CN1695624A - Combination of medication of containing kurarinone and glycyrrhetic acid, and application - Google Patents
Combination of medication of containing kurarinone and glycyrrhetic acid, and application Download PDFInfo
- Publication number
- CN1695624A CN1695624A CN 200410038017 CN200410038017A CN1695624A CN 1695624 A CN1695624 A CN 1695624A CN 200410038017 CN200410038017 CN 200410038017 CN 200410038017 A CN200410038017 A CN 200410038017A CN 1695624 A CN1695624 A CN 1695624A
- Authority
- CN
- China
- Prior art keywords
- kurarinone
- pharmaceutical composition
- glycyrrhizic acid
- glycyrrhizin
- sweet
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 15
- LTTQKYMNTNISSZ-MWTRTKDXSA-N (2S)-(-)-kurarinone Chemical compound C1([C@H]2OC=3C(C[C@@H](CC=C(C)C)C(C)=C)=C(O)C=C(C=3C(=O)C2)OC)=CC=C(O)C=C1O LTTQKYMNTNISSZ-MWTRTKDXSA-N 0.000 title claims description 102
- XQVFLLMCNGKXSM-UHFFFAOYSA-N kurarinone Natural products COc1cc(O)c(C(CC=C(C)C)C(=C)C)c2OC(CC(=O)c12)c3ccc(O)cc3O XQVFLLMCNGKXSM-UHFFFAOYSA-N 0.000 title claims description 102
- KDADHLPROOOPIC-UHFFFAOYSA-N neokurarinol Natural products COc1cc(O)ccc1C1CC(=O)c2c(OC)cc(O)c(CC(CCC(C)(C)O)C(C)=C)c2O1 KDADHLPROOOPIC-UHFFFAOYSA-N 0.000 title claims description 102
- 229940079593 drug Drugs 0.000 title description 5
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 title 1
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- 235000019410 glycyrrhizin Nutrition 0.000 claims abstract description 102
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 101
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- SPPIIOPGDLITJE-VLQRKCJKSA-N diazanium;(2s,3s,4s,5r,6s)-6-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-5-[(2r,3r,4s,5s,6s)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]oxy-3,4-dihy Chemical compound N.N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SPPIIOPGDLITJE-VLQRKCJKSA-N 0.000 description 4
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- MOCOXAJEZKHXSF-IHMBCTQLSA-M sodium;(2s,4as,6ar,6as,6br,8ar,10s,12as,14br)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylate Chemical compound [Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MOCOXAJEZKHXSF-IHMBCTQLSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A composite medicine or its medicinal kit for preventing and treating hepatitis B, hepatitis B, hepatitis C, AIDS and tumor features that its contains kurarinol (or kurarinol oxide) and glycyrrhizic acid, or their pharmacological acceptable salts.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and application thereof, described pharmaceutical composition contains the two pharmaceutically acceptable form or its officinal salt of kurarinone and glycyrrhizic acid or its, and this pharmaceutical composition be used for preparing prevent and treat hepatitis or with the application of the medicine of hepatitis relevant disease, particularly prevent and treat the application of hepatitis B.
Background technology
Hepatic disease is a kind of frequently-occurring disease and commonly encountered diseases in China.Its cause of disease and pathogeny are very complicated, still it are not had definite effective control medicine at present.Clinical adopt differentiation of tcm more, and add with some ancillary drugs improving curative effect, but many patients' prognosis is very poor, give social and family brings harmful effect.
Radix Sophorae Flavescentis have certain hepatitis virus resisting and hepatoprotective effect, be used for the treatment of chronic hepatitis clinically, but the clinical efficacy of the effective extract of Radix Sophorae Flavescentis or matrine is imprecise, and exists diuresis to arrange side effect such as sodium, causes the too much patient of urine amount to use.Glycyrrhizic acid has antiviral and hepatoprotective effect, the clinical chronic hepatitis that has been used for the treatment of, but effective component extracts or the glycyrrhizic acid of long-term a large amount of oral Radix Glycyrrhizaes can make patient have serious adverse reactions such as water-sodium retention, hypertension and hypokalemia, and its intravenous administration, because of the course of treatment oversize, the patient is difficult to accept.
The present invention is by a large amount of experiments, provide to have to add and synergism and the lower breakthrough drug compositions of toxic and side effects to hepatitis or with the relevant disease of hepatitis, and be used for preparing treatment hepatitis or with the application of the medicine of hepatitis relevant disease.
