CN1579408A - Medicine for spasmolysis and relieving pain and preparation method - Google Patents
Medicine for spasmolysis and relieving pain and preparation method Download PDFInfo
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- CN1579408A CN1579408A CN 03127673 CN03127673A CN1579408A CN 1579408 A CN1579408 A CN 1579408A CN 03127673 CN03127673 CN 03127673 CN 03127673 A CN03127673 A CN 03127673A CN 1579408 A CN1579408 A CN 1579408A
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- enoxolone
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Abstract
The invention is a spasmolysis and pain easing medicine and its manufacturing method, it extracts medicine active substance enoxolone glycyrrhetinic acid from liquorice and extracts active substance paeoniflorin from peony according to the curing mechanism of peony and liquorice. And then are blended with medicine carrier and/or excepient, thus the current medicine with the same curative effect to peony and liquorice soup can be produced; it has a small volume, convenient, and has no toxin and side effects.
Description
Technical field:
The present invention relates to a kind of composition of medicine, specifically a kind of composition of medicine and preparation method for the treatment of abdominal part smooth muscle spasm pain, headache.
Background technology:
Peony and licorice decoction is well-known name side, domestic traditional Chinese medical science field, and tcm clinical practice is mainly used in abdominal part smooth muscle spasm pains such as treatment menstrual pain, hysterospasm and stomachache.
Though peony and licorice decoction has unique curative effect, its dosage form still is traditional decoction.Obviously can not suitability for industrialized production, but the user oneself decoct.Because be that full material is used as medicine, medicament active composition is unclear again, and inefficacy even deleterious impurity are mixed in wherein.Therefore, Chinese herbal medicine being carried out pharmacology analysis, isolate active medicinal matter, and make the modern medicines of free from admixture, little, the easy circulation of dosage, taking convenience by large-scale production, is the trend of Chinese medicine development.
For inquiring into the pharmaceutically active of peony and licorice decoction, we are after giving the rats gavaged peony and licorice decoction, get the rat blood serum of taking medicine, with instrument detecting such as HPLC and the HPLC-MS animal serum of taking medicine, drawing the active ingredient that mainly is absorbed into blood is enoxolone (glycyrrhetinic acid, or glycyrrhetic acid), glycyrrhizic acid (glycyrrhizic acid, or glycyrrhizin), peoniflorin (paeoniflorin) and peoniflorin metabolite (paeonimetabolinel, PM-1) prove through further experiment, glycyrrhizic acid in the above-claimed cpd and enoxolone are the antiphlogistic active ingredient of spasmolytic, and enoxolone wherein is the suction blood metabolite of oral administration of compound glycyrrhizic acid, its spasmolysis obviously is better than glycyrrhizic acid, and enoxolone blood drug level is apparently higher than glycyrrhizic acid.For this reason can be with enoxolone as spasmolytic composition in the combination medicine, above-mentioned experiment proves that also peoniflorin and peoniflorin metabolite are analgesia and calm active ingredient, though peoniflorin metabolite analgesic activity is better than peoniflorin, are difficult to a large amount of preparations.And the peoniflorin metabolite is the product of the suction blood of peoniflorin after the intestinal flora metabolism, thereby can be with peoniflorin as the analgesia composition in the medicine.
Summary of the invention:
The objective of the invention is to have spasmolytic, a kind of spasmolytic, an analgesic medicine of being used for of analgesic pharmaceutically active substance combination with what analyze that peony and licorice decoction finds.
Another object of the present invention is to provide a kind of to be raw material with Radix Glycyrrhizae and Radix Paeoniae, to prepare the method for said medicine.
The technical scheme of medicine of the present invention by the enoxolone that contains abdominal part smooth muscle spasmolysis effective dose and the analgesia peoniflorin of effective dose and pharmaceutically useful carrier/or excipient form.
According to the present invention, this pharmaceutical composition can be made common tablet (sweet Chinese herbaceous peony sheet), capsule (sweet Chinese herbaceous peony capsule) and other solid dosage forms or injection.The preparation solid dosage forms can add excipient materials such as starch.Can add conventional solvent and make injection.
