CN101125136A - Application of alpinia officinarum hance diarylheptanes compound in pain-alleviating and anti-inflammatory and its extracting method - Google Patents
Application of alpinia officinarum hance diarylheptanes compound in pain-alleviating and anti-inflammatory and its extracting method Download PDFInfo
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Abstract
The present invention discloses an application of galangal diphenyl heptane compounds in analgesic and anti-inflammatory field and the extraction method. The present invention finds the new medical usage of the galangal diphenyl heptane compounds through the long-term studies and can be used in the preparation of the analgesic and anti-inflammatory drugs. The present invention adopts the supercritical carbon dioxide extraction method to extract the lipophilic effective active ingredients diphenyl heptane compounds from the galangal, the extraction efficiency is high, the present invention has no solvent residue toxicity, the natural active ingredients and the thermosensitive ingredients are not easy to be decomposed and damaged, so the natural characteristics of the natural extract can be maintained to the maximum extend. The present invention adopts the molecular distillation technology which is the most modest means for distillation and separation, thus overcoming the shortcomings of high temperature and long heating time in the traditional distillation operations, so the present invention is especially applicable to the separation of the materials with high boiling point and the thermosensitive materials.
Description
Technical field
The present invention relates to Rhizoma Alpiniae Officinarum Diphenylheptane compounds, be specifically related to application and the extracting method thereof of Rhizoma Alpiniae Officinarum Diphenylheptane compounds in antalgic and inflammation relieving.
Background technology
From Vogel reported first in 1815 separate from curcuma Curcuma Longa obtain curcumin since, found and established totally 67 of the natural linear diaryl heptane compounds of structure so far.This compounds mainly is distributed in the Alpinia (Alpinia) of Zingiberaceae (Zingiberaceae), the alder that Curcuma (Curruma) and Rhizoma Zingiberis Recens belong to (Zingiber) plant rhizome and pistil and Betulaceae (Betulaceae) belongs in the bark and pistil of (Alnus) plant, and minority also has discovery at the centrolobium platymiscium of pulse family (Leguminosae) and tool genus (Acer) plant of hard maple section (Aceraceae).
Linear diaryl heptane compounds is present in oriental countries (China more, Japan, India) among the zingiberaceous plant as traditional medicine, spice, food, dyestuff, pharmaceutical research to this class plant shows, they have multiple biological activitys such as anti-liver poison, antiinflammatory, bilification, parasite killing, therefore and the effective main component in the plant mostly is linear diaryl heptane compounds, in recent years the pharmacological research of this compounds is tending towards active.
Rhizoma Alpiniae Officinarum (Rhizoma Alpiniae Officinarum) is the dry rhizome of Zingiberaceae Alpinia plants Rhizoma Alpiniae Officinarum, and tool warming stomach for dispelling cold, the analgesic effect that helps digestion are used for coldness and pain in the epigastrium, gastrofrigid vomiting, heating installation acid regurgitation etc.Modern pharmacology studies show that: Rhizoma Alpiniae Officinarum extract has tangible antalgic and inflammation relieving activity, and this has confirmed the antalgic effect of Rhizoma Alpiniae Officinarum.Studies show that in test of antimony potassium tartrate writhing response and thermostimulation test, the Rhizoma Alpiniae Officinarum water decoction can significantly postpone the pain sensation response time.In the mouse writhing experiment and thermostimulation experiment that acetic acid causes, Rhizoma Alpiniae Officinarum ether extract and water extract have all shown the number of times effect of minimizing writhing response and have prolonged the effect of thermostimulation response latency.
The chloroform extract of Rhizoma Alpiniae Officinarum can hinder arachidonic acid (AA) and be metabolized to PG by suppressing prostaglandin (PG) synthetase series and phospholipase A2 activity, is the mechanism of its antalgic and inflammation relieving.
The application of relevant Rhizoma Alpiniae Officinarum Diphenylheptane compounds in the medicine of treatment analgesic activity do not appear in the newspapers as yet.
Summary of the invention
The purpose of this invention is to provide the application of Rhizoma Alpiniae Officinarum Diphenylheptane compounds in preparation antalgic and inflammation relieving medicine.
Another object of the present invention provides the extracting method of above-mentioned Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
The present invention is through a large amount of experiments, find that Rhizoma Alpiniae Officinarum Diphenylheptane compounds can be used to prepare the antalgic and inflammation relieving medicine, can be used for symptoms such as antiinflammatory after rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, scapulohumeral periarthritis, neck shoulder wrist syndrome, gout, hyperosteogeny, intervertebral disk hernia, cancerous pain and wound and the operation, analgesia.
