 2005101045551A CN 200510104555 A CN200510104555 A CN 200510104555A CN 1969922 B CN1969922 B CN 1969922B
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- Prior art keywords
- radix isatidis
- pharmaceutically acceptable
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- injection
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- 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.)
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Abstract
The invention discloses a pharmaceutical composition against hepatitis, its preparing process and use, wherein the composition comprises (by weight portions) radix isatidis 200-4000 parts, glycyrrhizic acid or its pharmaceutically acceptable salts 4-800 parts, or radix isatidis extract 2-50 parts, glycyrrhizic acid or its pharmaceutically acceptable salts 4-800 parts. The composition can be made into various pharmaceutically acceptable dose forms.
Description
1, technical field
The present invention relates to compound medicament composition of processing by Radix Isatidis or its extract and glycyrrhizic acid or its pharmaceutically acceptable salt and preparation method thereof, belong to medical technical field.
2, background technology
Hepatitis is one of common but severe infectious disease, is main with viral hepatitis wherein.According to incompletely statistics, have 8～10% to be hepatitis B virus carriers at present in the population of China, and still have every year a considerable amount of new patients to increase.Viral hepatitis can be divided on type: acute hepatitis, chronic hepatitis, hepatitis gravis and gallbladder hepatitis.Though the medicine of treatment hepatopathy has many kinds at present, because the pathogenesis of hepatopathy is not illustrated fully, is mostly to improve liver function, promotes liver cell regeneration, strengthens the medicine of the functions such as detoxification ability of liver.Press for a kind of treating both the principal and secondary aspects of a disease at present, the medicine of reinforcement and elimination in combination.
Radix Isatidis (Radix Isatidis) is called indigo-blue, Isatis indigotica Fort (Indigofera tinctoria L, Baphicanthus cusia (nees) Brem. Polygonum tinctorium Ait) root, indigo root, is the dry root of Cruciferae Isatis indigotica Fort. platymiscium Isatis indigotica Fort. (Isatis indigoticaFort.), and bitter in the mouth, cold in nature has the effect of heat-clearing and toxic substances removing, removing heat from blood sore-throat relieving.Be used for antibiotic, antiviral, antiendotoxin, antiinflammatory, raise immunity etc.; Be mainly used in treatment influenza, parotitis, epidemic febrile disease heating, send out speckle, anemopyretic cold, swelling throat are mashed, epidemic encephalitis type B, hepatitis etc. are one of traditional anti virus herb; Beginning is stated from Shennong's Herbal, and " 1985～2005 years versions of Chinese pharmacopoeia are recorded always.The Radix Isatidis chemical constituent is quite complicated, contains multiple composition,, indirubin indigo like Benzazole compounds etc., the biological alkaline color ammonia of quinoline azole ketone etc., sinigrin compounds, sulfur-bearing compounds, organic acid, base ucleosides guanine etc., amino acids etc.Its antibiotic main active of modern pharmacological research proof is chemical compounds such as color ammonia ketone, and the antiviral effective ingredient has purine, pyrimidine, indole etc., and the antiendotoxin active substance is an organic acid wherein, and what have immunoregulation effect is the Radix Isatidis polysaccharide.
Glycyrrhizic acid is the refining extract of the root and rhizome of glycyrrhizic legume, Glycyrrhiza glabra L., Glycyrrhiza inflata Bat..Because the refining glycyrrhizic acid that extracts of Radix Glycyrrhizae has the effect of 17-hydroxy-11-dehydrocorticosterone appearance, can improve the concentration of hepatitis patient serum's hydrocortisone, reduces interleukin-6 and tumor necrosis factor in chronic hepatitis patient serum and the periphery mononuclearcell; Alleviate the immunopathogenesis reaction; Promote liver function recovery, remove symptom, dwindle hepatosplenomegaly; It is fast to fall enzyme, and the jaundice eliminating subcutaneous ulcer is remarkable.Monoammonium glycyrrhizinate and diammonium glycyrrhizinate are the mono-ammonium and the di-ammonium salts of glycyrrhizic acid, and monoammonium glycyrrhizinate is to various acute, chronic hepatitis, hepatic fibrosis, and toxic hepatitis, traumatic hepatitis and cancer have certain auxiliary treatment effect.Diammonium glycyrrhizinate is the positive oleanane of 20 β-carboxyl-11 oxo-12-alkene-3 β base-2-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid di-ammonium salts, by dry product, contains C
42H
68N
2O
16Should be 97.0%～103.0%, have stronger antiinflammatory, protect liver plasma membrane and improve the effect of liver function, can hinder the deactivation of cortisone and aldosterone, thus the effect of performance steroid appearance, but do not have the untoward reaction of 17-hydroxy-11-dehydrocorticosterone.