The preparation method of medicine of the present invention is:
(1), the preparation of enoxolone: licorice piece adds water boil, leaches medicinal liquid, adds concentrated sulphuric acid to no longer separating out precipitation, places, leach precipitate, washing, drying gets glycyrrhizic acid inclusion compound, uses the acetone reflux, extract,, get acetone extract, put, add KOH ethanol liquid under stirring, place to alkalescence to room temperature, separate out crystallization, leach crystal (GLYCYRRHIZIC ACID POTASSIUM), drying, add the glacial acetic acid thermosol, put, separate out crystallization to room temperature, filter, get monopotassium glycyrrhizunate, add dilute sulfuric acid, heating, sucking filtration is washed to neutrality, drying gets white enoxolone crude product, it is dissolved in the hot chloroform again, filtered while hot with chloroformic solution, is put to room temperature, peroxidating aluminum chromatographic column is used the chloroform eluting, gets enoxolone, the ethanol thermosol is poured in the boiling water while hot, places, get crystallization, filter, promptly get medicinal enoxolone crystallization.
(2), peoniflorin extracts: get Radix Paeoniae Alba decoction pieces and add alcoholic solution hot reflux or merceration extraction, ethanol extract is concentrated, add the ethanol placement again and spend the night, filter, in ethanol filtrate, add activated carbon again, stir, filter, ethanol filtrate is concentrated into not to be had till the alcohol flavor, gained said extracted thing purification on macroporous resin washes with water earlier to Molish reaction and is negative the reuse ethanol elution, collect ethanol elution, concentrating under reduced pressure, dry light yellow peoniflorin.
(3), formulation preparation:
Enoxolone and peoniflorin were mixed by weight in 1: 1 to 1: 2, add pharmaceutical carrier and/or excipient again and make sheet, capsule or injection.
It at first is to obtain little, the good effect of a kind of volume that good effect of the present invention is embodied in, have no side effect, and taking convenience, the smooth muscle spasmolysis analgesic, next has finished a kind of treatment abdominal part smooth muscle spasmolysis analgesic active substance that extracts from the Radix Glycyrrhizae Radix Paeoniae.The experimentation and the result of curative effect of the present invention are as follows:
1. to the influence of spontaneous activity in mice: divide 9 groups with 90 mices are even, every group of male and female half and half, press dosage shown in the table 1 and route of administration administration 1 time, first group is a jar stomach matched group, jar stomach 0.2%CMC aqueous suspension 10ml/kg. is the drug administration by injection matched group for the 6th group, subcutaneous injection normal saline 10ml/kg.1-5 group mice after administration 1 hour, 6-9 organizes after administration 30 minutes, mice is placed in the spontaneous activity scope, writing down the spontaneous activity number of times of every mice in 5 minutes. the result is as shown in table 1. and by table 1 as seen, sweet Chinese herbaceous peony capsule and sweet Chinese herbaceous peony injection all have the effect of obvious suppression spontaneous activity in mice.
Sweet Chinese herbaceous peony capsule of table 1. and sweet Chinese herbaceous peony injection are to the influence of the spontaneous activity in mice (n=10 of X ± S)
Movable number of times (5min) suppression ratio (%) of group dosage (mg/kg) mice
1. contrast 0.2%CMC po 144.8 ± 22.5
2. stable 5 po 56.8 ± 23.1
* *60.7
3. sweet Chinese herbaceous peony capsule 300 po 45.2 ± 9.9
* *68.8
4. 150 po 53.5±20.8
** 63.1
5. 75 po 73.5±22.5
* 49.2
6. normal saline 10ml/kg im 132.7 ± 36.7
7 sweet Chinese herbaceous peony injection 60 sc 50.4 ± 12.9
*62.0
8. 30 sc 64.3±16.5
** 51.5
9. 15 sc 71.4±13.6
* 44.2
Annotate: compare * P＜0.05, * * P＜0.01, * * * p＜0.001 with negative control group
2. to the influence of lumbar injection acetic acid induced mice writhing response and abdominal cavity exudative inflammation reaction:
This experiment mice grouping and administration are same as experiment 1.1-5 and organize mice after administration 1 hour, 6-9 organizes in administration 30 minutes, give mouse tail vein injection AZO-blue (2%, 5ml/kg), in injecting AZO-blue after 2 minutes, inject every mice of 1% acetic acid 10ml/kg. record to mouse peritoneal and behind injection acetic acid, turn round the body number of times in 10 minutes, immediately mice is broken cervical vertebra then and put to death, cut open the belly and ooze out dyestuff with normal saline 4ml/ Mus flushing abdominal cavity. measure the dyestuff seepage discharge with electrophotometer (620nm). the results are shown in Table 2.
