CN1947757A - Leave of glutinous rehmannia extractive, its prepn. method and use, medicines prepd. with said extractives - Google Patents
Leave of glutinous rehmannia extractive, its prepn. method and use, medicines prepd. with said extractives Download PDFInfo
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- CN1947757A CN1947757A CN 200610021877 CN200610021877A CN1947757A CN 1947757 A CN1947757 A CN 1947757A CN 200610021877 CN200610021877 CN 200610021877 CN 200610021877 A CN200610021877 A CN 200610021877A CN 1947757 A CN1947757 A CN 1947757A
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Abstract
An extract of rehmannia leaf used for preparing the medicines and health-care food to prevent and treat the renal function diseases, such as albuminuria, hematuria, chronic glomerulonephritis is disclosed. Its preparing process is also disclosed.
Description
[technical field]
The present invention relates to a kind of extraction of active ingredients of plants, relate in particular to a kind of Folium Rehmanniae extract and its production and use, and with the medicine of this extract preparation.
[background technology]
Scrophulariaceae rehmannia glutinosa plant (Rehamnnia glutinosa Libosch) is known Chinese crude drug, normal and other Chinese crude drug compatibility is treated renal function disease, for example classical prescription " LIUWEI DIHUANG WAN ", " JINGUI SHENQI WAN " etc., Radix Rehmanniae all is " monarch " medicine that plays a major role.According to tradition, Radix Rehmanniae is to be used as medicine with its tuber, and its leaf is then passed into disuse.Modern pharmacology studies show that contained main component is the Folium Rehmanniae total glycosides in Folium Rehmanniae/stem and leaf, and the tuber of Radix Rehmanniae does not contain the Folium Rehmanniae total glycosides, the enriching yin and nourishing kidney of Folium Rehmanniae total glycosides tool, removing heat from blood and promoting blood circulation, consolidating semen hemostasis.Can be used for albuminuria, hematuria, chronic glomerulonephritis and belong to syndrome of deficiency of both qi and yin,, should make full use of the Radix Rehmanniae resource, excavate the medical value of Folium Rehmanniae, it is made the best use of everything in Chinese material medicine resource deficient day by day today.Still useless at present Folium Rehmanniae effective component extracting Folium Rehmanniae total glycosides is as medicinal or other purposes.
[summary of the invention]
Goal of the invention
Primary and foremost purpose of the present invention provides a kind of Folium Rehmanniae extract that contains effective composition Folium Rehmanniae total glycosides and preparation method thereof.
Another object of the present invention provides a kind of purposes of Folium Rehmanniae extract.
A further object of the present invention, providing a kind of is the medicine of effective ingredient with the Folium Rehmanniae total glycosides, especially a kind of medicine that is mainly used in the treatment renal function disease.
Technical scheme
The objective of the invention is to realize like this:
Folium Rehmanniae extract of the present invention, this extract contain effective active composition Folium Rehmanniae total glycosides.The main component of Folium Rehmanniae total glycosides is the acteoside class, and its dry product contains content 〉=50% of the total sterioside of Ergota in acteoside, the content of acteoside 〉=25%.
Folium Rehmanniae preparation method of extract of the present invention, take following steps:
1.. Folium Rehmanniae/stem and leaf directly or after pulverizing, is adopted solvent heating and refluxing extraction method or supercritical fluid extraction extraction method, extracting solution.
2.. with extracting liquid filtering, reclaim solvent and be concentrated into the concentrated solution a of relative density 1.01～1.10.
3.. a leaves standstill clarification with concentrated solution, get supernatant and pass through adsorption resin column, water elution adsorption resin column with 1～6 times of amount of resin column volume, discard water liquid, the concentration of 1～6 times of amount of reuse resin column volume is 20～96% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the concentrated solution b of relative density 1.01～1.10.
4.. b leaves standstill clarification with concentrated solution, get supernatant and pass through adsorption resin column, water eluting adsorption resin column is closely neutral to effusive liquid, discard water liquid, the concentration of 1～3 times of amount of reuse resin column volume is 10～20% ethanol elution, discards ethanol elution, and continuing with 1～6 times of resin column volume amount concentration is 60～96% ethanol elution, reclaim ethanol and be concentrated into the extractum of relative density 1.20～1.40, promptly get product Folium Rehmanniae total glycoside extract.
5.. with extract dry, promptly get product Folium Rehmanniae total glycosides solid.
In the 1. described solvent heating and refluxing extraction of the above-mentioned steps method, solvent reflux, extract, 1～3 time under 50～100 ℃ of conditions, each 0.5～1.5 hour, merge extractive liquid.Solvent is selected for use:
(a). a kind of solvent in water, methanol, the ethanol; Perhaps
(b). a kind of in the mixed solvent that water or methanol or ethanol and acetic acid are formed, its consumption volume ratio is concentration 30～96% ethanol or concentration 30～96% methanol or water: acetic acid=80～99.99: 20～0.01 (V: V); Perhaps
(c). the mixed solvent that any two or more arbitrary proportions are formed in above-mentioned (a) and (b).Described solvent preferred alcohol.
Contain 0.01～10% acetic acid (V: V) in the 3. described ethanol of above-mentioned steps; The 3. described adsorption resin column of step adopts a kind of in the macroporous adsorptive resins such as D201, D101, H103, X-5, NKA-II.