Utilize the interaction of Radix Isatidis or its extract and glycyrrhizic acid or its pharmaceutically acceptable salt at present, composition of prescription is used to treat the medicine of hepatitis aspect, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs; Better treat hepatitis; Improve the people ' s health level, the invention provides a kind of compound medicament composition and preparation method thereof, mainly be prepared from Radix Isatidis or its extract and glycyrrhizic acid or its pharmaceutically acceptable salt; Being used for aspects such as preparation treatment hepatitis, control hepatic fibrosis, produced beyond thought effect.
Pharmaceutical composition of the present invention mainly is prepared from Radix Isatidis and glycyrrhizic acid or its pharmaceutically acceptable salt, and its ratio of weight and number is: 4～800 parts of 200～4000 parts of Radix Isatidis, glycyrrhizic acid or its pharmaceutically acceptable salts; Be preferably: 10～400 parts of 500～2000 parts of Radix Isatidis, glycyrrhizic acid or its pharmaceutically acceptable salts; Optimum is: 20～200 parts of 1000 parts of Radix Isatidis, glycyrrhizic acid or its pharmaceutically acceptable salts.
Radix Isatidis in the aforementioned pharmaceutical compositions can extract with The suitable solvent and method and prepare extract, and extract is processed arbitrary preparation with mixing acceptable accessories again.
Radix Isatidis mentioned above can obtain Radix Isatidis extract through extracting processing with The suitable solvent, wherein solvent preferred water or ethanol, and the method for distilling of Radix Isatidis can be infusion process, percolation, decocting method, reflux extraction or continuous extraction.As can obtain through refining through water and obtain Radix Isatidis extract fully.
The invention provides a kind of preferred for preparation technology of Radix Isatidis, specific as follows:
Get the Radix Isatidis medical material, be ground into coarse powder, decocte with water secondary, 2 hours for the first time, 1 hour for the second time; Collecting decoction filters, and filtrating is concentrated into relative density 1.15～1.20 concentrated solutions, adds 1% hydrochloric acid adjust pH to 5～6, is added on the strong acid cation exchange resin column; Add 2 times of water gagings towards post, discard flushing liquor, add 1% ammonia solution again, collect eluent, add 1% hydrochloric acid adjust pH to 7～7.5 again towards post; Hold over night filters, and concentrates, and drying promptly gets.
The Radix Isatidis extract yield that makes through this technology is 0.5～2%, and content of total nitrogen is not less than 10% in the extract.
Radix Isatidis extract also can be by following prepared, but is not limited only to following method:
Technology one: get the Radix Isatidis medical material, be ground into coarse powder, decocte with water secondary, 2 hours for the first time; 1 hour for the second time, collecting decoction filtered, and filtrating is concentrated into relative density 1.15～1.20 concentrated solutions; Put coldly, add ethanol and make and contain alcohol amount and reach 80%, stir, left standstill 24 hours; Filter, filtrate recycling ethanol also is concentrated into relative density 1.32～1.35 thick pastes, and vacuum drying promptly gets.
The Radix Isatidis extract yield that makes through this technology is 10～12%, and content of total nitrogen is not less than 2% in the extract.
Technology two: get the Radix Isatidis medical material, decocte with water 2 times added 12 times of amounts of water for the first time in 2 hours, added 10 times of amounts of water, collecting decoction for the second time in 1 hour; Filter, being evaporated to relative density is 1.03～1.11, and adding ethanol makes and contains the alcohol amount to 70%, stirs, and leaves standstill 24 hours; Filter, filtrate recycling ethanol is not to there being the alcohol flavor, and it is 8.0～8.5 that filtrating uses ammonia solution to regulate pH value, stirs cold preservation 48 hours; Add heat extraction ammonia, it is an amount of to add water, and cold preservation filters; It is 7.0～7.5 that filtrating uses 1% sodium hydroxide to regulate pH value, and cold preservation filters, and filtrate decompression is concentrated into the thick paste shape, and spray drying promptly gets Radix Isatidis extract.
Radix Isatidis extract yield through this prepared is 2～4%, and content of total nitrogen is not less than 5% in the extract.