Summary of the invention
There is wonderful discovery in the present application people, and the pharmaceutical composition of kurarinone and glycyrrhizic acid can provide useful especially hepatoprotective, hepatitis virus resisting effect, and does not observe side effect.And this pharmaceutical composition is particularly suitable for treating acute and chronic hepatitis, especially chronic viral hepatitis B or the disease relevant with hepatitis.
Purpose one of the present invention provide a kind of be used for controlling in advance people's hepatitis or with the pharmaceutical composition of hepatitis relevant disease or tumor, described pharmaceutical composition comprises that order gives or give simultaneously pharmaceutically acceptable amount, perhaps medicine effective dose kurarinone and glycyrrhizic acid, perhaps the medicine of kurarinone and glycyrrhizic acid can be accepted form or its pharmaceutical salts, wherein human consumption every day of kurarinone is 50-3000mg, and consumption every day of glycyrrhizic acid is 30-2000mg.
This shows, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises that order gives or give simultaneously the kurarinone and the glycyrrhizic acid of pharmaceutically acceptable form, and the weight proportion of kurarinone and glycyrrhizic acid is 10 in the compositions: 1-1: 10.For example the content of kurarinone is 50-3000mg in compositions of the present invention, and the content of glycyrrhizic acid is 30-2000mg.
People's consumption every day of kurarinone be selected from 50-500mg, 200-1000mg, 1000-2000mg or 2000-3000mg glycyrrhizic acid every day people's consumption for being selected from 30-500mg, 200-1000mg, 1000-2000mg.Pharmaceutical composition according to claim 1, the weight proportion of kurarinone and glycyrrhizic acid is 4 in the compositions: 1-1: 4.
Administration simultaneously comprises and gives kurarinone and glycyrrhizic acid, perhaps with the independent preparation administration simultaneously basically of every kind of activating agent.
Should be appreciated that kurarinone and glycyrrhizic acid be respectively with its pharmaceutically acceptable form as the pharmaceutically active agents administration, its pharmaceutically acceptable form comprises pharmaceutically acceptable salt, ester and solvate.
" kurarinone " of the present invention comprises kurarinone, matrine, oxymatrine, especially kurarinone or its officinal salt." glycyrrhizic acid " of the present invention comprises glycyrrhizic acid, glycyrrhetate, glycyrrhizin, and suitable glycyrrhetate comprises diammonium glycyrrhizinate, monoammonium glycyrrhizinate, potassium glycyrrhizana, sodium glycyrrhetate or glycyrrhizic acid calcium salt, especially glycyrrhizin or its officinal salt." pharmaceutically acceptable form " of the present invention comprises people and veterinary purpose.
For fear of query, the kurarinone of the pharmaceutically acceptable form that the present invention provides or the scalar of glycyrrhizic acid, when comprising the mg amount, this scalar provides about chemical compound itself, and for example the kurarinone of 50mg hydrochloride form is meant the amount of the hydrochlorate that contains the 50mg kurarinone; For example the glycyrrhizic acid of 200mg diamidogen salt form is meant the amount of two amine salt of the glycyrrhizic acid that contains 200mg.
A particular aspects, this pharmaceutical composition comprises the kurarinone that gives 50-3000mg every day.Particularly, this pharmaceutical composition comprises the kurarinone that gives 50-500mg, 200-1000mg, 1000-2000mg or 2000-3000mg every day.Preferably, this pharmaceutical composition comprises the kurarinone that gives 500-1000mg every day.
A particular aspects, this pharmaceutical composition comprises the glycyrrhizic acid that gives 30-2000mg every day.Particularly, this pharmaceutical composition comprises the glycyrrhizic acid that gives 30-500mg, 200-1000mg, 1000-2000mg every day.Preferably, this pharmaceutical composition comprises the glycyrrhizic acid that gives 500-1000mg every day.
The present invention proves by experiment, the available useful especially hepatoprotective of the pharmaceutical composition of kurarinone and glycyrrhizic acid, hepatitis virus resisting effect, and show with respect to the synergism that contrasts, described contrast is contemplated to the effect summation of independent active agents.
Hepatoprotective can utilize conventional method to describe its feature, for example characterizes the liver protection function of pharmaceutical composition by the reduction of serum Mid-Heaven Gate winter propylhomoserin aminotransferase (AST) and ALT (ALT) after the mensuration administration.
One preferred aspect, the dosage level of two kinds of activating agents of pharmaceutical composition of the present invention will less than reach add merely and the needed dosage of hepatoprotective, antivirus action.
In the present invention, active medicine is preferably with the form administration of pharmaceutical composition, and is as implied above, and this compositions can comprise multiple medicine or only a kind of medicine.