Described Rhizoma Alpiniae Officinarum Diphenylheptane compounds general formula is as follows:
Wherein R is
Or
Wherein X is H or methyl;
R
1, R
2, R
3, R
4, R
5, R
6Be H, hydroxyl or methoxyl group.
Particular compound is as shown in the table:
Chemical compound 1:5-hydroxyl-1, and 7-diphenyl-3-heptanone (5-hydroxy-1,7-diphenyl-3-heptanone), molecular weight: 282, molecular formula: C
19H
22O
2, its character is colourless acicular crystal, mp.48.5～49.5 are soluble in ethanol.
Chemical compound 2:5-hydroxyl-7-(4 "-hydroxy phenyl)-1-phenyl-3-heptanone (5-hydroxy-7-(4 '-hydroxyphenyl)-1-phenyl-3-heptanone), molecular weight: 298, molecular formula: C
19H
22O
3, its character is a colorless oil, is soluble in ethanol.
Chemical compound 3:5-hydroxyl-7 (4 '-hydroxyl-3 '-methoxyphenyl)-1-phenyl-3-heptanone (5-hydroxy-7-(4 " hydroxy-3 "-methoxyphenyl)-1-phenyl-3-heptanone), molecular weight: 328, molecular formula: C
20H
24O
4, its character is colourless acicular crystal, mp.60.0～61.5 are soluble in ethanol.
Chemical compound 4:5-hydroxyl-1, two (4 '-hydroxyl-3 '-the methoxyphenyl)-3-heptanone of 7-(5-hydroxy-1, and 7-di (4 " hydroxy-3 "-methoxyphenyl)-3-heptanone), molecular weight: 374, molecular formula: C
21H
26O
6, its character is colourless acicular crystal, mp.90.0～91.0 are soluble in ethanol.
Chemical compound 5:5-methoxyl group-1, and 7-diphenyl-3-heptanone (5-methoxy-1,7-diphenyl-3-heptanone), molecular weight: 296, molecular formula: C
20H
24O
2, its character is a colorless oil, is soluble in ethanol.
Chemical compound 6:5-methoxyl group-7-(4 "-hydroxy phenyl)-1-phenyl-3-heptanone (5-hydroxy-7-(4 " hydroxyphenyl)-1-phenyl-3-heptanone), molecular weight: 312, molecular formula: C
20H
24O
3, its character is colourless acicular crystal, mp.68.0～70.0 are soluble in ethanol.
Chemical compound 7:5-methoxyl group-7-(4 '-hydroxyl-3 '-methoxyphenyl)-1-phenyl-3-heptanone (5-methoxy-7-(4 " hydroxy-3 "-methoxyphenyl)-1-phenyl-3-heptanone), molecular weight: 342, molecular formula: C
21H
26O
4, its character is a colorless oil, is soluble in ethanol.
Chemical compound 8:1, and 7-diphenyl-4-alkene-3-heptanone (1,7-diphenylhept-4-eh-3-one), molecular weight: 264, molecular formula: C
19H
20O, its character is a colorless oil, is soluble in ethanol.
Chemical compound 9:7-(4 "-hydroxy phenyl)-1-phenyl-4-alkene-3-heptanone (7-(4 " hydroxyphenyl)-1-phenyl-hept-4-en-3-one), molecular weight: 280, molecular formula: C
19H
20O
2, its character is a colorless oil, is soluble in ethanol.
Chemical compound 10:7-(4 "-hydroxyl-3 "-methoxyphenyl)-1-phenyl-4-alkene-3-heptanone (7-(4 " hydroxy-3 "-methoxyphenyl)-1-phenyl-hept-4-en-3-one), molecular weight: 310, molecular formula: C
20H
22O
3, its character is a colorless oil, is soluble in ethanol.
Chemical compound 11:5-hydroxyl-7-(4 " hydroxyl-3 "-methoxyphenyl)-1-phenyl-4-alkene-3-heptanone (5-hydroxy-7-(4 " hydroxy-3 "-methoxyphenyl)-1-phenyl-3-heptanone), molecular weight: 326, molecular formula: C
20H
22O
4, its character is a colorless oil, is soluble in ethanol.