Pharmaceutical composition of the present invention except that available above-mentioned medical material directly feeds intake make, can also feed intake by the extract of Radix Isatidis and glycyrrhizic acid or its pharmaceutically acceptable salt and process, Radix Isatidis extract contains total nitrogen and preferably is not less than 2%.Calculate with respect to the yield of medical material according to extract, the present composition is by ratio of weight and the number of copies: 4～800 parts of 2～50 parts of Radix Isatidis extracts, glycyrrhizic acid or its pharmaceutically acceptable salts; Be preferably: 10～400 parts of 5～20 parts of Radix Isatidis extracts, glycyrrhizic acid or its pharmaceutically acceptable salts; Optimum is: 20～200 parts of 10 parts of Radix Isatidis extracts, glycyrrhizic acid or its pharmaceutically acceptable salts.
More than form to be by weight as proportioning; When producing, can or reduce according to the corresponding proportion increase; Like large-scale production can be unit with the kilogram, or is unit with the ton, and 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.
More than form,, can process the preparation of 100～10000 consumptions,, can be made into 100～10000,1～10 of each consumption as as injection as if being unit with the gram.As as tablet, can be made into 100～10000, take 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%.
The consumption of drug component of the present invention is groped to sum up to draw through the inventor in a large number, and each amounts of components all has better curative effect in above-mentioned weight portion scope.
Pharmaceutical composition of the present invention, the glycyrrhizic acid pharmaceutically acceptable salt can be slaine or organic nitrogen salt, preferred mono-ammonium and di-ammonium salts.
The invention provides a kind of medicine that is used to prepare aspect diseases such as treatment hepatitis.Pharmaceutical composition of the present invention has antihepatitic activity, and Radix Isatidis has the effect of heat-clearing and toxic substances removing, can antiinflammatory, and enhancing immunity; Hepatitis is had therapeutical effect, and glycyrrhizic acid can improve the concentration of hepatitis patient serum's hydrocortisone, reduces interleukin-6 and tumor necrosis factor in chronic hepatitis patient serum and the periphery mononuclearcell; Alleviate the immunopathogenesis reaction, promote liver function recovery, remove symptom; Dwindle hepatosplenomegaly, it is fast to fall enzyme, the jaundice eliminating subcutaneous ulcer; Its deutero-salt monoammonium glycyrrhizinate is to various acute, chronic hepatitis, hepatic fibrosis, and toxic hepatitis, traumatic hepatitis and cancer have certain auxiliary treatment effect, and diammonium glycyrrhizinate has stronger antiinflammatory, protect liver plasma membrane and improve the effect of liver function; Can hinder the deactivation of cortisone and aldosterone, thereby performance steroid appearance acts on, but do not have the untoward reaction of 17-hydroxy-11-dehydrocorticosterone.Two medicine composition of prescription are used to treat hepatitis disease, and the control hepatic fibrosis has beyond thought good effect.
Said composition 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; Like 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, process 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, like liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion etc.The preferred dosage form of this compositions is injection or oral formulations.
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 the conventional diluent of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant etc.
Pharmaceutical composition of the present invention in order to increase its dissolubility, can add solubilizing agents such as polyoxyethylene sorbitan monoleate when processing 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 invention shows through pharmaceutical research and drug effect animal experiment study result, and the medicine of being processed by Radix Isatidis or its extract and glycyrrhizic acid or its pharmaceutically acceptable salt is to carbon tetrachloride (CCl
4) SGPT, LTG and the MDA of liver of poisoning induced mice have tangible restitution, to carbon tetrachloride (CCl
4) liver, the spleen index of poisoning mice have good reduction effect, has obvious inhibition duck to infect the effect of DHBV virus.Pharmacological experiment study is the result prove, Radix Isatidis and glycyrrhizic acid or its pharmaceutically acceptable salt drug combination are synergism, good again antihepatitic activity, and drug effect obviously strengthens.