The 4. described adsorption resin column of above-mentioned steps adopts a kind of in the macroporous adsorptive resins such as SP825, HP-20 type.
Above-mentioned steps 5. extract dry method can be cold drying or spray drying.
Unstable under high temperature, super-humid conditions because of the Folium Rehmanniae total glycosides, therefore in extraction solvent of the present invention, added acetic acid, improving its stability in preparation process, and can guarantee the effectiveness of product yield and pharmaceutical preparation.
The Folium Rehmanniae extract that adopts said method to make is a kind of compositions, except that the Folium Rehmanniae total glycosides, also contain other component, but Folium Rehmanniae total glycosides content height can reach more than 75%.This Folium Rehmanniae total glycosides calculates in dry product: contain the total sterioside of Ergota with acteoside 〉=50%; Contain acteoside 〉=25%.
Pharmaceutical research shows that the function of Folium Rehmanniae total glycosides cures mainly: enriching yin and nourishing kidney, removing heat from blood and promoting blood circulation, consolidating semen hemostasis.Be used for albuminuria, hematuria, chronic glomerulonephritis; Belong to syndrome of deficiency of both qi and yin, disease meeting color is simple and unadorned, weak breath is weak, feverish sensation in the palms and soles, lumbago, edema, lassitude and weak, dry mouth and throat, laryngopharynx swelling and pain, dizziness and tinnitus, the few tongue of red tongue, thready and weak pulse etc.
The purposes of above-mentioned Folium Rehmanniae extract: can be used for preparing the medicine or the preparation health food for the treatment of disease.
The purposes of above-mentioned Folium Rehmanniae extract: in particular for preparing a kind of medicine that is mainly used in the treatment renal function disease, this medicine contains effective active component Folium Rehmanniae total glycosides.
Above-mentioned being used to prepares the medicine for the treatment of renal function disease, is the medicine that is used for the treatment of renal function diseases such as albuminuria, hematuria, chronic glomerulonephritis.
Above-mentionedly being used to prepare health food, is the health food that is used to prepare immunomodulating class and resisting fatigue class.
Described health food contains Folium Rehmanniae extract Folium Rehmanniae total glycosides in this health food.
The medicine of prepared treatment renal function disease, this medicine contain effective active component Folium Rehmanniae total glycosides.
The medicine of prepared treatment renal function disease, this medicine are to add the medicament that acceptable accessories or complementary composition are prepared from by the Folium Rehmanniae total glycosides.The weight proportion component of its Folium Rehmanniae total glycosides, adjuvant or complementary composition is: yellow leaf total glycosides 1～100%, adjuvant (or complementary composition) 0～99%.
Above-mentioned medicament can be said any dosage form on the pharmaceutics.
The dosage form of said medicine is capsule, soft capsule, tablet (comprising oral ordinary tablet, buccal tablet, chewable tablet, effervescent tablet, slow releasing tablet, controlled release tablet), granule, pill, powder, mixture, syrup.
Beneficial effect
The present invention extracts, utilizes the effective active composition Folium Rehmanniae total glycosides in the Folium Rehmanniae, turns waste into wealth, and has opened up application for Folium Rehmanniae, makes full use of the Radix Rehmanniae plant resources, has alleviated imbalance between supply and demand.Especially with the medicine of this extract Folium Rehmanniae total glycosides preparation, have enriching yin and nourishing kidney, removing heat from blood and promoting blood circulation, the merit of consolidating semen hemostasis is specially adapted to albuminuria, hematuria, the chronic glomerulonephritis person that belongs to the qi-yin deficiency syndrome.What the present invention developed is the medicine of effective ingredient with the Folium Rehmanniae total glycosides, I, II, III clinical trial phase and the pharmacological toxicology test this medicine capsule preparations wherein carried out through five tame clinical units such as Chengdu University of Traditional Chinese Medicines show: have enriching yin and nourishing kidney, removing heat from blood and promoting blood circulation, the merit of consolidating semen hemostasis, be used for albuminuria, hematuria, chronic glomerulonephritis and belong to the syndrome of deficiency of both qi and yin person is evident in efficacy, safety is good.
[specific embodiment]
Embodiment one
1.. with Folium Rehmanniae or glutinous rehmannic stem and leaf dry product after crushed, add solvent 400L (for the first time), 350L (for the second time) respectively with 50kg Radix Rehmanniae leaf (or glutinous rehmannic stem and leaf), solvent adopts the ethanol (glacial acetic acid that wherein contains volume 0.5%) of concentration 80%, twice of 80 ℃ of reflux, extract,, each 1 hour, collect extracting solution.
2.. extracting solution is filtered, get filtrate at 60～70 ℃ of concentrated solution a that are concentrated into relative density 1.02～1.04 (50-60 ℃).
3.. a leaves standstill clarification with concentrated solution, get supernatant by the D101 macroporous adsorptive resins, water elution resin column with 2 times of amounts of resin column volume, discard water liquid, the alcohol solvent of 1.5 times of amounts of reuse resin column volume (concentration is 50% ethanol: concentration is 5% glacial acetic acid=99.5: 0.5) eluting resin column, collect ethanol elution, 60～70 ℃ of concentrated solution b that reclaim ethanol and be concentrated into relative density 1.02～1.04 (50～60 ℃).