Chemical compound 12: octahydro curcumin (octahydrocurcumin), molecular weight: 376, molecular formula: C
21H
28O
6, its character is colourless acicular crystal, mp.132.0～134.0 are soluble in ethanol.
Chemical compound 13:1-(4 " hydroxyl-3 "-methoxyphenyl)-7-phenyl-3, and the 5-heptadione (1-(4 " hydroxy-3 "-methoxyphenyl)-7-phenyl-3,5-heptanedione), molecular weight: 326, molecular formula: C
20H
22O
4, its character is a colorless oil, is soluble in ethanol.
Chemical compound 14:(3R, 5R)-1-(4 " hydroxy phenyl)-7-phenyl-3, the 5-heptandiol ((3R, 5R)-1-(4 " hydroxyphenyl)-7-phenyl-3,5-heptanediol), molecular weight: 300, molecular formula: C
19H
24O
3, its character is colourless acicular crystal, mp.109.0～111.0 are soluble in ethanol.
In above-mentioned 14 Rhizoma Alpiniae Officinarum Diphenylheptane compounds, preferred 5-hydroxyl-7-(4 '-hydroxy phenyl)-1-phenyl-3-heptanone, 1,7-diphenyl-4-alkene-3-heptanone, 7-(4 '-hydroxy phenyl)-1-phenyl-4-alkene-3-heptanone, 7-(4 '-hydroxyl-3 '-methoxyphenyl)-1-phenyl-4-alkene-3-heptanone or 5-hydroxyl-1,7-diphenyl-3-heptanone.It promptly is chemical compound 1,2,8,9,10.
Rhizoma Alpiniae Officinarum Diphenylheptane compounds can be formed the medicine of various dosage forms with medically acceptable adjuvant, as gel, tincture, unguentum, spray, tablet, capsule or drop pill.
Gel can be made up of Rhizoma Alpiniae Officinarum Diphenylheptane compounds and carbomer, glycerol, triethanolamine, azone.Concrete preparation method is: get carbomer 2g, add 50ml water and 20g glycerol leaves standstill swelling, add the transdermal enhancer azone of Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g and 0.25% again and use triethanolamine adjust pH to 10, add water to 200g at last and stir evenly promptly with refiner.
Ointment can be made up of Rhizoma Alpiniae Officinarum Diphenylheptane compounds and stearic acid, lanoline, liquid paraffin, triethanolamine, glycerol and distilled water.Its preparation method is: get Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g and 100ml liquid paraffin and grind well, mix homogeneously promptly with substrate (liquid paraffin 150ml, stearic acid 150g, lanoline 20g, triethanolamine 20g, glycerol 50ml, distilled water 500ml are prepared mixed-matrix by emulsion process).
Tincture can be made up of Rhizoma Alpiniae Officinarum Diphenylheptane compounds and 50～70% ethanol.Its preparation method is: get Rhizoma Alpiniae Officinarum Diphenylheptane compounds 100g, add 70% dissolve with ethanol to 1000ml.
Spray can be made up of Rhizoma Alpiniae Officinarum Diphenylheptane compounds and Arlacel-80, sodium lauryl sulphate, tween 80, glycerol and distilled water.Its preparation method is: get Rhizoma Alpiniae Officinarum Diphenylheptane compounds 60g and 200g Arlacel-80, sodium lauryl sulphate 115g, 170g tween 80 mixing, adding distil water filters to 8000ml, packing, and every bottle is pressed into the about 5.5g of propellant F12, makes 1000 bottles altogether.
Tablet is got the stirring of Rhizoma Alpiniae Officinarum Diphenylheptane compounds adding equivalent ethanol and is made dissolving, makes the alcoholic solution of extract.Take by weighing an amount of beta-schardinger dextrin-again, add the suitable quantity of water high speed shear and stir.Slowly add the alcoholic solution of extract under stirring, high speed shear is stirred to the formation suspension, leaves standstill and makes precipitation, sediment separate out, dry below 40 ℃, solidfied material was pulverized 24 order nylon mesh made into granule, add appropriate amount of starch again, after mixing is pulverized, cross 80 mesh sieves 2 times, put in the blender, the adding distilled water is an amount of, stirs 10 minutes, the system soft material, cross 16 mesh sieves and granulate, wet grain is dry in 60 ℃ of air dry ovens, and dry granular is crossed 16 mesh sieve granulate.Add carboxymethyl starch sodium and magnesium stearate, mix homogeneously, tabletting, the bag film-coat, promptly.