The present composition has the following advantages:
(1) a kind of pharmaceutical composition that is used to treat hepatitis disease is provided, has satisfied urgent clinical needs;
(2) first the interaction and the composition of prescription of the present composition carried out pharmacodynamic study; Found that compositions has tangible antihepatitic activity; SGPT, LTG and MDA to the liver of carbon tetrachloride poisoning induced mice have tangible restitution, to carbon tetrachloride (CCl
4) liver, the spleen index of poisoning mice have good reduction effect, has obvious inhibition duck to infect the effect of DHBV virus; In above-mentioned each experimental group; The compositions experimental group is compared with Radix Isatidis extract group or glycyrrhetate group with single; Significant difference is remarkable (p＜0.05) all; It is remarkable to show that Radix Isatidis and glycyrrhizic acid or its pharmaceutically acceptable salt two medicines share anti-hepatitis effect, and consequently those skilled in the art institute is beyond thought;
(3) each proportioning of the present composition is carried out pharmacodynamic study, drawn the optimal proportion of the present composition;
(4) 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;
(5) stability experiment that carries out shows that medicine composition injection each item index of the present invention is all more stable, has guaranteed safety of clinical administration;
(6) Radix Isatidis has the effect of heat-clearing and toxic substances removing, can antiinflammatory, and enhancing immunity; Hepatitis there is therapeutical effect; Glycyrrhizic acid or its pharmaceutically acceptable salt are to acute, chronic hepatitis, hepatic fibrosis, and toxic hepatitis, traumatic hepatitis and cancer have certain therapeutical effect, two medicine drug combination determined curative effects; And reduced relative dosage, be with a wide range of applications.
Below come further to set forth the beneficial effect of medicine according to the invention through experimental example.In the following experimental example: the compositions of Radix Isatidis extract, ammonium glycyrrhizinate hereinafter to be referred as
The BG compositionsUsed Radix Isatidis extract is taken from embodiment 1 in the experimental example.
A pair of carbon tetrachloride (the CCl of experimental example 1 BG compositions drug combination drug efficacy study
4) influence of poisoning mice SGPT, LTG, MDA
Test sample: blank group: 0.9% normal saline solution, self-control;
CCl
4Matched group: CCl
4Injection, self-control;
Radix Isatidis extract group: Radix Isatidis extract injection, self-control;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, self-control;
BG composite injection group, self-control (method for preparing is referring to embodiment 3).
Animal subject: healthy Kunming mouse, body weight 18～22g, is divided into 13 groups at random by 130.
Experimental technique: get 130 of mices, be divided into 13 groups at random, be respectively blank group, CCl
4Matched group, Radix Isatidis extract group, diammonium glycyrrhizinate group, BG composite injection group, 10 every group.Blank group lumbar injection 0.9% normal saline 10ml/kg, the equal lumbar injection CCl of all the other each treated animals
410ml/kg, overnight fasting.Administration group intraperitoneal injection, every day 1 time, dosage is seen table 1; Continuous 10d, matched group is given the normal saline of respective volume, after last administration; The sacrificed by decapitation animal is got the blood regulating liver-QI and measures serum glutamic pyruvic transminase (SGPT), glyceric acid three ester (LTG), malonaldehyde (MDA) respectively.The result sees table 1.
Table 1 BG composite injection is to carbon tetrachloride (CCl
4) influence (X ± SD) of poisoning mice SGPT, LTG, MDA
Annotate:
*P＜0.05,
*P＜0.01 is compared with the blank group;
#P＜0.05,
##P＜0.01 is with CCl
4Matched group is compared;
&P＜0.05 is compared with the Radix Isatidis extract group;
△P＜0.05 is compared with the monoammonium glycyrrhizinate group.
Experimental result: CCl
4Matched group compare with the blank group that there were significant differences (
*P＜0.01), the modeling success is described.Each administration group is all to carbon tetrachloride (CCl
4) SGPT, LTG and the MDA of liver of poisoning induced mice have tangible restitution (
#P＜0.05 draw
##P＜0.01).Wherein the effect of BG composite injection group all obviously be better than single with Radix Isatidis extract or diammonium glycyrrhizinate (
&P＜0.05 draw
△P＜0.05).Proof Radix Isatidis and diammonium glycyrrhizinate compatibility have tangible restitution to SGPT, LTG and the MDA of the liver of carbon tetrachloride poisoning induced mice, make SGPT, LTG and the MDA level of liver recover normal, and comparing with the blank group does not have notable difference.And relevant with the dosage ratio of compositions, effect is best during Radix Isatidis extract+diammonium glycyrrhizinate in the BG composite injection=10mg+150mg.