4.. b leaves standstill clarification with concentrated solution, gets supernatant, and by the SP825 macroporous adsorptive resins, water eluting adsorption resin column is closely neutral to effusive liquid, discards water liquid; The Diluted Alcohol eluting resin column of the concentration 18% of 2 times of amounts of reuse resin column volume discards this ethanol elution; Continue with the ethanol-eluting resin column of 1.5 times of amounts of resin column volume concentration 95%, collect this eluent, reclaim the extractum that ethanol and vacuum decompression are concentrated into relative density about 1.20 (60～70 ℃).
5.. extractum is spray dried to solid, promptly gets product Folium Rehmanniae total glycosides.This product Folium Rehmanniae total glycosides be light brown to chocolate brown powder, feeble QI, mildly bitter flavor.This product is calculated with dry product, contains the total sterioside of Ergota (in acteoside C29H36015) and counts 58.5%; Acteoside (C29H36015) is 27.3%.
Get above-mentioned Folium Rehmanniae total glycosides 75g, be ground into fine powder, with 124g starch mix homogeneously, add 50% alcohol granulation, in 50～60 ℃ of dryings, add the 1g micropowder silica gel, be mixed, fill becomes capsule, makes 1000, promptly gets capsule (content of dispersion 75mg/ grain).
Embodiment two
1.. with Folium Rehmanniae or glutinous rehmannic stem and leaf dry product after crushed, add solvent 400L, 350L solvent respectively with 50kg Radix Rehmanniae leaf (or glutinous rehmannic stem and leaf), adopt the methanol (glacial acetic acid that wherein contains volume 0.5%) of concentration 80%, twice of 80 ℃ of reflux, extract,, each 1 hour, collect extracting solution.
2.. extracting solution is filtered, get the concentrated solution a that 60～70 ℃ of filtrates are concentrated into relative density 1.02～1.04 (50～60 ℃).
3.. a leaves standstill clarification with concentrated solution, gets supernatant by the NKA-II macroporous adsorptive resins, with the water elution resin column of 3 times of amounts of resin column volume.The alcohol solvent of 3 times of amounts of reuse resin column volume (concentration is 80% ethanol: concentration is 5% glacial acetic acid=99.5: 0.5) eluting resin column, collect ethanol elution, 60～70 ℃ of concentrated solution b that reclaim ethanol and be concentrated into relative density 1.02～1.04 (50～60 ℃).
4.. b leaves standstill clarification with concentrated solution, takes out supernatant, by the SP825 macroporous adsorptive resins, water eluting adsorption resin column, closely neutral up to water liquid, discard water liquid; The Diluted Alcohol eluting resin column of the concentration 18% of 3 times of amounts of reuse resin column volume discards this ethanol elution; Continue with the ethanol-eluting resin column of 2 times of amounts of resin column volume concentration 95%, collect this eluent, reclaim the extractum that ethanol and vacuum decompression are concentrated into relative density 1.20～1.3 (60～70 ℃).
5.. extractum is dried to solid for 50～65 ℃, promptly gets product Folium Rehmanniae total glycosides.This product Folium Rehmanniae total glycosides be light brown to chocolate brown powder, feeble QI, mildly bitter flavor.This product is calculated with dry product, contains the total sterioside of Ergota (in acteoside C29H36015) and counts 62.8%; Acteoside (C29H36015) is 30.4%.
Get above-mentioned Folium Rehmanniae total glycosides 75g, be ground into fine powder,, add 50% alcohol granulation,, add the 1g magnesium stearate, be mixed, be pressed into 1000, promptly get medicinal tablet (content of dispersion 75mg/ sheet) in 50 ~ 60 ℃ of dryings with 124g starch mix homogeneously.
Embodiment three
1.. with Folium Rehmanniae or glutinous rehmannic stem and leaf dry product after crushed, add 400L, 350L water (glacial acetic acid that wherein contains volume 0.5%) respectively with 50kg Radix Rehmanniae leaf (or glutinous rehmannic stem and leaf), 75～85 ℃ of reflux, extract, twice each 1 hour, are collected extracting solution.
2.. extracting solution is filtered, get the concentrated solution a that 60～70 ℃ of filtrates are concentrated into relative density 1.02～1.04 (50～60 ℃).
3.. a leaves standstill clarification with concentrated solution, gets supernatant by the X-5 macroporous adsorptive resins, with the water elution resin column of 2 times of amounts of resin column volume.The alcohol solvent of 1.5 times of amounts of reuse resin column volume (concentration is 80% ethanol: concentration is 5% glacial acetic acid=99.5: 0.5) eluting resin column, collect ethanol elution, 60～70 ℃ of concentrated solution b that reclaim ethanol and be concentrated into relative density 1.02～1.04 (50～60 ℃).
4.. b leaves standstill clarification with concentrated solution, takes out supernatant, by the SP825 macroporous adsorptive resins, water eluting adsorption resin column, closely neutral up to water liquid, discard water liquid; The Diluted Alcohol eluting resin column of the concentration 18% of 2 times of amounts of reuse resin column volume discards this ethanol elution; Continue with the ethanol-eluting resin column of 1.5 times of amounts of resin column volume concentration 95%, collect this eluent, reclaim the extractum that ethanol and vacuum decompression are concentrated into relative density 1.20～1.3 (60～70 ℃).