Therefore, another object of the present invention provides a kind of pharmaceutical composition, and said composition contains the kurarinone of 50-3000mg and glycyrrhizic acid or its two pharmaceutically acceptable form or its officinal salt of 30-2000mg, and pharmaceutically acceptable carrier.A particular aspects, can contain the kurarinone of 50-500mg, 200-1000mg, 1000-2000mg or 2000-3000mg in this pharmaceutical composition, preferably, contain the kurarinone of 500-1000mg in this pharmaceutical composition; In another particular aspects, can contain the glycyrrhizic acid of 30-500mg, 200-1000mg, 1000-2000mg in this pharmaceutical composition, preferably, this pharmaceutical composition contains the glycyrrhizic acid of 500-1000mg.Said composition can by with the kurarinone of pharmaceutically acceptable amount and glycyrrhizic acid or its two pharmaceutically acceptable form or its officinal salt with after pharmaceutically acceptable carrier mixes, prepared according to the formulation preparation method of routine.
Another object of the present invention provides the compositions of the kurarinone and the glycyrrhizic acid of specified weight proportioning, and these compositionss have excellent synergism, and can obviously reduce the toxicity of single-activity agent.The approrpiate wts proportioning of kurarinone and glycyrrhizic acid is 10: 1-1: 10, preferred 4: 1-1: 4, more preferably 4: 1-1: 2,2: 1-1: 4 or 2: 1-1: 2, most preferably 2: 1-1.5: 1.
Except as otherwise noted, proportioning of the present invention is weight proportion.
Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication, for example percutaneous dosing.
Said composition can be tablet, capsule, powder, granule, lozenge, suppository, or oral liquid or liquid preparation forms such as aseptic parenteral solution or suspension.
Said composition can be big or dosage forms such as small-volume injection, freeze-dried powder, aseptic powder packing.
In order to reach the concordance of administration, the present composition is preferably single agent form.
The single agent representation that is used for oral administration can be tablet and capsule, and can contain conventional excipients such as binding agent, for example syrup, arabic gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Filler, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tabletting lubricant, for example magnesium stearate; Disintegrating agent, for example starch, polyvinylpyrrolidone, Explotab or microcrystalline Cellulose; Or pharmaceutically acceptable wetting agent, such as sodium lauryl sulphate.
These compositionss are preferably to make unit dose with the amount that relevant daily dose suits.The unit dose of suitable kurarinone comprises the various dosage of 50-3000mg.Can the administration every day 1-6 time, but most preferably administration every day 1 time (drug administration by injection) or 3 times (oral administration).
The suitable dose of glycyrrhizic acid comprises the various dosage that give 30-2000mg every day, can 50-450mg/ day (injection, for example each administration 1-2 time) or (oral, three times on the one) administration of 300-1500mg/ day.
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for activating agent fully is distributed to the compositions of using a large amount of filling doses.Conventional in such operation yes this area.Tablet can make coated tablet or plain sheet according to conventional preparation method.
Oral liquid can be the form of example emulsion, syrup or elixir, perhaps can be used as dry products and exists, and water or other suitable carriers reconstitute again before the use.This liquid preparation can contain conventional additives, such as suspending agent, and for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Anhydrous carrier (can comprise edible oil), for example almond oil, heating up in a steamer Oleum Cocois or oily ester, described oily ester comprises glyceride, propylene glycol or ethanol; Antiseptic, for example methyl parahydroxybenzoate or propyl ester or sorbic acid; If desired, also can add conventional flavoring agent or coloring agent.
For parenteral, particularly injection can utilize two kinds of active components to prepare the unit liquid dosage form with sterile carrier respectively, and according to used concentration with its suspension or be dissolved in the carrier.When preparation solution, active component can be dissolved in water for injection and filtration sterilization, be filled in bottle or the ampoule afterwards and sealing.Advantageously, adjuvant such as local anesthetic, antiseptic and buffer agent can be dissolved in this carrier.For enhanced stability, recharge in the bottle after can be with said composition freezing, and under vacuum, remove moisture.The parenteral suspension is to prepare and get with identical in fact mode, and just active component is not to be dissolved in the carrier, but is suspended in the carrier, and sterilizes and be not accomplished by filtration.This active component can be by with after oxirane contacts, and resuspending is in sterile carrier and sterilize.Advantageously, in said composition, comprise surfactant or wetting agent to promote this chemical compound uniform distribution.
In addition, also can single active ingredient in the pharmaceutical composition or pharmaceutical composition thing be made sustained-release preparation, as slow-release micro-pill or controlled release micro pill according to conventional method.