Soft capsule preparation, this soft capsule preparation is made up of Rhizoma Alpiniae Officinarum Diphenylheptane compounds and an amount of vegetable oil, 3%～5% Cera Flava and a small amount of wetting agent.Its preparation method is, earlier with the mixture of Rhizoma Alpiniae Officinarum extract and the adjuvant mixed by 1: 2.5, goes up the Zhanang machine again and suppresses and form.
Dropping pill formulation, this dropping pill formulation are mixed with PEG4000 and PEG6000 by Rhizoma Alpiniae Officinarum Diphenylheptane compounds and form.Its preparation method is, earlier Rhizoma Alpiniae Officinarum Diphenylheptane compounds mixed by 1: 0.5: 1.5 with PEG4000 and PEG6000, and fusion again splashes in the coolant fluid paraffin body and makes.
Rhizoma Alpiniae Officinarum extract is made exterior-applied gel, directly coat skin surface, have characteristics such as topical therapeutic concentration height, effect is rapid, systemic side effects is little.The gel appearance colorless is transparent, good visual effect; It adopts water-soluble base, compares with ointment, has not pollution clothes, the characteristics of easy cleaning; Compare with the externally used solution agent, coating is convenient, and medicine is difficult for running off, in characteristics such as storing property of skin surface are good.Gel is single-phase disperse system, does not have stratified problem, and stability is better, and fabrication process condition requires low than ointment.Therefore, develop the Rhizoma Alpiniae Officinarum extract gel, a kind of new treatment approach is provided, can bring good social benefit.
Rhizoma Alpiniae Officinarum Diphenylheptane compounds of the present invention is a raw material with the Rhizoma Alpiniae Officinarum rhizome, obtains through the molecular distillation enrichment after the employing supercritical liquid extraction technique extracts again, and extraction step is as follows:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, 40～60 ℃ of oven dry down are ground into 20～100 order fine powders.Is 30～60 ℃, extracting pressure 20～35mPa with Rhizoma Alpiniae Officinarum powder in extraction temperature, and resolution temperature is 30～60 ℃, resolves under pressure 6～20mPa condition and extracted 2～5 hours.The further molecular distillation of gained extract, distillation condition is: 80～150 ℃ of temperature, vacuum (10 ± 5) Pa, knifing rotating speed 250～300r/min, flow velocity 1.8～2.0ml/min, 3～5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
In the Rhizoma Alpiniae Officinarum Diphenylheptane compounds that extraction obtains, contain 50%～99% above-claimed cpd 1,2,8,9,10.
Compared with prior art, the present invention has following beneficial effect: the present invention has found the novel medical use of Rhizoma Alpiniae Officinarum Diphenylheptane compounds through long term studies, can be used to prepare the antalgic and inflammation relieving medicine.The present invention adopts the carbon dioxide supercritical fluid extraction method to extract the lipotropy effective active composition (Diphenylheptane compounds) of Rhizoma Alpiniae Officinarum, the extraction efficiency height, no solvent residue toxicity, active skull cap components heat-sensitive ingredients are difficult for decomposing to be destroyed, and can keep the extract natural feature to greatest extent.Adopt molecular distillation technique the gentleest this separated means, overcome traditional distillation procedure temperature height, the long shortcoming of heated time, be particularly useful for the separation of high boiling point, heat sensitive material.
The specific embodiment
Embodiment 1:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 28Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 4 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 120 ℃.Open the vacuum pump evacuation.When vacuum reaches 10Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 270r/min, flow velocity 1.8ml/min, 5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 2:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 30Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 4 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 120 ℃, open the vacuum pump evacuation.When vacuum reaches 10Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 300r/min, flow velocity 1.8ml/min, 3 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 3:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 32Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 3.5 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 150 ℃, open the vacuum pump evacuation.When vacuum reaches 10Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 250r/min, flow velocity 1.8ml/min, 5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 4:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 32Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 3.5 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 80 ℃.Open the vacuum pump evacuation.When vacuum reaches 15Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 250r/min, flow velocity 2.0ml/min, 5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 5:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 30Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 3.5 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 80 ℃, open the vacuum pump evacuation.When vacuum reaches 15Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 270r/min, flow velocity 1.8ml/min, 5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 6:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, oven dry is pulverized.Then dry powder is placed in the supercritical fluid extraction jar, begins to supply with supercritical CO
2, with extracting pressure 28Mpa, 40 ℃ of extraction temperature are resolved pressure 6Mpa, extract 3.5 hours with 22L/ hour flow under the condition that resolution temperature is 40 ℃, extract the grease of rufous, promptly.