The influence of table 2. glycosides Chinese herbaceous peony capsule and sweet Chinese herbaceous peony injection Dichlorodiphenyl Acetate induced mice writhing response and abdominal cavity exudative inflammation. (X ± S), n=10.
Body number of times suppression ratio is turned round in dying that group dosage intraperitoneal penetrates
(mg/kg) material amount μ g/ml 10min %
1. contrast 0.2%CMC po 56 ± 8 15.6 ± 2.9
2. aspirin 400 po 33 ± 11
*4.7 ± 2.2
* *69.9
3. sweet Chinese herbaceous peony capsule 300 po 26 ± 8
* *3.1 ± 0.9
*80.1
4. 150 po 28±8u 5.3±1.9
* 66.0
5. 75 po 33±3
** 6.1±1.6
* 60.9
6. contrast normal saline 10 (ml.kg) im 57 ± 11 14.1 ± 2.4
7. sweet Chinese herbaceous peony injection 60 im 27 ± 5
* *3.7 ± 1.6
* *70.8
8 30 im 32±3
** 5.0±1.2
** 64.5
9 15 im 35±4
* 6.0±1.5
* 57.5
Annotate: with matched group comparison separately, * p＜0.05, * * p＜0.01, * * * p＜0.001.
3. sweet Chinese herbaceous peony capsule spasmolytic test-to the active influence of isolated rat intestinal smooth muscle
Materials and methods:
Animal Wistar rat, body weight 250 ± 20g, female, male dual-purpose.
The paeoniflorin of medicine variable concentrations, enoxolone, sweet Chinese herbaceous peony injection is carried by natural drug institute plant chamber, Jilin; Acecoline (1g/ props up, east, Beijing ring amalgamation factory); Atropine sulfate injection (specification: 0.5mg/mL, Kaifeng, Henan Province pharmaceutical factory).
Instrument Powerlab/8s data record analyser and related accessories (Australian Ai De company product); YSD-4G type pharmacology Physiological Experiment is used instrument and constant temperature water bath apparatus (Bengbu radio two factory's products) thereof more.
The fasting of method rat was put to death after 48 hours, open the abdominal cavity, place the culture dish that fills tyrode's solution, separate mesentery gently along intestinal wall at one section intestinal tube of upper part of small intestine clip, with after rinsing well in the intestinal tube, the segment that is cut into about several 2cm is standby with tyrode's solution.By reconciling with the many mercury contact thermometers that link to each other with instrument of YSD-4G type pharmacology Physiological Experiment, the temperature of control constant temperature water bath, make it constant at 37 ± 0.5 ℃, the tyrode's solution volume is about 50mL in the maxwell bath pipe, the liquid level of tyrode's solution liquid level and water bath is basic identical, air feeding amount is controlled at about 50 bubbles/minute, choose one section small intestinal, one end is tightened on the crotch that is fixed on breather with line, the other end is connected with the glass capillary of filling water. when intestine in vitro is shunk, water column rises in the glass capillary. and the amplitude that liquid level rises is relevant with the intestine in vitro contraction intensity. stablized 20 minutes, liquid level in the capillary tube is transferred to " 0 " position, in the maxwell bath pipe, add 0.001% acecoline 0.1ml subsequently, make intestinal tube generation spasm and be in nervous contraction state, shrink the most obvious place at intestinal tube, divide three kinds of method administrations: 1. add tyrode's solution 1mL; 2. add Ah bundle's product 1mL; 3. the enoxolone that adds variable concentrations subsequently, paeoniflorin, sweet Chinese herbaceous peony injection. observe the spasmolysis of medicine.Whenever finish a step, intestinal tube that more renews and nutritional solution are stablized and are carried out next step after 20 minutes again.
Experimental result
Enoxolone and sweet Chinese herbaceous peony injection all have in various degree inhibitory action to the spastic activity of rat intestinal tube due to the acecoline, and the spasmolysis of sweet Chinese herbaceous peony injection is more obvious. but peoniflorin spasmolysis not obvious (table 3).