According to different medications, compositions can contain 0.1%-99% weight, the active substance of preferred 10-60% weight.
The specific embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1: the immunity mouse liver injury model due to the concanavalin A, Con A (Con-A)
Animal: 1) kunming mice, male, the 18-22 gram is provided by Chinese Academy of Medical Sciences's zoopery breeding field.
Licence numbering: SCXK11-00-0006.
2) ICR mice: male, body weight 20-24g provides the quality certification by dimension tonneau China laboratory animal technology company limited: SCXK (capital) 2002-0003
Sample: be subjected to reagent thing kurarinone, glycyrrhizin to be mixed with desired concn with the injection normal saline respectively.
Male mouse of kunming is divided into normal control group, model control group at random and is subjected to reagent thing group, 12 every group.
Except that the normal control group, model control group and be subjected to reagent thing group respectively at the afternoon first day, morning next day, each lumbar injection of the next afternoon (ip) corresponding normal saline or be subjected to reagent once, after the last administration one hour, the intravenous injection respective concentration was the ConA20ml/kg of 20mg/kg.Being subjected to reagent thing component is single component administration group, and the different proportioning administration groups of kurarinone and glycyrrhizin, and its proportioning situation is found in table 1.Behind the animal overnight fasting 16 hours, the sacrificed by decapitation animal is got blood system from serum, presses the test kit explanation and measures glutamate pyruvate transaminase (ALT), glutamate pyruvate transaminase (AST) activity in the serum.
By comparing with the ConA model group, as seen, kurarinone has significant protective effect with the mouse liver injury that the different proportioning compositionss (lumbar injection 4 times) of glycyrrhizin cause ConA.
The protective effect of the mouse liver injury that the different proportioning compositionss of table 1 kurarinone and glycyrrhizin cause ConA
| Group | Dosage (mg/kg) | ??ALT(U/L±SD) |
| Normally (matched group) | ??0 | ??23.35±4.69 |
| ConA (model group) | ??28 | ??285.29±82.93 |
| Bitter 100+ sweet 100 | ??100+100 | ??227.31±91.96 |
| Bitter 100+ sweet 50 | ??100+50 | ??132.16±79.84 ** |
| Bitter 100+ sweet 25 | ??100+25 | ??186.8±160.24 |
| Bitter 50+ sweet 100 | ??50+100 | ??197.79±87.94 * |
| Bitter 50+ sweet 50 | ??50+50 | ??127.94±76.37 ** |
| Bitter 50+ sweet 25 | ??50+25 | ??245.76±151.24 |
| Bitter 25+ sweet 100 | 25+100 | ?216.8±142.68 |
| Bitter 25+ sweet 50 | 25+50 | ?195.72±81.00 ** |
| Bitter | 200 | ?139.75±89.76 ** |
| Sweet | 200 | ?175.34±60.16 ** |
Remarks:
*Expression p＜0.05,
*Expression p＜0.0l." hardship " the expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 2: the different proportioning compositionss of kurarinone and glycyrrhizin are to the protective effect of the immunologic liver injury due to the concanavalin A, Con A (Con-A)
Present embodiment is by the immunity mouse liver injury model due to the concanavalin A, Con A (Con-A), observed the significant protective effect that has that accumulated dose is the different proportioning compositionss of 190mg/kg a mouse liver injury that ConA is caused of share of kurarinone and glycyrrhizin.
Used experimental technique and ConA model are tested 12 male mouse of kunming for every group with embodiment 1.Reduce kurarinone from the activity of transaminase lowering: 2: 1 of glycyrrhizin or 1: 4 pharmaceutical composition of kurarinone and glycyrrhizin reduce the effect that action effect obviously is better than using separately kurarinone or glycyrrhizin to ALT, AST activity.
By comparing with the ConA model group, as seen, kurarinone: the mouse liver injury that the different proportioning compositionss of glycyrrhizin (lumbar injection 4 times) cause ConA has significant protective effect.