Molecular distillation: molecular distillation apparatus is heated.When temperature reaches 80 ℃, open the vacuum pump evacuation.When vacuum reaches (10 scholar 5) Pa, will add from charging aperture behind the supercritical extract, the rotating speed of regulating the rotor knifing is 270r/min. flow velocity 1.8ml/min, 5 ℃ of cooling water temperatures.From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
Embodiment 7: the preparation of gel preparation
1, prescription and proportioning:
Carbomer-940 10g azone 50ml
Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g 95% ethanol 10ml
Glycerol 50ml triethanolamine 15g
Ethyl hydroxybenzoate 1g PEG-400 10ml
Distilled water adds to 1000g
Preparation method is: 1. carbomer-940 is scattered in temperature and is in 40-50 ℃ the 20ml purified water, leave standstill 24h after, stir down and add glycerol, ethyl hydroxybenzoate, azone and PEG-400 by said ratio.2. get Rhizoma Alpiniae Officinarum Diphenylheptane compounds, make dissolving with an amount of 95% ethanol.3. will be 2. solution grind and slowly add down 1. in the solution, fully stir and add purified water to full dose, dripping triethanolamine simultaneously, to regulate pH value be 6～7, promptly makes gel.
2, prescription and proportioning:
Carboxymethyl cellulose 15g Mentholum 80ml
Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g 95% ethanol 10ml
Glycerol 50ml triethanolamine 15g
Ethyl hydroxybenzoate 1g PEG-400 10ml
Distilled water adds to 1000g
Preparation method is: 1. carboxymethyl cellulose is scattered in the 20ml purified water, leave standstill 24h after, stir down and add glycerol, ethyl hydroxybenzoate, Mentholum and PEG-400 by said ratio.2. get Rhizoma Alpiniae Officinarum Diphenylheptane compounds, make dissolving with an amount of 95% ethanol.3. will be 2. solution grind and slowly add down 1. in the solution, fully stir and add purified water to full dose, dripping triethanolamine simultaneously, to regulate pH value be 6～7, promptly makes gel.
3, prescription and proportioning:
Sodium alginate 30g calcium gluconate 0.5g
Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g 95% ethanol 10ml
Glycerol 50ml triethanolamine 15g
Ethyl hydroxybenzoate 1g
Distilled water adds to 1000g
Preparation method is: 1. sodium alginate and glycerol are mixed into pasty state (heating in case of necessity), and standby; Other gets ethyl hydroxybenzoate, calcium gluconate is dissolved in the hot purified water, with the disposable adding of sodium alginate glycerol mixture wherein, stirs fast then, places a few hours to becoming stiff gel.2. get Rhizoma Alpiniae Officinarum Diphenylheptane compounds, make dissolving with an amount of 95% ethanol.3. will be 2. solution grind and slowly add down 1. in the solution, fully stir and add purified water to full dose, dripping triethanolamine simultaneously, to regulate pH value be 6～7, promptly makes gel.
4, prescription and proportioning:
Carbomer-940 10g azone 50ml
Rhizoma Alpiniae Officinarum Diphenylheptane compounds 15g 95% ethanol 10ml
Glycerol 50ml triethanolamine 15g
Ethyl hydroxybenzoate 1g PEG-400 10ml
Distilled water adds to 1000g
Preparation method is: 1. carbomer-940 is scattered in temperature and is in 40-50 ℃ the 20ml purified water, leave standstill 24h after, stir down and add glycerol, ethyl hydroxybenzoate, azone and PEG-400 by said ratio.2. get Rhizoma Alpiniae Officinarum Diphenylheptane compounds, make dissolving with an amount of 95% ethanol.3. will be 2. solution grind and slowly add down 1. in the solution, fully stir and add purified water to full dose, dripping triethanolamine simultaneously, to regulate pH value be 6～7, promptly makes gel.