5.. extractum is dried to solid for 50～65 ℃, promptly gets product Folium Rehmanniae total glycosides.This product Folium Rehmanniae total glycosides be light brown to chocolate brown powder, feeble QI, mildly bitter flavor.This product is calculated with dry product, contains the total sterioside of Ergota (in acteoside C29H36015) and counts 50.7%; Acteoside (C29H36015) is 25.2%.
Get above-mentioned Folium Rehmanniae total glycosides 75g, be ground into fine powder,, add alcohol granulation with 3925g dextrin mix homogeneously, in 50～60 ℃ of dryings, granulate, fill becomes 1000 bags, promptly gets medicinal granule (content of dispersion 75mg/ bag).
Embodiment four
1.. with Folium Rehmanniae or glutinous rehmannic stem and leaf dry product after crushed, add solvent 400L, 350L respectively with 50kg Radix Rehmanniae leaf (or glutinous rehmannic stem and leaf), solvent adopts the ethanol (glacial acetic acid that wherein contains volume 1%) of concentration 80%, twice of 80 ℃ of left and right sides reflux, extract,, each 1 hour, collect extracting solution.
2.. extracting solution is filtered, get the concentrated solution a that 60～70 ℃ of filtrates are concentrated into relative density 1.02～1.04 (50～60 ℃).
3.. a leaves standstill clarification with concentrated solution, gets supernatant by the D201 macroporous adsorptive resins, with the water elution resin column of 2 times of amounts of resin column volume.The alcohol solvent of 2.5 times of amounts of reuse resin column volume (concentration is 70% ethanol: concentration is 5% glacial acetic acid=99.5: 0.5) eluting resin column, collect ethanol elution, 60～70 ℃ of concentrated solution b that reclaim ethanol and be concentrated into relative density 1.02～1.04 (50～60 ℃).
4.. b leaves standstill clarification with concentrated solution, takes out supernatant, by the SP825 macroporous adsorptive resins, water eluting adsorption resin column, closely neutral up to water liquid, discard water liquid; The Diluted Alcohol eluting resin column of the concentration 18% of 2 times of amounts of reuse resin column volume discards this ethanol elution; Continue with the ethanol-eluting resin column of 1.5 times of amounts of resin column volume concentration 95%, collect this eluent, reclaim the extractum that ethanol and vacuum decompression are concentrated into relative density 1.20～1.3 (60～70 ℃).
5.. be dried to solid with extractum 50-65 ℃, promptly get product Folium Rehmanniae total glycosides.This product Folium Rehmanniae total glycosides be light brown to chocolate brown powder, feeble QI, mildly bitter flavor.This product is calculated with dry product, contains the total sterioside of Ergota (in acteoside C29H36015) and counts 56.2%; Acteoside (C29H36015) is 28.6%.
Get above-mentioned Folium Rehmanniae total glycosides 75g, be ground into fine powder, with 200g sucrose, 70g dextrin, 2g steviosin mix homogeneously, granulation, drying, spray into the alcoholic solution 20ml that contains the 5ml Oleum menthae, airtight 2 hours, add magnesium stearate and each 1.5g mixing of micropowder silica gel, be pressed into 1000, promptly get medicine buccal tablet (content of dispersion 75mg/ sheet).
Embodiment five
1.. with Folium Rehmanniae or glutinous rehmannic stem and leaf dry product after crushed, add solvent 400L, 350L respectively with 50kg Radix Rehmanniae leaf (or glutinous rehmannic stem and leaf), solvent adopts the ethanol (glacial acetic acid that wherein contains volume 0.5%) of concentration 60%, twice of 85 ℃ of reflux, extract,, each 1 hour, collect extracting solution.
2.. extracting solution is filtered, get the concentrated solution a that 60～70 ℃ of filtrates are concentrated into relative density 1.02～1.04 (50～60 ℃).
3.. a leaves standstill clarification with concentrated solution, gets supernatant by the H103 macroporous adsorptive resins, with the water elution resin column of 2 times of amounts of resin column volume.The alcohol solvent of 1.5 times of amounts of reuse resin column volume (concentration is 80% ethanol: concentration is 5% glacial acetic acid=99.5: 0.5) eluting resin column, collect ethanol elution, 60～70 ℃ of concentrated solution b that reclaim ethanol and be concentrated into relative density 1.02～1.04 (50～60 ℃).
4.. b leaves standstill clarification with concentrated solution, takes out supernatant, by the HP-20 macroporous adsorptive resins, water eluting adsorption resin column, closely neutral up to water liquid, discard water liquid; The Diluted Alcohol eluting resin column of the concentration 18% of 2 times of amounts of reuse resin column volume discards this ethanol elution; Continue with the ethanol-eluting resin column of 2 times of amounts of resin column volume concentration 90%, collect this eluent, reclaim the extractum that ethanol and vacuum decompression are concentrated into relative density 1.20～1.3 (60～70 ℃).
5.. extractum is dried to solid for 50～65 ℃, promptly gets product Folium Rehmanniae total glycosides.This product Folium Rehmanniae total glycosides be light brown to chocolate brown powder, feeble QI, mildly bitter flavor.This product is calculated with dry product, contains the total sterioside of Ergota (in acteoside C29H36015) and counts 52.6%; Acteoside (C29H36015) is 26.3%.