Experimental example 2 BG compositionss are to carbon tetrachloride (CCl
4) liver, the influence of spleen index of acute liver damage mice due to the poisoning
Test sample: blank group: 0.9% normal saline solution, self-control;
CCl
4Matched group: CCl
4Injection, self-control;
Radix Isatidis extract group: Radix Isatidis extract injection, self-control;
Monoammonium glycyrrhizinate group: monoammonium glycyrrhizinate injection, self-control;
BG composite injection group (Radix Isatidis extract+monoammonium glycyrrhizinate=10mg+40mg): be divided into basic, normal, high three dose groups, self-control (method for preparing is referring to embodiment 3).
Animal subject: healthy Kunming mouse, body weight 18～22g, is divided into 7 groups at random by 70.
Experimental technique: get 70 of mices, be divided into 7 groups at random, be respectively blank group, CCl
4Matched group, Radix Isatidis extract group, monoammonium glycyrrhizinate group, basic, normal, high three dose groups of BG composite injection, 10 every group.Administration group intraperitoneal injection, every day 1 time, dosage is seen table 2, continuous 10d, matched group is given the normal saline of respective volume, and after last administration, the sacrificed by decapitation animal is got liver and spleen, inhales the liquid of dehematizing, and cuts off fat, mesentery, accurately weighs.The result sees table 2.
Table 2 BG compositions is to carbon tetrachloride (CCl
4) influence of liver, the spleen index of acute liver damage mice due to the poisoning (X ± SD)
| Group | Number of animals (only) | Dosage (mg/kg) | Liver index (g/100g) | Spleen index (g/100g) |
| The blank group | 10 | - | 6.26±1.02 | 0.631±0.145 |
| CCl 4Matched group | 10 | 10 | 8.42±0.67 ** | 0.732±0.080 ** |
| The Radix Isatidis extract group | 10 | 30 | 7.53±0.75 *# | 0.690±0.043 *# |
| The monoammonium glycyrrhizinate group | 10 | 30 | 7.34±0.74 *# | 0.701±0.056 *# |
| BG composite injection group (low dosage) | 10 | 10 | 6.72±0.82 ##&△ | 0.651±0.053 ##&△ |
| BG composite injection group (middle dosage) | 10 | 20 | 6.64±0.74 ##&△ | 0.642±0.048 ##&△ |
| BG composite injection group (high dose) | 10 | 30 | 6.49±0.80 ##&△ | 0.635±0.057 ##&△ |
Annotate:
*P＜0.05,
*P＜0.01 is compared with the blank group;
#P＜0.05,
##P＜0.01 is with CCl
4Matched group is compared;
&P＜0.05 is compared with the Radix Isatidis extract group;
△P＜0.05 is compared with the monoammonium glycyrrhizinate group.
Experimental result: each administration group can both significantly reduce carbon tetrachloride (CCl
4) poisoning mice liver, spleen index (
#P＜0.05 draw
##P＜0.01).Wherein the effect of BG composite injection group all obviously be better than single with Radix Isatidis extract or monoammonium glycyrrhizinate (
&P＜0.05 draw
△P＜0.05).Proof Radix Isatidis and monoammonium glycyrrhizinate compatibility have good reduction carbon tetrachloride (CCl
4) liver of poisoning mice, the effect of spleen index, comparing with the blank group does not have significant difference.And relevant with the dosage of compositions, effect is best during high dose.
Experimental example 3 BG compositionss are to the inhibitory action of DHBV-DNA
Test sample: blank group: 0.9% normal saline solution, self-control;
Positive controls: acycloguanosine (ACV) injection, self-control;
Radix Isatidis extract group: Radix Isatidis extract injection, self-control;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, self-control;
BG composite injection group (Radix Isatidis extract+diammonium glycyrrhizinate=10mg+150mg): be divided into basic, normal, high three dose groups, self-control (method for preparing is referring to embodiment 3).
Animal subject: commercially available 1 age in days Beijing duck.
Virus: DHBV positive serum.
Experimental technique: (1) animal model Beijing duck is got blood through sufficient intravenous injection 0.2ml DHBV positive serum behind the 7d, and separation of serum is preserved check for-20 ℃.
(2) Drug therapy filters out 42 of the positive ducks that infect successfully, is divided into 7 groups at random, 6 every group.Be respectively blank group, positive controls, Radix Isatidis extract group, diammonium glycyrrhizinate group, basic, normal, high three dose groups of BG composite injection, dosage sees the following form.Intravenous administration, 2 weeks of administration.Respectively at before the medicine, after medication the 7th day, medication the 14th day and the drug withdrawal the 3rd day, from duck lower limb vein haemospasia, separation of serum ,-20 ℃ of preservations are to be tested.