The protective effect of the mouse liver injury that the different proportioning compositionss of table 2 kurarinone and glycyrrhizin cause ConA
| Group | Dosage mg/kg | ????ALT(U/L±SD) | ????AST(U/L±SD) |
| Contrast | ????0 | ????33.7±7.74 | ????77.57±17.07 |
| ????ConA | ????28 | ????657.89±130.88 | ????548.69±74.10 |
| Sweet | ????190 | ????385.76±141.91 ** | ????410.77±83.85 ** |
| Bitter | ????190 | ????370.97±210.07 ** | ????431.18±120.48 * |
| Bitter 152+ sweet 38 | ????152+38(4∶1) | ????368.26±164.35 ** | ????421.3±81.48 ** |
| Bitter 127+ sweet 63 | ????127+63(2∶1) | ????331.74±157.59 ** | ????387.66±92.57 ** |
| Bitter 95+ sweet 95 | ????95+95(1∶1) | ????393.02+201.76 ** | ????430.66±103.45 ** |
| Bitter 63+ sweet 127 | ????63+127(1∶2) | ????350.25±190.21 ** | ????396.21±117.75 ** |
| Bitter 38+ sweet 152 | ????38+152(1∶4) | ????258.44±77.72 ** | ????343.39±53.82 ** |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 3: the mouse liver injury model that acetaminophen (PHAA) causes
Male mouse of kunming is divided into normal control group, model control group at random and is subjected to reagent thing group, 12 every group.Except that the normal control group, model control group and be subjected to the reagent thing component afternoon small pin for the case first day, morning next day, the corresponding normal saline of each lumbar injection of the next afternoon (ip) or be subjected to reagent once, after the last administration one hour, the lumbar injection respective concentration was the acetaminophen 20ml/kg of 185mg/kg.The animal overnight fasting, sacrificed by decapitation animal after 16 hours is got blood system from serum, presses the test kit explanation and measures glutamate pyruvate transaminase (ALT), glutamate pyruvate transaminase (AST) activity in the serum.
By comparing with the acetaminophen model group, as seen, the mouse liver injury that the different proportioning compositionss of kurarinone, glycyrrhizin (lumbar injection 3 times) cause acetaminophen (PHAA) has significant protective effect.
The protective effect of the mouse liver injury that the different proportioning compositionss of table 3 kurarinone and glycyrrhizin cause PHAA
| Group | Dosage (mg/kg) | ??ALT(U/L±SD) | ????AST(U/L±SD) |
| Contrast | ??0 | ??36.36±6.68 | ????91.5±23.45 |
| ??PHAA | ??185 | ??440.5±238.3 | ????235.65±157.09 |
| Sweet | ??190 | ??133.39±51.43 ** | ????137.81±51.7 |
| Bitter | ??190 | ??412.98±248.84 | ????219.46±119.13 |
| Bitter 152+ sweet 38 | Sweet 38 (4: 1) of bitter 152+ | ??432.75±289.12 | ????260.84±142.06 |
| Bitter 127+ sweet 63 | Sweet 63 (2: 1) of bitter 127+ | ??117.45±57.95 ** | ????99.71±36.7 * |
| Bitter 95+ sweet 95 | Sweet 95 (1: 1) of bitter 95+ | ??137.18±62.29 ** | ????140.16±41.32 |
| Bitter 63+ sweet 127 | Sweet 127 (1: 2) of bitter 63+ | ??196.63±99.14 ** | ????159.57±28.9 |
| Bitter 38+ sweet 152 | Sweet 152 (1: 4) of bitter 38+ | ??181.84±58.59 ** | ????160.11±41.18 |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 4: kurarinone: glycyrrhizin is the protective effect of the compositions of 1.5: 1 and 2: 1 to ConA mouse liver injury model
According to the literature; Radix Sophorae Flavescentis have certain hepatitis virus resisting effect; and glycyrrhizin only has hepatoprotective effect; and the toxicity of kurarinone is bigger than glycyrrhizin; therefore; we have further studied and have share the compositions that dosage is 50mg/Kg, 100mg/Kg, 200mg/Kg according to above-mentioned orthogonal experiments, and having compared weight proportion is kurarinone: the protective effect of glycyrrhizin=2: 1 or 1.5: 1 pairs of ConA mouse liver injury models.12 of every group of experiment mices, the result shows, kurarinone and glycyrrhizin are that 1.5: 1 compositions is better than 2: 1 compositionss to the reduction effect of ALT, and all effective when share dosage and being 100mg/Kg, 200mg/kg, referring to table 4.