Get above-mentioned Folium Rehmanniae total glycosides 75g, be ground into fine powder,, add magnesium stearate and each 1.5g mixing of micropowder silica gel, be pressed into 1000, promptly get medicinal chewing tablet (content of dispersion 75mg/ sheet) with 200g sucrose, 72g dextrin, 1.5g flavoring orange essence mixing, drying.
Embodiment six
Get embodiment one gained Folium Rehmanniae total glycosides 75g, with 53.5g sucrose, 180g starch, mixing, granulate, drying must be done granule; Add citric acid and each 20g mixing of sodium bicarbonate, add 1.5g magnesium stearate mixing again, be pressed into 1000, promptly get medicine effervescent tablet (content of dispersion 75mg/ sheet).
Embodiment seven
Get embodiment one gained Folium Rehmanniae total glycosides 75g, suspending agent (1 part of oil with hydrogenated soybean: 4 parts of vegetable oil) add the mixture of making in the 150g edible vegetable oil with 75g, grind mixing with colloid mill and make soft capsule content, this content is made 1000 soft capsules with pressing.This soft capsule shell gelatin: glycerol: distilled water (weight ratio 100: 35: 80) is made, and promptly gets medicinal soft capsule agent (content of dispersion 75mg/ grain).
Embodiment eight
Get embodiment one gained Folium Rehmanniae total glycosides 75g, add the dissolving of 200ml purified water, filter, add 40% simple syrup ml, mixing adds purified water and is diluted to 1L, adds the potassium sorbate mixing, fill, and sterilization gets drug mixture 1000ml.
In the above-described embodiments, 1. step in the solvent for use, can not contain acetic acid.
Make other dosage forms such as pill, powder, syrup, slow releasing tablet and controlled release tablet as need, the weight proportion component of its Folium Rehmanniae total glycosides, adjuvant or complementary composition is: Folium Rehmanniae total glycosides 10～70%, adjuvant or complementary composition 90～30% by existing conventional formulation method, promptly make.
Embodiment nine
The Folium Rehmanniae preparation method of extract, different with the foregoing description one is step 1. in, the extracting method of extracting solution adopts the supercritical fluid extraction extraction method: get Folium Rehmanniae/stem and leaf (or pulverizing), supercritical CO
2Fluid extraction extracts, and collects extracting solution.Wherein extracting pressure is 38MPa, and extraction temperature is 63 ℃, and the extraction flow is 20L/h, and separating pressure is 6.5MPa, and separation temperature is 33 ℃.Other steps are identical with embodiment one.
Below by other four tame hospitals such as Chengdu University of Traditional Chinese Medicine and Huaxi Hospital Attached to Sichuan Univ to this medicine capsule (embodiment one's) I, II, III clinical trial phase and pharmacological toxicology test, further specify the property evident in efficacy and the drug safety of albuminuria that Folium Rehmanniae extract of the present invention is used for the treatment of renal function disease, hematuria, chronic glomerulonephritis etc.
1.I clinical trial phase
1.1 test objective: select the healthy volunteer,, investigate toleration and the safety of normal human, for the II clinical trial phase district dosage regimen of formulating this medicine provides foundation to this medicine from the predose that is perfectly safe.
1.2 establishing 50mg, 100mg, 150mg, 250mg, 350mg, 500mg etc., the single-dose tolerance test dodges a dosage group, the result from minimum dose 50mg to maximal dose 500mg, untoward reaction all do not occur, show that the normal human is better to the toleration of this medicine single-dose.
1.3 on the basis of single-dose tolerance test, carried out the successive administration tolerance test, according to single-dose tolerance test result, clinical practice in conjunction with the raw materials used main component of this medicine, the dosage regimen of this capsule successive administration tolerance test is defined as: low dose group: oral, each 75mg, 3 times on the 1st, successive administration 7 days; High dose group: oral, each 150mg, 3 times on the 1st, successive administration 7 days.
In the seriality drug tolerance process of the test, untoward reaction does not all appear in all experimenters, shows that the normal human is better to the toleration of this medicine, and clinical use is safer.
2.II clinical trial phase
2.1 test objective: preliminary assessment has been made in effectiveness and safety to this Drug therapy chronic glomerulonephritis (syndrome of deficiency of both qi and yin).
2.2 the commencement date and deadline of test: year February in April, 2003-2004
2.3 EXPERIMENTAL DESIGN: take by test center layering, section at random, double blinding, parallel positive drug control design.
2.4 test crowd: meet chronic glomerulonephritis diagnosis and the dialectical standard of syndrome of deficiency of both qi and yin; Age is the patient of 18-65 between year.
2.5 dosage regimen:
Test group: this medicine capsule, oral, 1 time 2,2 times on the 1st.
Matched group: the SHENYANKANG capsule, oral, 1 time 2,2 times on the 1st.
2.6 observation index:
The health giving quality observation index:
1, leading indicator: (1) urine protein; (2) urine erythrocyte; (3) renal function.
2, less important index: traditional Chinese medical science syndrome of deficiency of both qi and yin syndrome.
The safety observation index:
Blood, urine, just conventional, ALT, BUN, Cr, electrolyte (K+, Na+, Cl-, Ca2+, P3+), electrocardiogram.
2.7 the course of treatment: 8 weeks of medication.