(3) detection method adopts DHBV-DNA Dot Blot method, with hybridization spot absorbance (A) as BIAO and BEN DHBV-DNA level value.
(4) compare before statistical procedures medication group different time dna content and the medication, adopt paired t-test; Same time D NA content of administration group and virus control group relatively adopt the t check.The result sees table 3.
Experimental result: each administration group all obviously suppress DHBV virus (
&P＜0.05 draw
& &P＜0.01).Wherein the effect of BG composite injection group all obviously be better than single with Radix Isatidis extract or diammonium glycyrrhizinate (
#P＜0.01 draw
△P＜0.05), do not have and after the drug withdrawal before knock-on and the administration comparing difference significantly (
*P＜0.05 draw
*And positive controls does not relatively have significant difference after drug withdrawal with before the administration P＜0.01).And relevant with the dosage of compositions, effect of high dosage is best.
Table 3 BG compositions is to the inhibitory action of DHBV-DNA (X ± SD)
| Group | Dosage (mg/kg) | DHBV-DNA titre before the treatment | Treatment back 7d DHBV-DNA titre | Treatment back 14d DHBV-DNA titre | 3d DHBV-DNA titre after the drug withdrawal |
| The blank group | - | 1.62±0.06 | 1.61±0.03 | 1.61±0.04 | 1.64±0.03 |
| Positive controls | 50 | 1.65±0.04 | 0.78±0.14 **&& | 0.80?±0.12 **&& | 1.63±0.02 |
| The Radix Isatidis extract group | 15 | 1.59±0.03 | 1.33±0.08 *& | 1.32±0.06 *& | 1.40±0.02 *& |
| The diammonium glycyrrhizinate group | 15 | 1.62±0.06 | 1.32±0.10 *& | 1.29±0.08 *& | 1.36±0.07 *& |
| BG composite injection group (low dosage) | 5 | 1.58±0.05 | 1.15±0.12 *& | 0.99±0.09 **&&#△ | 1.10±0.11 *& |
| BG composite injection group (middle dosage) | 10 | 1.60±0.02 | 1.03±0.15 **&&#△ | 0.92±0.11 **&&#△ | 1.01±0.08 **&&#△ |
| BG composite injection group (high dose) | 15 | 1.62±0.03 | 0.93±0.16 **&&#△ | 0.82±0.12 **&&#△ | 0.96±0.10 **&&#△ |
Annotate:
*P＜0.05,
*P＜0.01, with on the same group the treatment before compare;
&P＜0.05,
& &P＜0.01 is compared with the blank group;
#P＜0.05 is compared with the Radix Isatidis extract group;
△P＜0.05 is compared with the diammonium glycyrrhizinate group.
Experimental example 4 injected in mice administration acute toxicity testings
(1) experimental technique
Test sample: the BG composite injection (self-control, 5ml: Radix Isatidis extract+monoammonium glycyrrhizinate=10mg+40mg);
(self-control, 5ml: Radix Isatidis extract+diammonium glycyrrhizinate=10mg+150mg).
Animal subject: mice, each 5 of every group of male and female, male body weight 25～28g, female body weight 21～24g.
Route of administration: intravenous injection, lumbar injection.
Observation item: death toll, general state, body weight, cut open inspection, median lethal dose(LD 50).
(2) experimental result
Require to carry out prerun according to acute toxicity testing, lumbar injection and intravenous injection two route of administration all can't be measured the median lethal dose(LD 50) of medicine, also do not see tangible toxic reaction, so carry out maximum dosage-feeding experiment in a day.Dosage: tail vein injection 0.3ml/10g, lumbar injection 0.3ml/10g, 2 times on the one.
Death toll: do not occur dead.
General state: no abnormality seen changes.
Body weight: after preceding 1 day of administration, administration day, administration, measured in 1,3,7,14 day; No abnormality seen changes.
Cut open inspection: the heart, liver, lung, kidney etc. organize no abnormality seen to change.
(3) conclusion
Occur death in this experiment, infer that the BG composite injection is 0.6ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, be equivalent to 120 times of maximum consumption 30ml of the 60kg body weight day for human beings.Show these article low toxicity, safe.
Experimental example 5 BG composite injection stability experiments
Test sample: the BG composite injection (self-control, 5ml: Radix Isatidis extract+monoammonium glycyrrhizinate=10mg+40mg);
(self-control, 5ml: Radix Isatidis extract+diammonium glycyrrhizinate=10mg+150mg).