5, prescription and proportioning:
Carbomer-940 10g azone 50ml
Rhizoma Alpiniae Officinarum Diphenylheptane compounds 20g 95% ethanol 10ml
Glycerol 50ml triethanolamine 15g
Ethyl hydroxybenzoate 1g PEG-400 10ml
Distilled water adds to 1000g
Preparation method is: 1. carbomer-940 is scattered in temperature and is in 40-50 ℃ the 20ml purified water, leave standstill 24h after, stir down and add glycerol, ethyl hydroxybenzoate, azone and PEG-400 by said ratio.2. get Rhizoma Alpiniae Officinarum extract Diphenylheptane compounds, make dissolving with an amount of 95% ethanol.3. will be 2. solution grind and slowly add down 1. in the solution, fully stir and add purified water to full dose, dripping triethanolamine simultaneously, to regulate pH value be 6～7, promptly makes gel.
Embodiment 8: the preparation of ointment
Liquid paraffin 150ml, stearic acid 150g, lanoline 20g, triethanolamine 20g, glycerol 50ml, distilled water 500ml are prepared mixed-matrix by emulsion process, get Rhizoma Alpiniae Officinarum Diphenylheptane compounds 10g and 100ml liquid paraffin and grind well, again with the substrate mix homogeneously promptly.
Embodiment 9: the preparation of tablet
Rhizoma Alpiniae Officinarum Diphenylheptane compounds is used the beta-cyclodextrin inclusion compound of 1.5 times of amounts respectively, clathrate adds 150g starch, mix,, put in the blender after 80 mesh sieves 2 times, it is an amount of to add distilled water, stirred 10 minutes, the system soft material is crossed 16 mesh sieves and is granulated, wet grain is dry in 60 ℃ of air dry ovens, and dry granular is crossed 16 mesh sieve granulate.Add carboxymethyl starch sodium 25g and magnesium stearate 5g, mix homogeneously, tabletting, the bag film-coat, promptly.
The pharmaceutically active experiment:
Experiment material: self-control Rhizoma Alpiniae Officinarum Diphenylheptane compounds gel, blank gel, carrageenin, Fu Shi Freund's complete adjuvant, glacial acetic acid, dimethylbenzene are analytical pure, Vitalin Emulgel, Fastum gel.Laboratory animal: Kunming mouse, Wister rat.
Method and result:
1. Rhizoma Alpiniae Officinarum Diphenylheptane gel (being called for short GLJNJ) xylol causes the influence of mice ear:
Choose 30 of the female Kunming mouses of body weight 17～21g, be divided into blank group, GLJNJ group, Fastum gel group at random, 10 every group.At the dimethylbenzene 0.03ml of the two sides, front and back of mouse right ear separate application concentration 100%, left ear is left intact.Each group respectively at cause scorching before with cause scorching back 30min auris dextra and be coated with blank gel, GLJNJ, Fastum gel 0.1ml.Cause scorching back 4h and take off cervical vertebra execution animal, cut ears and lay round auricle in the ear same area respectively with 9mm diameter card punch, torsion balance is weighed.Calculate the swelling degree, date processing is analyzed with K IndependentSamples Test.Relatively treatment group and matched group difference condition.
Table 1 Rhizoma Alpiniae Officinarum Diphenylheptane gel xylol causes the influence of mice ear
| Group | Left side ear heavy (mg) | Auris dextra heavy (mg) | Swelling degree (%) |
| Blank gel group GLJNJ group Fastum gel | 15.03±1.12 14.34±0.95 14.37±1.14 | 17.09±1.68 14.79±0.89 15.08±1.28 | 13.68±6.83 1.55±4.20* 5.46±4.36* |
Annotate: * represents to compare P＜0.05 with blank gel group.
After causing inflammation, each organizes the equal visible height redness of mouse right ear.Fastum gel and Rhizoma Alpiniae Officinarum Diphenylheptane gel xylol cause mice ear all the obvious suppression effect, sees Table 1.
2. Rhizoma Alpiniae Officinarum Diphenylheptane gel on Carrageenan causes the influence of rat foot claw swelling:
Selecting body weight for use is 24 of the female Wister rats of 150～200g, is divided into 3 groups at random, blank gel matched group, Rhizoma Alpiniae Officinarum Diphenylheptane gel group, Fastum gel positive controls.Each group of 3d is given and blank gel, Rhizoma Alpiniae Officinarum Diphenylheptane gel, Fastum gel 0.5ml, every day 2 times respectively before the test.Test the evening before yesterday with the rat overnight fasting.For guaranteeing the concordance of moisture in the body, cause the scorching preceding stomach feedwater 5mL that irritates.Behind the 30min, subcutaneous injection 0.1ml 1% carrageenin at the bottom of the two metapedes of rat.Cause scorching before 30min and cause inflammation after, each group awards blank gel, Rhizoma Alpiniae Officinarum Diphenylheptane gel, Fastum gel 0.5ml respectively at left back sufficient sole of the foot portion.Cause scorching before 0.5h and cause scorching back 1,3,4,6h adopts the capillary tube amplifying method to measure the rat paw volume, calculating swelling degree.The swelling degree is through variance analysis, the difference of relatively treatment group and each matched group.