Table 4 kurarinone: glycyrrhizin is that the compositions of 2: 1 and 1.5: 1 is to the mouse liver injury model due to the ConA
Hepatoprotective effect relatively
| Group | Dosage (mg/kg) | ??ALT(U/L±SD) | ??AST(U/L±SD) |
| Normally | ??0 | ??41.31±3.7 | ??42.6±16.6 |
| ??ConA | ??28 | ??510.7±148.0 | ??289.1±94.8 |
| Bitter: sweet (2: 1) ratio prescription | ??50 | ??591.0±144.7 | ??389.1±78.9 |
| ??100 | ??451.0±184.0 | ??335.2±99.5 | |
| ??200 | ??335.8±135.8 * | ??313.9±122.3 | |
| Hardship+sweet (1.5: 1) ratio prescription | ??50 | ??528.1±203.8 | ??351.4±118.7 |
| ??100m | ??331.5±98.91 ** | ??318.0±125.3 | |
| ??200 | ??289.2±148.2 ** | ??272.1±92.0 | |
| Bitter | ??200 | ??240.9±52.8 ** | ??216.5±88.8 * |
| Sweet | ??200 | ??375.5±85.5 * | ??323.2±47.6 |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 5: kurarinone, glycyrrhizic acid and compositions thereof are to the comparison of chmice acute toxic action
Kunming mice is divided into the normal control group at random and is subjected to reagent thing group, and 10 every group, male and female half and half.Except that the normal control group, be subjected to reagent thing group respectively the heavy dose of kurarinone of lumbar injection (ip), glycyrrhizin and two kinds of components compositions once, observed death time and the death toll of record animal continuously 7 days.
The result shows, the dosage of kurarinone has bigger toxicity during for 952mg/kg, 8 death are arranged in 10 mices, the dosage of glycyrrhizin is in 10 mices 2 death to be arranged in the 952mg/kg group, kurarinone: the Radix Glycyrrhizae glucin is 2: 1 and an animal dead is arranged when share dosage for 952mg/kg, illustrating still has certain toxicity slightly, and kurarinone: the Radix Glycyrrhizae glucin is 1.5: 1 and does not have animal dead when share dosage 952mg/kg that its toxicity was less than 2: 1 proportioning groups.As seen, kurarinone: the Radix Glycyrrhizae glucin carried out proportioning by 1.5: 1 and makes up existing tangible liver protective effect, and its toxicity is very low, and this compound preparation has the advantage for the treatment of preferably to hepatitis or its relevant disease.
Table 5 kurarinone: glycyrrhizin is the acute toxicity of the compositions (ip once) of 2: 1 and 1.5: 1 to mice
Effect relatively
| Group | Dosage (mg/kg) | Death toll/sum |
| Normally | ??0 | ??0/10 |
| Bitter | ??952 | ??8/10 |
| Sweet | ??952 | ??2/10 |
| Bitter+sweet | ????952(1.5∶1) | ????0/10 |
| Bitter+sweet | ????952(2∶1) | ????1/10 |
Remarks: " hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 6: kurarinone: glycyrrhizin is 1-5: 1.0 compositions causes the protective effect of mouse liver injury to D-galactosamine+lipopolysaccharide (LPS)
Experimental technique is with embodiment 1.
12 of every group of experiment mices.Compare with model control group; kurarinone: glycyrrhizin is that 1.5: 1.0 compositions (i.p 3 times/2 days) mouse liver injuries that D-galactosamine+lipopolysaccharide is caused have significant protective effect; and compositions can obviously reduce the activity of ALT and AST when it share dosage and is 200mg/kg, 100mg/kg, and the kurarinone of dosage or glycyrrhizin are invalid basically on year-on-year basis.As seen, compositions obviously is better than the hepatoprotective effect of single-activity agent to the protective effect of hepatic injury.
Table 6 kurarinone: glycyrrhizin is that 1.5: 1.0 compositions is to D-galactosamine+lipopolysaccharide (LPS)
Cause the protective effect of mouse liver injury
| Group | Dosage (mg/kg) | ????ALT ????U/L±SD | ????AST ????U/L±SD |
| Normal control | ????0 | ????36±3 | ????123±17 |
| D-galactosamine+LPS | ????800mg/kg+ ????500ug/kg | ????2535±308 | ????2181±256 |
| Glycyrrhizin | ????80 | ????1594±1205 * | ????1587±979 |
| Kurarinone | ????120 | ????2090±1050 | ????1843±859 |
| Bitter 120+ sweet 80 | ????200 | ????726±523 ** | ????827±307 ** |
| Bitter 60+ sweet 40 | ????100 | ????656±220 ** | ????792±323 ** |
| Bitter 30+ sweet 20 | ????50 | ????1557±1303 | ????1682±1140 |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 7: kurarinone: the weight proportion of glycyrrhizin is that 1.5: 1.0 compositions is to the protective effect of the immunity mouse liver injury due to the Con-A
Experimental technique is with embodiment 1.
Test 12 of male mouse of kunming for every group.Compare with model control group; as seen; kurarinone: glycyrrhizin is that 1.5: 1.0 compositions (ip.3 time/2 days) has significant protective effect to the immunity mouse liver injury due to the Con-A; and compositions significantly reduces the activity of ALT and AST when share dosage and be 100mg/kg, 200mg/kg; though and the kurarinone of dosage or glycyrrhizin also have certain effect to ALT and the active reduction of AST on year-on-year basis, it is obvious to can not show a candle to the effect that compound recipe share.