2.8 the experimenter goes into the group situation:
Group 240 examples are gone in test, reject 23 examples, rejecting rate 9.58%, 12 examples that come off, expulsion rate 5.0%.Meet scheme collection 205 examples (test group 103 examples, matched group 102 examples), meet complete analysis collection 239 examples (test group 119 examples, matched group 120 examples), meet safety analysis collection 239 examples (test group 119 examples, matched group 120 examples).
2.9 respectively organize the efficiency analysis result of study:
2.9.1 the curative effect to chronic glomerulonephritis compares:
PP analyzes, and test group clinic control rate is 14.56%, and it is 43.69% that control shows rate, total effective rate 75.73%; Matched group is respectively 12.75%, 33.34%, 61.76%, compares not statistically significant between group.
FAS analyzes, and test group clinic control rate is 13.45%, and it is 42.02% that control shows rate, total effective rate 72.27%; Matched group is respectively 10.83%, 30.83%, 59.17%, and statistical significance is relatively arranged between group, and test group is better than matched group.
2.9.1 relatively to albuminuretic curative effect:
PP analyzes, and test group clinic control rate is 35.29%, and it is 58.82% that control shows rate, total effective rate 88.24%; Matched group is respectively 19.00%, 41.00%, 74.00%, and statistical significance is relatively arranged between group, and test group is better than matched group.
FAS analyzes, and test group clinic control rate is 31.36%, and it is 55.09% that control shows rate, total effective rate 83.90%; Contrast
Group is respectively 16.10%, 38.98%, 69.49%, and statistical significance is relatively arranged between group, and test group is better than matched group.
2.9.3 the curative effect to hematuria compares:
PP analyzes: test group clinic control rate is 28.05%, and it is 69.21% that control shows rate, total effective rate 89.02%; Matched group is respectively 29.63%, 56.79%, 76.54%, compares not statistically significant between group.
FAS analyzes, and test group clinic control rate is 28.57%, and it is 68.13% that control shows rate, total effective rate 85.71%; Matched group is respectively 27.59%, 55.18%, 75.86%, compares not statistically significant between group.
2.9.4 the curative effect to syndrome of deficiency of both qi and yin compares:
PP analyzes, and it is 22.33% that the test group control shows rate, total effective rate 90.29%; Matched group is respectively 24.51%, 76.47%, compares not statistically significant between group.
FAS analyzes, and it is 22.69% that the test group control shows rate, total effective rate 86.55%; Matched group is respectively 24.16%, 76.67%, compares not statistically significant between group.
2.9.5 two groups to lusterless complexion, weak breath is weak, feverish sensation in the palms and soles, lumbago or dry mouth and throat, and syndrome of deficiency of both qi and yin symptoms such as laryngopharynx swelling and pain all have clear improvement, the group difference not statistically significant.
2.10 respectively organize the safety analysis result:
In the clinical trial process, not observing trial drug has anomalous effects and other untoward reaction to the heart, liver function, hemopoietic system, electrolyte.
2.11 conclusion:
This medicine and crude drug thereof, its main pharmacodynamics composition has enriching yin and nourishing kidney, removing heat from blood and promoting blood circulation, and the merit of consolidating semen hemostasis is used for the chronic glomerulonephritis syndrome of deficiency of both qi and yin.The current period clinical test results shows: this medicine can significantly reduce chronic nephritis patient albuminuria and hematuria level, can obviously improve symptoms such as its lusterless complexion, weak breath are weak, feverish sensation in the palms and soles, lumbago, edema.This medicine is better than the SHENYANKANG capsule to the albuminuretic curative effect of chronic nephritis patient, has safety preferably simultaneously.
3, III clinical trial phase
3.1 test objective: further evaluation is made in effectiveness and safety to this Drug therapy chronic glomerulonephritis (syndrome of deficiency of both qi and yin).
3.2 the commencement date and deadline of test: in May, 2004-2005 year March
3.3 EXPERIMENTAL DESIGN:
Take by test center layering, section at random, double blinding, parallel positive drug control design.
3.4 test crowd: meet chronic glomerulonephritis diagnosis and the dialectical standard of syndrome of deficiency of both qi and yin;
Age is the patient of 18-65 between year.
3.5 dosage regimen:
Test group: this medicine capsule, oral, 1 time 2,2 times on the 1st.
Matched group: the SHENYANKANG capsule, oral, 1 time 2,2 times on the 1st.
3.6 observation index:
The health giving quality observation index:
1, leading indicator: (1) urine protein; (2) urine erythrocyte; (3) renal function.
2, less important index: traditional Chinese medical science syndrome of deficiency of both qi and yin syndrome.
The safety observation index:
Blood, urine, just conventional, ALT, BUN, Cr, electrolyte (K+, Na+, Cl-, Ca2+, P3+), electrocardiogram.
3.7 the course of treatment: 8 weeks of medication.
3.8 the experimenter goes into the group situation:
Group 480 examples are gone in test, reject 23 examples, rejecting rate 4.79%, 29 examples that come off, expulsion rate 6.04%.Meet scheme collection 428 examples (test group 320 examples, matched group 108 examples), meet complete analysis collection 478 examples (test group 358 examples, matched group 120 examples), meet safety analysis collection 478 examples (test group 358 examples, matched group 120 examples).