Investigation project: character, pH value, clarity.
Long-time stability experimental technique and result: the condition held 6 months, 12 months of each compositions of these article being put 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%; Each item index has no significant change, and experimental result shows that the long-term placement of these article composite injection is basicly stable.
4, the specific embodiment
Below, foregoing of the present invention is done further to specify through the specific embodiment of embodiment form.But should this 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.Radix Isatidis extract among the embodiment 2～11 is taken from embodiment 1.
The preparation of embodiment 1 Radix Isatidis extract
The method for preparing of Radix Isatidis extract
Get the Radix Isatidis medical material, be ground into coarse powder, decocte with water secondary, 2 hours for the first time, 1 hour for the second time; Collecting decoction filters, and filtrating is concentrated into relative density 1.15～1.20 concentrated solutions, adds 1% hydrochloric acid adjust pH to 5～6, is added on the strong acid cation exchange resin column; Add 2 times of water gagings towards post, discard flushing liquor, add 1% ammonia solution again, collect eluent, add 1% hydrochloric acid adjust pH to 7～7.5 again towards post; Hold over night filters, and concentrates, and drying promptly gets.
The Radix Isatidis extract identification experiment
These article of getting 0.1g adds ethanol 10ml, and supersound process 15min, evaporate to dryness, residue add ethanol 1ml makes dissolving, as need testing solution.Other gets Radix Isatidis control medicinal material 1g, adds ethanol 30ml and shines medical material solution in pairs with legal system.Get L-proline reference substance again, add 80% ethanol and process the solution that every 1ml contains 2mg, as reference substance solution.Drawing above-mentioned three kinds of each 2ul of solution, put respectively on same silica gel g thin-layer plate, is developing solvent with n-butanol-water-glacial acetic acid (4: 1: 1), launches, and takes out, and dries, and spray is with 0.2% ethanol solution of ninhydrin, and it is clear to be heated to the speckle colour developing at 105 ℃.In the test sample chromatograph, with control medicinal material chromatograph and the corresponding position of comparison film chromatograph on, show the speckle of same color respectively.
The Radix Isatidis extract assay
Content of total nitrogen is measured
Total nitrogen is measured, and measures according to the pharmacopeia N2 method to get final product.
According to above-mentioned technology, make Radix Isatidis extract three lot sample article, its content and yield see the following form.Radix Isatidis extract yield through this prepared is 0.5～2%, and wherein content of total nitrogen is not less than 10%.
Radix Isatidis extract total nitrogen content and yield
| Lot number | Total nitrogen content (%) | Yield (%) |
| 1 | 15.67 | 1.54 |
| 2 | 16.13 | 1.31 |
| 3 | 16.51 | 1.34 |
| On average | 16.10 | 1.40 |
The preparation of embodiment 2 BG composition powder injections
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
2, concrete steps:
1) vessel and the antibiotic glass bottle at first dosing used, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) get the sterile water for injection of dosing amount 80%, Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) are added the heated and stirred dissolving fully.Add the dissolving of mannitol heated and stirred more fully, add sterile water for injection to full dose.
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) the microporous filter membrane fine straining of warp 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 3 BG compositions aqueous injection
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Water for injection adds to 5000ml
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
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) get the water for injection of dosing amount 80%, add Radix Isatidis extract and the monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) of recipe quantity, the heated and stirred dissolving is complete, and 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) the microporous filter membrane fine straining of warp 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 4 BG compositions sodium chloride transfusion
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
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) water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate).Sodium chloride is complete with the water for injection dissolving of dosing amount 40%.Merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) go into the needle-use activated carbon of dosing amount 0.1%, heated and stirred 15 minutes.
4) sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) the microporous filter membrane fine straining of warp 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 5 BG compositions glucose infusion liquids
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles 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) water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate).Glucose is complete with the water for injection dissolving of dosing amount 40%.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) the microporous filter membrane fine straining of warp 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 6 BG composition tablets
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Carboxymethylstach sodium 4.0g
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Carboxymethylstach sodium 4.0g
Prepare 1000 altogether
2, concrete steps:
1) it is subsequent use Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution processed soluble in water is subsequent use.
4) with Radix Isatidis extract, monoammonium glycyrrhizinate (or diammonium glycyrrhizinate), starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and processes 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.