Table 3. enoxolone, peoniflorin and sweet Chinese herbaceous peony injection are to the influence of the high body intestinal tube of rat contractile motion. (X ± S), n=3.
Group intestinal tube shrinkage amplitude suppression ratio
Drug level (g/ml) mm % in the bath
Acecoline 4 25 ± 3.0
Atropine 10 6 ± 1.0 76
Enoxolone 40 8 ± 2.0 68
20 12±2.0 52
10 16±1.7 36
5 24±2.0 4
Acecoline 4 20 ± 1.0
Atropine 10 7 ± 1.0 65
Peoniflorin 40 19 ± 3.0 5
20 20±2.0 0
10 20±2.0 0
Acecoline 4 24 ± 2
Atropine 10 6 ± 2 75
Sweet Chinese herbaceous peony injection agent 40 6 ± 2 75
20 8±2 67
10 12±2 58
5 20±1 17
25 23±1 4
Embodiment:
1, the preparation of enoxolone: licorice piece adds water boil 3 times, is respectively 3 hours, 2 hours, 1 hour, and leaching also merges medicinal liquid, adds concentrated sulphuric acid to no longer separating out precipitation, places, and leaches precipitate, washing, and drying under reduced pressure gets glycyrrhizic acid inclusion compound.With acetone reflux, extract, 3 times, acetone extract, put to room temperature, stir the pure liquid of the KOH that adds concentration 20% down to alkalescence (PH8-9), place, separate out crystallization, leach crystal (GLYCYRRHIZIC ACID POTASSIUM), drying under reduced pressure adds 60 ℃ of thermosols of glacial acetic acid, put to room temperature, separate out crystallization, filter, get monopotassium glycyrrhizunate, add concentration 5% dilute sulfuric acid, boil heating 10 hours, sucking filtration is washed to neutrality, drying under reduced pressure, get white enoxolone crude product, it is dissolved in 50 ℃ of hot chloroforms, filtered while hot is with chloroformic solution again, put to room temperature, peroxidating aluminum chromatographic column is used the chloroform eluting, gets enoxolone.With 50 ℃ of ethanol thermosols, pour into while hot in the 1/2 volume boiling water, place, get crystallization, filter, promptly get medicinal enoxolone crystallization.
2, peoniflorin extracts: get Radix Paeoniae Alba decoction pieces, doubly measure (volume) with 3-8, concentration is that hot reflux of 30%-60% alcoholic solution or room temperature merceration extract 2 times, each 8 hours of merceration, ethanol extract is concentrated into relative density 1.1 (50 ℃), the ethanol of reuse concentration 95% adds to determining alcohol 70%-90%, placement is spent the night, filter, in ethanol filtrate, add 1%-2% (M/V) active carbon again, stir, filter, ethanol filtrate is concentrated into not to be had till the alcohol flavor, gained said extracted thing is at D101, purification on two kinds of macroporous resins of D201, wash with water earlier to Molish reaction and be negative, reuse concentration 10%-30% ethanol elution is collected ethanol elution, concentrating under reduced pressure, dry light yellow peoniflorin.
3, preparation and preparation thereof
(1) sweet Chinese herbaceous peony capsule (tablet) prescription:
Peoniflorin (purity 90%) 153g
Enoxolone (purity 95%) 97g
Starch is an amount of
Make 1000 (sheets)
Method for making:, incapsulate or pelletizing press sheet with peoniflorin and enoxolone and the abundant mixing of appropriate amount of starch.Pastille 0.25g in per 1 capsules or per 1 tablet.
Indication: abdominal part smooth muscle Crampy Pain (menstrual pain, hysterospasm pain, gastrointestinal convulsion pain due to the gastric ulcer) and headache.
Usage and consumption: 1 oral 1-2 grain (sheet) during pain.
(2.) sweet Chinese herbaceous peony injection
Peoniflorin (purity 90%) 30g
Enoxolone (purity 95%) 20g
1, the 2-propylene glycol is an amount of
Make 1000 of 2ml peace bottle injections
Method for making: peoniflorin and enoxolone dissolved in be dissolved in an amount of propylene glycol, filter, packing, sterilization is promptly. and per 1 contains medicine 50mg.