Table 7 kurarinone: glycyrrhizin is that 1.5: 1.0 compositions is to the guarantor of the immunity mouse liver injury due to the Con-A
Protect effect
| Group | Dosage (mg/kg) | ????ALT(U/L±SD) | ????AST(U/L±SD) |
| Normal control | ????0 | ????22±8 | ????58±13 |
| ????Con-A | ????28 | ????262±186 | ????298±127 |
| Glycyrrhizin | ????80 | ????127±99 | ????196±59 * |
| Kurarinone | ????120 | ????116±85 * | ????209±74 |
| Bitter 120+ sweet 80 | ????200 | ????70±23 ** | ????148±30 ** |
| Bitter 60+ sweet 40 | ????100 | ????87±41 ** | ????185±37 ** |
| Bitter 30+ sweet 20 | ????50 | ????144±126 | ????214±85 |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 8: kurarinone: glycyrrhizin is 1.5: 1.0 compositions causes mouse liver injury to acetaminophen (PHAA) protective effect
Experimental technique is with embodiment 3.
Test 12 of male mouse of kunming for every group.Compare with model control group; as seen; kurarinone: glycyrrhizin is that 1.5: 1.0 compositionss cause that to acetaminophen (PHAA) mouse liver injury has significant protective effect; and compositions significantly reduces the activity of ALT and AST when share dosage and be 100mg/kg, 200mg/kg; though and the kurarinone of dosage or glycyrrhizin also have certain effect to ALT and the active reduction of AST on year-on-year basis, it is obvious to can not show a candle to the effect that compound recipe share.
Table 8 kurarinone: glycyrrhizin is that 1.5: 1.0 compositions causes Mouse Liver to acetaminophen (PHAA)
The protective effect of damage
| Group | Dosage (mg/kg) | ????ALT ????U/L±SD | ????AST ????U/L±SD |
| Normal control | ????0 | ????15±8 | ????57±16 |
| ????PHAA | ????185 | ????352±214 | ????240±108 |
| Glycyrrhizin | ????80 | ????76±37 ** | ????127±34 ** |
| Kurarinone | ????120 | ????55±30 ** | ????128±21 ** |
| Bitter 120+ sweet 80 | ????200 | ????51±40 ** | ????112±34 ** |
| Bitter 60+ sweet 40 | ????100 | ????60±38 ** | ????130±69 ** |
| Bitter 30+ sweet 20 | ????50 | ????157±155 ** | ????145±66 ** |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 9: kurarinone: glycyrrhizin is that 1.5: 1.0 compositions is to CCl
4Cause the protective effect of mouse liver injury
Experimental technique is with embodiment 1, and experimental technique provides experimental model or incorporated by reference document.
Test 12 of male mouse of kunming for every group.With model control group relatively, as seen, kurarinone: glycyrrhizin be 1.5: 1.0 compositions (i.p 3 times/2 days) to CCl
4Cause that mouse liver injury has significant protective effect, and significantly reduce the activity of ALT and AST during the share dosage and be 200mg/kg of compositions, and on year-on-year basis the kurarinone of dosage or glycyrrhizin to ALJ and the active reduction nearly unavailable of AST.
Table 9 kurarinone: glycyrrhizin is that 1.5: 1.0 compositions is to CCl
4Cause the protective effect of mouse liver injury
| Group | Dosage (mg/kg) | ????ALT ????U/L±SD | ????AST ????U/L±SD |
| Normal control | ????0 | ????19±11 | ????81±13 |
| ????CCl 4 | ????459±173 | ????262±73 | |
| Glycyrrhizin | ????80 | ????357±162 | ????207±92 |
| Kurarinone | ????120 | ????324±258 | ????221±127 |
| Bitter 120+ sweet 80 | ????200 | ????147±226 ** | ????194±140 |
| Bitter 60+ sweet 40 | ????100 | ????326±177 | ????259±72 |
| Bitter 30+ sweet 20 | ????50 | ????470±232 | ????331±115 |
Remarks:
*Expression p＜0.05,
*Expression p＜0.01." hardship " expression kurarinone, " sweet " expression glycyrrhizin.
Embodiment 10:
Kurarinone 200mg
Diammonium glycyrrhizinate 150mg
Microcrystalline Cellulose 27.5mg
Lactose fruit monohydrate is an amount of
Magnesium stearate 0.5mg
——————————————————
Every 378.15mg
After pressing above-mentioned raw materials, adjuvant mix homogeneously, according to conventional wet granulation, drying, tabletting.