Rhizoma Alpiniae Officinarum Diphenylheptane gel and Fastum gel on Carrageenan cause rat foot claw swelling all the obvious suppression effect, sees Table 2.
Table 2 Rhizoma Alpiniae Officinarum Diphenylheptane gel on Carrageenan causes the influence of rat foot claw swelling
| Group | n | Different time foot sole of the foot volume (ml) | ||||
| Before causing inflammation | Cause scorching back 1h | Cause scorching back 3h | Cause scorching back 4h | Cause scorching back 6h | ||
| Blank gel group GLJNJ group Fastum gel | 16 16 16 | 0.97±0.07 0.96±0.08 0.95±0.06 | 1.38±0.11 1.22± 0.06** 1.17± 0.13** | 1.35± 0.05 1.20± 0.10** 1.29± 0.09* | 1.50± 0.13 1.25± 0.13** 1.29± 0.11** | 1.58± 0.10 1.42± 0.09** 1.35± 0.13** |
Annotate: * represents to compare with blank gel group, P＜0.05, and * * represents to compare P＜0.01 with blank gel group.
3. Rhizoma Alpiniae Officinarum Diphenylheptane gel is to the influence (hot plate method) of thermostimulation mice pain threshold:
Choose body weight 17～21g, the basic threshold of pain＞5s, 30 of the female Kunming mouses of＜60s are divided into blank group, Rhizoma Alpiniae Officinarum Diphenylheptane gel group, Fastum gel positive controls, 10 every group at random.Hot plate temperature is controlled at 55～56 ℃.With stopwatch record reaction time of occurrence, promptly to end when occurring licking foot to the hot plate beginning from putting animal, this section period is the hot plate threshold of pain.Before each group gives the logical gel of blank gel, Rhizoma Alpiniae Officinarum Diphenylheptane gel, method phase respectively and after the administration 30,60,90min writes down the reaction time of occurrence respectively.As mice still painless reaction after stopping 60s on the hot plate, press 60s and calculate.Ease pain percentage rate (%) through variance analysis, the difference condition of relatively treatment group and matched group.
The result: Rhizoma Alpiniae Officinarum Diphenylheptane gel can obviously prolong thermostimulation (by the use of thermal means) mice pain threshold, and effect obviously is better than the Fastum gel, sees Table 3.Prompting Rhizoma Alpiniae Officinarum Diphenylheptane gel has significant analgesia role.
Table 3 Rhizoma Alpiniae Officinarum Diphenylheptane gel to the influence of thermostimulation mice pain threshold (n=10,
)
| Group | The threshold of pain, basis | Different time after the administration (h) pain threshold/s | ||
| 0.5 | 1 | 1.5 | ||
| Blank gel group GLJNJ group Fastum gel | 16.44±8.17 16.01±6.34 17.03±6.21 | 15.56±6.59 17.75±6.32 15.19±4.36 | 16.38±7.26 22.64±8.79 17.62±4.65 | 18.68±9.35 30.89± 10.28*#$ 19.82±7.98 |
Annotate: * represents to compare with blank gel group, P＜0.05, and # represents to compare with Fastum gel group, P＜0.05, $ represents to compare P＜0.01 with the basic threshold of pain.