9) the sheet weight sheet of confirming according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 BG composition capsules
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Prepare 1000 altogether
2, concrete steps:
1) it is subsequent use Radix Isatidis extract and glycyrrhizic acid list (diammonium) to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution processed soluble in water is subsequent use.
4) with Radix Isatidis extract, monoammonium glycyrrhizinate (or diammonium glycyrrhizinate), starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and processes 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 confirming according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 BG composition soft agent
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Soybean oil 500.0g
Soybean phospholipid 50g
Cera Flava 50g
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Soybean oil 500.0g
Soybean phospholipid 50g
Cera Flava 50g
Prepare 1000 altogether
2, concrete steps:
Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) pulverize separately are crossed 100 mesh sieves, subsequent use.With the soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put coldly, adds Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) and grinds well, and is pressed into soft capsule and gets final product.
The preparation of embodiment 9 BG composition granules
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
2, concrete steps:
1) it is subsequent use sucrose to be pulverized 100 mesh sieves.With Radix Isatidis extract, that monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) was pulverized 100 mesh sieves was subsequent use.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that Radix Isatidis extract, monoammonium glycyrrhizinate (or diammonium glycyrrhizinate) and Icing Sugar is progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and processes suitable soft material.
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is confirmed loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 BG composition dripping agent
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Polyethylene glycol 6000 600g
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Polyethylene glycol 6000 600g
2, concrete steps:
With polyethylene glycol 6000 heating and melting in water-bath, treat to add after whole fusions Radix Isatidis extract and monoammonium glycyrrhizinate (or diammonium glycyrrhizinate), stirring and dissolving, the filtration of 60 mesh sieves keeps 60 ℃ to splash in the liquid paraffin that is chilled to below 10 ℃ and process ball.
The preparation of embodiment 11 BG composition oral liquid
1, prescription:
BG composition prescription 1
Radix Isatidis extract 10g
Monoammonium glycyrrhizinate 40g
Sodium benzoate 15g
Cyclamate 10g
Water adds to 10000ml
Prepare 1000 altogether
BG composition prescription 2
Radix Isatidis extract 10g
Diammonium glycyrrhizinate 150g
Sodium benzoate 15g
Cyclamate 10g
Water adds to 10000ml
Prepare 1000 altogether
2, concrete steps:
1) earlier that EDTA-2NA is complete with the water dissolution of dosing amount 60%, again Radix Isatidis extract and monoammonium glycyrrhizinate are added the heated and stirred dissolving fully.
2) sodium benzoate and cyclamate is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned solution, mend and add water to full dose.
4) filtering with microporous membrane of mistake 0.8 μ m.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (4)
1. a pharmaceutical composition that is used to treat hepatitis is characterized in that, this pharmaceutical composition is processed by following bulk drugs: Radix Isatidis extract and glycyrrhizic acid or its pharmaceutically acceptable salt, and its weight proportion is: 2～50 parts of Radix Isatidis extracts, 4～800 parts of glycyrrhizic acid or its pharmaceutically acceptable salts; Described Radix Isatidis extract is prepared from following method: get the Radix Isatidis medical material, be ground into coarse powder, decocte with water secondary, 2 hours for the first time; 1 hour for the second time, collecting decoction filtered, and filtrating is concentrated into relative density 1.15～1.20 concentrated solutions; Add 1% hydrochloric acid adjust pH to 5～6, be added on the strong acid cation exchange resin column, add 2 times of water gagings, discard flushing liquor towards post; Add 1% ammonia solution again towards post, collect eluent, add 1% hydrochloric acid adjust pH to 7～7.5 again, hold over night; Filter, concentrate, drying promptly gets.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the weight proportion of its crude drug is: 5～20 parts of Radix Isatidis extracts, 10～400 parts of glycyrrhizic acid or its pharmaceutically acceptable salts.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, the weight proportion of its crude drug is: 10 parts of Radix Isatidis extracts, 20～200 parts of glycyrrhizic acid or its pharmaceutically acceptable salts.
4. like claim 1,2,3 described arbitrary pharmaceutical compositions, it is characterized in that said composition can be processed clinically any or pharmaceutically acceptable dosage form with mixing acceptable accessories.
Priority Applications (1)
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| CN1969922B true CN1969922B (en) | 2012-04-18 |
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| Title |
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| 赵云燕.甘草酸对板兰根抗内毒素活性的影响.《基层中药杂志》.2001,第15卷(第6期),第21－22页. * |
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