Indication: abdominal part smooth muscle Crampy Pain (menstrual pain, hysterospasm pain, gastrointestinal convulsion pain and headache due to the gastric ulcer.
Usage and consumption: the time spent is diluted in the 500ml normal saline intravenous drip with 1 sweet Chinese herbaceous peony injection liquid. and each 1-2 props up.
Claims (3)
1, a kind of spasmolytic, analgesic is characterized in that: be made up of the enoxolone that contains abdominal part smooth muscle spasmolysis effective dose and the analgesia peoniflorin of effective dose and pharmaceutically useful carrier and/or excipient.
2, according to a kind of spasmolytic, the analgesic of claim 1, it is characterized in that: use enoxolone that from liquorice root, extracts and the peoniflorin that from Radix Paeoniae, extracts to add sheet, capsule or injection that carrier and/or excipient are made.
3, the preparation method of a kind of spasmolytic, analgesic is characterized in that:
(1), the preparation of enoxolone: licorice piece adds water boil, leaches medicinal liquid, adds concentrated sulphuric acid to no longer separating out precipitation, places, leach precipitate, washing, drying gets glycyrrhizic acid inclusion compound, uses the acetone reflux, extract,, get acetone extract, put, add KOH ethanol liquid under stirring, place to alkalescence to room temperature, separate out crystallization, leach crystal (GLYCYRRHIZIC ACID POTASSIUM), drying, add the glacial acetic acid thermosol, put, separate out crystallization to room temperature, filter, get monopotassium glycyrrhizunate, add dilute sulfuric acid, heating, sucking filtration is washed to neutrality, drying gets white enoxolone crude product, it is dissolved in the hot chloroform again, filtered while hot with chloroformic solution, is put to room temperature, peroxidating aluminum chromatographic column is used the chloroform eluting, gets enoxolone, the ethanol thermosol is poured in the boiling water while hot, places, get crystallization, filter, promptly get medicinal enoxolone crystallization.
(2), peoniflorin extracts: get Radix Paeoniae Alba decoction pieces and add alcoholic solution hot reflux or merceration extraction, ethanol extract is concentrated, add the ethanol placement again and spend the night, filter, in ethanol filtrate, add activated carbon again, stir, filter, ethanol filtrate is concentrated into not to be had till the alcohol flavor, gained said extracted thing purification on macroporous resin washes with water earlier to Molish reaction and is negative the reuse ethanol elution, collect ethanol elution, concentrating under reduced pressure, dry light yellow peoniflorin.
(3), formulation preparation:
Enoxolone and peoniflorin were mixed by weight in 1: 1 to 1: 2, add pharmaceutical carrier and/or excipient again, make sheet, capsule or injection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03127673 CN1579408A (en) | 2003-08-08 | 2003-08-08 | Medicine for spasmolysis and relieving pain and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03127673 CN1579408A (en) | 2003-08-08 | 2003-08-08 | Medicine for spasmolysis and relieving pain and preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926815A (en) * | 2010-05-07 | 2010-12-29 | 宁波立华制药有限公司 | Paeoniflorin and glycyrrhetinic acid composition and preparation method and application thereof |
| CN115025113A (en) * | 2022-07-25 | 2022-09-09 | 中国中医科学院中医基础理论研究所 | New use of polysaccharide extract of peony and licorice root decoction |
| CN115040633A (en) * | 2022-07-25 | 2022-09-13 | 中国中医科学院中医基础理论研究所 | New use of protein extract of peony and licorice decoction |
-
2003
- 2003-08-08 CN CN 03127673 patent/CN1579408A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926815A (en) * | 2010-05-07 | 2010-12-29 | 宁波立华制药有限公司 | Paeoniflorin and glycyrrhetinic acid composition and preparation method and application thereof |
| CN101926815B (en) * | 2010-05-07 | 2013-03-06 | 宁波立华制药有限公司 | Paeoniflorin and glycyrrhetinic acid composition and preparation method and application thereof |
| CN115025113A (en) * | 2022-07-25 | 2022-09-09 | 中国中医科学院中医基础理论研究所 | New use of polysaccharide extract of peony and licorice root decoction |
| CN115040633A (en) * | 2022-07-25 | 2022-09-13 | 中国中医科学院中医基础理论研究所 | New use of protein extract of peony and licorice decoction |
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