4. Rhizoma Alpiniae Officinarum Diphenylheptane gel is to the treatment of rheumatoid arthritis effect:
Choose 30 of body weight 130-160g Wister rats, be divided into blank gel matched group, Rhizoma Alpiniae Officinarum Diphenylheptane gel group, Vitalin Emulgel group at random, every group each 10.Purifying natural II Collagen Type VI is dissolved in 0.1M glacial acetic acid (2mg/ml, 4 ℃ of refrigerator overnight), under the ice bath, itself and equal-volume Fu Shi Freund's complete adjuvant is fully ground emulsifying at superclean bench.Every rat is in root of the tail portion, back this Emulsion of Intradermal multi-point injection 1ml modeling.Inject this Emulsion 0.5ml with every Mus of quadrat method 7d and do booster immunization.Modeling 15d, blank group and Rhizoma Alpiniae Officinarum Diphenylheptane gel group give blank gel and Rhizoma Alpiniae Officinarum Diphenylheptane gel respectively, the Vitalin Emulgel group gives the diclofenac latex, every Mus 0.5ml, evenly be applied in 0.5cm on biped and the ankle joint, every day 2 times, successive administration 14d.Modeling 8d begins, every other day 1 extremity inflammation of observed and recorded integration.Since the 2nd week, observe to measure weekly before blank group and the administration of treatment administration group that the sufficient tenderness of 30min is worth 1 time behind the 30min and administration.
Experimental result as seen, from modeling 10d, arthritis reaction appears in each group successively, can reduce the arthritis reaction during the administration.Compare with the blank group, the obvious prolong rats foot of energy tenderness threshold value sees Table 4 after the administration of Rhizoma Alpiniae Officinarum Diphenylheptane gel.
Table 4 Rhizoma Alpiniae Officinarum Diphenylheptane gel to the influence of the collagen-induced rats with arthritis foot tenderness threshold of pain (n=10,
)
| Group | Before the administration | After the administration | The analgesia rate |
| Blank group GLJNJ group Vitalin Emulgel group | 348.00±135.13 361.00±132.00 358.00±125.47 | 250.00±60.32 375.00±89.46 367.00±74.56 | -25.68±18.65 10.09±21.49** 7.33±11.58** |
Annotate: * * represents to compare P＜0.01 with blank gel group.
Interpretation:
Rhizoma Alpiniae Officinarum Diphenylheptane gel has obvious anti-inflammatory analgesic to multiple animal inflammation and pain model, especially the hot plate analgesic experiment is more obvious, analgesic effect obviously is better than the Fastum gel, illustrate that Rhizoma Alpiniae Officinarum Diphenylheptane gel has tangible analgesic effect, be used for the treatment of pain and inflammation treatment provides experimental basis for clinical.
Claims (5)
1. the application of Rhizoma Alpiniae Officinarum Diphenylheptane compounds in preparation antalgic and inflammation relieving medicine, the general structure of described Rhizoma Alpiniae Officinarum Diphenylheptane compounds is as follows:
Wherein R is
Or
Wherein X is H or methyl;
R
1, R
2, R
3, R
4, R
5, R
6Be H, hydroxyl or methoxyl group.
2. application as claimed in claim 1, it is characterized in that described Rhizoma Alpiniae Officinarum Diphenylheptane compounds is 5-hydroxyl-7-(4 '-hydroxy phenyl)-1-phenyl-3-heptanone, 1,7-diphenyl-4-alkene-3-heptanone, 7-(4 '-hydroxy phenyl)-1-phenyl 4-alkene-3-heptanone, 7-(4 '-hydroxyl-3 '-methoxyphenyl)-1-phenyl-4-alkene-3-heptanone or 5-hydroxyl-1,7-diphenyl-3-heptanone.
3. application as claimed in claim 1 or 2 is characterized in that described Rhizoma Alpiniae Officinarum Diphenylheptane compounds can make the antalgic and inflammation relieving medicine of various dosage forms with medically acceptable carrier.
4. application as claimed in claim 3 is characterized in that described dosage form can be gel, tincture, unguentum, spray, tablet, capsule or drop pill.
5. the extracting method of a Rhizoma Alpiniae Officinarum Diphenylheptane compounds is characterized in that extraction separation from Rhizoma Alpiniae Officinarum, and step is as follows:
Get the Rhizoma Alpiniae Officinarum rhizome and clean, 40～60 ℃ of oven dry down are ground into 20～100 order fine powders.Is 30～60 ℃, extracting pressure 20～35mPa with Rhizoma Alpiniae Officinarum powder in extraction temperature, and resolution temperature is 30～60 ℃, resolves under pressure 6～20mPa condition and extracted 2～5 hours; The further molecular distillation of gained extract, distillation condition is: 80～150 ℃ of temperature, vacuum 5～15Pa, knifing rotating speed 250～300r/min, flow velocity 1.8～2.0ml/min, 3～5 ℃ of cooling water temperatures; From two discharging openings collect respectively two groups of fractions, wherein one group of fraction is Rhizoma Alpiniae Officinarum Diphenylheptane compounds.
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