Embodiment 11:
Kurarinone 600mg
Diammonium glycyrrhizinate 150mg
NaCl????????????????????0.9g
Water for injection is an amount of
—————————————————
Every 100ml
Get sodium chloride, use the water for injection stirring and dissolving, add kurarinone, diammonium glycyrrhizinate then respectively, continue to stir to make fully and dissolve, add water for injection, filter to clear and bright to total amount, embedding, sterilization, promptly.
Embodiment 12:
The slow-release micro-pill preparation
Slow-released part prescription (ball 1)
Ball core prescription
Kurarinone 200g
Glycyrrhizin 150g
Microcrystalline Cellulose 15g
Hypromellose 5g
Pure water 200ml
———————————————————
Make 1000
The coating prescription
25% ethyl cellulose aqueous dispersions 184g
Pure water 123g
———————————————————
Make 1000
Respectively microcrystalline Cellulose, kurarinone, glycyrrhizin were pulverized 80 mesh sieves in advance, took by weighing by ball 1 prescription, mix homogeneously, the hydroxypropyl methylcellulose aqueous solution is done binding agent, and the system micropill in 50～60 ℃ of dryings, selects 20～30 purpose pillers with it, and is standby.
With the micropill for preparing and choose, put in the fluid bed, adopt end spray mode, by hot-air suspension fluidisation, inlet temperature is 55 ℃, when the material bed tempertaure is controlled at 30 ℃, regulates peristaltic pump and make its speed provide coating solution, atomizing pressure 2bar by per minute 5g serosity, begin fluidizing piller is whitewashed continuously, after whitewashing finishes, reduce air quantity, make micropill for a moment dry in 40 ℃ under slight boiling condition.Taking-up was placed in 40 ℃ of baking ovens dry 24 hours, and it is about 18% to increase weight, and measures content, promptly.
Claims (15)
1. pharmaceutical composition, described pharmaceutical composition comprise that order gives or give simultaneously the kurarinone and the glycyrrhizic acid of pharmaceutically acceptable form, and the weight proportion of kurarinone and glycyrrhizic acid is 10 in the compositions: 1-1: 10.
2. pharmaceutical composition according to claim 1, wherein the content of kurarinone is 50-3000mg, the content of glycyrrhizic acid is 30-2000mg.
3. pharmaceutical composition according to claim 2, wherein people's consumption every day of kurarinone is 50-3000mg, consumption every day of glycyrrhizic acid is 30-2000mg;
4. pharmaceutical composition according to claim 3, wherein people's consumption every day of kurarinone be selected from 50-500mg, 200-1000mg, 1000-2000mg or 2000-3000mg glycyrrhizic acid every day people's consumption for being selected from 30-500mg, 200-1000mg, 1000-2000mg.
5. pharmaceutical composition according to claim 4, wherein people's consumption every day of kurarinone is 500-1000mg, consumption 500-1000mg every day of glycyrrhizic acid.
6. pharmaceutical composition according to claim 1, the weight proportion of kurarinone and glycyrrhizic acid is 4 in the compositions: 1-1: 4.
7. pharmaceutical composition according to claim 6, the weight proportion of kurarinone and glycyrrhizic acid is 4 in the compositions: 1-1: 2 or 1: 2-4: 1.
8. pharmaceutical composition according to claim 7, the weight proportion of kurarinone and glycyrrhizic acid is 2 in the compositions: 1-1: 2.
9. pharmaceutical composition according to claim 8, wherein the weight proportion of kurarinone and glycyrrhizic acid is 2: 1-1.5: 1.
10. pharmaceutical composition according to claim 9, the weight proportion of wherein middle kurarinone and glycyrrhizic acid is 1.5: 1.
11. according to the arbitrary described pharmaceutical composition of claim 1-10, wherein said kurarinone is oxymatrine or its officinal salt.
12. according to the arbitrary described pharmaceutical composition of claim 1-10, wherein said glycyrrhizic acid is glycyrrhizin or its officinal salt.
13. according to the arbitrary described pharmaceutical composition of claim 1-11, the dosage form of wherein said pharmaceutical composition is injection, injectable powder, tablet, slow releasing agent, drop pill, electuary, capsule or slow-release micro-pill.
14. according to the arbitrary described pharmaceutical composition of claim 1-11 preparation prevent and treat hepatitis or with the medicine of hepatitis relevant disease or tumor in application.
15. application according to claim 14, described hepatitis are hepatitis B.
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