3.9 respectively organize the efficiency analysis result:
3.9.1 the curative effect to chronic glomerulonephritis compares:
PP analyzes, and it is 42.00% that the clinical control of test group shows rate, total effective rate 75.54%; Matched group is respectively 29.63%, 69.44%, compares not statistically significant between group.
FAS analyzes, and test group clinic control rate is 18.56%, and it is 42.07% that control shows rate, total effective rate 72.95%; Matched group is respectively 16.81%, 27.73%, 65.55%, compares not statistically significant between group.
3.9.2 relatively to albuminuretic curative effect:
PP analyzes, and test group clinic control rate is 25.81%, to show rate be 54.84% in control, total effective rate 87.74%; Matched group is respectively 19.63%, 38.32%, 72.90%, compares not statistically significant between group, and test group is better than matched group FAS to be analyzed, and test group clinic control rate is 24.34%, and it is 51.91% that control shows rate, total effective rate 82.12%; Matched group is respectively 18.64%, 35.59%, 68.64%, and statistical significance is relatively arranged between group, and test group is better than matched group.
3.9.3 the curative effect to hematuria compares:
PP analyzes, and it is 63.55% that the clinical control of test group shows rate, total effective rate 81.33%; Matched group is respectively 59.74%, 85.71%, compares not statistically significant between group.
FAS analyzes, and it is 59.60% that the clinical control of test group shows rate, total effective rate 76.40%; Matched group is respectively 57.14%, 82.14%, compares not statistically significant between group.
3.9.4 the curative effect to syndrome of deficiency of both qi and yin compares:
PP analyzes, and the test group control rate is 1.88%, and control shows that rate is 32.82%, total effective rate is 93.13%; Matched group is respectively 1.85%, 25.92%, 88.88%, compares not statistically significant between group.
FAS analyzes, and the test group control rate is 1.96%, control shows that rate is 31.29%, total effective rate 88.55%; Matched group is respectively 1.67%, 23.34%, 85.01%, compares not statistically significant between group.
3.9.5 two groups to lusterless complexion, weak breath is weak, feverish sensation in the palms and soles, and lumbago, edema, dry mouth and throat, syndrome of deficiency of both qi and yin symptoms such as laryngopharynx swelling and pain all have clear improvement, the group difference not statistically significant.
3.10 respectively organize the safety analysis result:
In the clinical trial process, not observing trial drug has anomalous effects and other untoward reaction to the heart, liver function, hemopoietic system, electrolyte.
3.11 conclusion:
The current period clinical test results shows: this medicine is better than the SHENYANKANG capsule to the albuminuretic curative effect of chronic nephritis patient, this medicine capsule of data show can significantly reduce chronic nephritis patient albuminuria and hematuria level, can improve obviously that its lusterless complexion, weak breath are weak, symptom such as feverish sensation in the palms and soles, lumbago, edema and dry mouth and throat, laryngopharynx swelling and pain, have safety preferably simultaneously.Phase iii clinical trial conclusion and phase ii clinical trial conclusion have concordance, have further verified the safety and the effectiveness of this Drug therapy chronic nephritis.
The pharmacological toxicology test
Experimental example 1: the test of pesticide effectiveness
This medicine capsule is the preparation of being made by crude drug Folium Rehmanniae total glycosides, the Folium Rehmanniae total glycosides is with 3 weeks of 20-80mg/kg mice oral administration, 20-40mg/kg rat oral administration 16 days, mice and rat IgG accelerating type nephrolytic sera nephritis there is the obvious treatment effect, show obvious reduction urine protein, the rising plasma albumin, reduce blood urea nitrogen, cholesterol and creatinine, morphological observation at rat experiment, the pathology damage that the Folium Rehmanniae total glycosides can alleviate nephridial tissue (comprises that GCBM thickens, the necrosis of fibrosis sample, crescent formation etc.) and IgG in the deposition of glomerule: on rat C-BSA nephritis model, the oral rat of Folium Rehmanniae total glycosides 20-40mg/kg 1 month, the obvious treatment effect is also arranged, obviously reduce urine protein, blood urea nitrogen, cholesterol and creatinine, morphological observation have clear improvement and (comprise that glomerule increases, the mesentery hypertrophy, the bead inner cell increases etc.); Also can reduce IgG and C3 complement deposition at glomerule.The Folium Rehmanniae total glycosides is similar to cycli phosphate amine 10mg/kgip effect to the therapeutical effect of nephritis, but animal state, survival rate all are better than cycli phosphate amine group.
There is the obvious treatment effect in oral 3 weeks of Folium Rehmanniae total glycosides 20-40mg/kg to passive Heymann nephritis, reducing urine protein, improve the blood biochemical measured value and are reducing IgG and C
3Complement is close with the effect of cycli phosphate glue 10mg/kg group aspect the deposition of glomerule.Animal survive aspect Folium Rehmanniae total glycosides group obviously be better than cycli phosphate amine group.
The oral formation that can obviously suppress mouse antibodies IgM of Folium Rehmanniae total glycosides 20-40mg/kg, the oral phagocytic function that improves Turnover of Mouse Peritoneal Macrophages of 5-20mg/kg, this result might partial interpretation its to brightic therapeutical effect mechanism.Folium Rehmanniae total glycosides 15-60mg/kg is once oral certain diuresis.
Above result provides the pharmacodynamics foundation for this clinical drug treatment glomerulonephritis.
Experimental example 2: general pharmacology experiment
The preparation that this medicine capsule is made by crude drug Folium Rehmanniae total glycosides, the Folium Rehmanniae total glycosides once gavages 60,30 and 15mg/kg (be equivalent to human dosage 12,6 and 3 times), and observe and anesthetized cat blood pressure, heart rate, electrocardiogram, respiratory frequency and amplitude do not had obvious influence in 4 hours: same dosage does not have obvious shadow to sleep percentage rate, the pentobarbital sodium length of one's sleep and the mice autonomic activities of mice pentobarbital sub-threshold dose.
Experimental example 3: toxicological test
3.1 animal acute toxicity experiment
The preparation that this medicine capsule is made by crude drug Folium Rehmanniae total glycosides, the Folium Rehmanniae total glycosides is with each 20 of continuous irrigation stomach mices in the dose of the tolerant Cmax of animal, maximum volume one day, and male and female half and half were observed 7 days continuously, found dead.Total dosage is 16mg/kg (being equivalent to crude drug 1333g/kg), is equivalent to 3200 times of clinical consumption.This experiment provides reference for this clinical drug safe medication.
3.2 long term toxicity test
The preparation that this medicine capsule is made by crude drug Folium Rehmanniae total glycosides, gavage with Folium Rehmanniae total glycosides 250,100 and 40mg/kg (be equivalent to clinical consumption 50,20,8 times) and to give rat, with 200,100 and 40mg/kg (be equivalent to clinical consumption 40,20,8 times) gavage and give dog, continuous 26 weeks, observed for 4 weeks after the rat drug withdrawal, observed for 2 weeks after the dog drug withdrawal, animal ordinary circumstance, body weight all there is not tangible influence, hematology's detection, blood parameters and urine detection all fluctuate in normal range, and electrocardiogram is normal substantially.Three groups of rat body weight growths and food-intake and matched group (SHENYANKANG capsule) are than no significant difference, and food utilization and matched group are basic identical.Vitals are not caused tangible pathological change.Experiment shows that this medicine is safe in institute's amount of reagent scope.
Claims (10)
1. Folium Rehmanniae extract, it is characterized in that: this extract contains effective active composition Folium Rehmanniae total glycosides.
2. the described Folium Rehmanniae preparation method of extract of claim 1 comprises the steps:
1.. Folium Rehmanniae/stem and leaf directly or after pulverizing, is adopted solvent heating and refluxing extraction method, solvent reflux, extract, 1～3 time under 50～100 ℃ of conditions, each 0.5～1.5 hour, merge extractive liquid;
2.. with extracting liquid filtering, reclaim solvent and be concentrated into the concentrated solution a of relative density 1.01～1.10;
3.. a leaves standstill clarification with concentrated solution, get supernatant and pass through adsorption resin column, water elution adsorption resin column with 1～6 times of amount of resin column volume, discard water liquid, the concentration of 1～6 times of amount of reuse resin column volume is 20～96% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the concentrated solution b of relative density 1.01～1.10;
4.. b leaves standstill clarification with concentrated solution, get supernatant and pass through adsorption resin column, water eluting adsorption resin column is closely neutral to effusive liquid, discard water liquid, the concentration that reuse resin column volume 1-3 doubly measures is 10～20% ethanol elution, discards ethanol elution, and continuing with 1～6 times of resin column volume amount concentration is 60～96% ethanol elution, reclaim ethanol and be concentrated into the extractum of relative density 1.20～1.40, promptly get product Folium Rehmanniae total glycoside extract;
5.. with extract dry, promptly get product Folium Rehmanniae total glycosides solid.
3. Folium Rehmanniae method for preparing extractive according to claim 2 is characterized in that: described solvent is selected for use
(a). a kind of in water, methanol, the ethanol; Perhaps
(b). a kind of in the mixed solvent that water or methanol or ethanol and acetic acid are formed, its consumption volume ratio, concentration 30-96% ethanol or concentration 30-96% methanol or water: acetic acid=80～99.99: 20～0.01; Perhaps
(c). the mixed solvent that any two or more arbitrary proportions are formed in (a) and (b).
4. Folium Rehmanniae method for preparing extractive according to claim 2 is characterized in that: contain 0.01～10% acetic acid (V: V) in the 3. described ethanol of step.
5. Folium Rehmanniae method for preparing extractive according to claim 2 is characterized in that: the 1. described extracting method of step adopts the supercritical fluid extraction extraction method.
6. the purposes of the described Folium Rehmanniae extract of claim 1: be used to prepare the medicine for the treatment of disease or be used to prepare health food.
7. according to the purposes of the described Folium Rehmanniae extract of claim 6, it is characterized in that: be used to prepare the medicine for the treatment of renal function disease.
8. medicine for the treatment of renal function disease, it is characterized in that: this medicine contains effective active composition Folium Rehmanniae total glycosides.
9. the medicine of treatment renal function disease according to claim 8 is characterized in that: this medicine is to add the medicament that acceptable accessories or complementary composition are prepared from by the Folium Rehmanniae total glycosides.
10. the medicine of treatment renal function disease according to claim 9 is characterized in that: described medicament is capsule, soft capsule, tablet, granule, powder, pill, mixture, syrup.
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