CN101695520A - Preparation method of medicament for treating diabetes - Google Patents
Preparation method of medicament for treating diabetes Download PDFInfo
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- CN101695520A CN101695520A CN 200910309588 CN200910309588A CN101695520A CN 101695520 A CN101695520 A CN 101695520A CN 200910309588 CN200910309588 CN 200910309588 CN 200910309588 A CN200910309588 A CN 200910309588A CN 101695520 A CN101695520 A CN 101695520A
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Abstract
The invention discloses a preparation method of a medicament for treating diabetes and belongs to the preparation method of a medical preparation which contains raw materials derived from traditional Chinese medicaments. In the preparation method, membranous milkvetch root is processed by cellulose and then is subjected to alcohol circumfluence extraction; golden thread and honeysuckle flower are processed by the cellulose and pectinase respectively and then subjected to cold extraction. Compared with the conventional extraction method, the preparation method improves extraction rate of total saponins of the membranous milkvetch root by 30 to 50 percent, improves extraction rate of berberine and total alkaloid by 20 to 40 percent, and improves yield of chlorogenic acid by 15 to 30 percent, and 30 to 50 percent respectively. The preparation method improves transference rate of effective substance in plant medicinal materials and can fully use medicinal material resources.
Description
Technical field
The raw material that the present invention relates to contain derives from the preparation method of the medical configuration product of Chinese medicine, the preparation method of the treatment diabetes medicament that specifically to be the applying biological zymolysis technique extract material medicine.
Background technology
JINQI JIANGTANG PIAN is as a kind of pure Chinese medicinal preparation.Mainly form, the function of heat clearing away QI invigorating is arranged, be used for heat symptom-complex in the diabetes deficiency of vital energy by the Radix Astragali, Flos Lonicerae, Rhizoma Coptidis etc.Radix Astragali QI invigorating, make the strong fortune of taste, hypoglycemic activity is preferably arranged; Flos Lonicerae has heat-clearing and toxic substances removing, the effect of the QI invigorating of quenching the thirst and the immunity that improves, reduce the cholesterol absorption effect; Rhizoma Coptidis clearing away heat-fire remuval of damp and hot is quenched one's thirst, and by suppressing the glycogen heteroplasia and promoting that glycolysis produces blood sugar reducing function, the effect of blood fat reducing is arranged simultaneously.The modern pharmacology experiment shows: alkaloid has the obvious functions of blood sugar effect in astragalus polysaccharides and the Rhizoma Coptidis, so the number of chemical component in the JINQI JIANGTANG PIAN is from a plurality of links such as carbohydrate metabolism, lipid metabolism, antioxidation, immunomodulating, effect by varying levels such as integral body, cell, molecules, improved the effect of body, be of value to the control of some microvascular complication of diabetes the sensitivity and the enhancing human body immunity function of insulin.
Chinese patent 155954 discloses " a kind of treatment diabetes medicament and preparation method thereof ", and this medicine trade name is a JINQI JIANGTANG PIAN.It is to be the raw material extraction process of prescription with Rhizoma Coptidis, golden stilbene, Flos Lonicerae, and wherein Rhizoma Coptidis is directly pulverized and is used as medicine; The extraction process of the Radix Astragali is 50% ethanol extraction three times, 4,2,2 hours time; The extraction process of Flos Lonicerae is that total amount 1/6 is pulverized, and 5/6 water temperature is soaked.
Chinese patent 1965929A is disclosed to be " a kind of preparation method for the treatment of diabetes medicament ", and this medicine trade name is a JINQI JIANGTANG PIAN.It is to be the raw material extraction process of prescription with Rhizoma Coptidis, the Radix Astragali, Flos Lonicerae, and wherein Rhizoma Coptidis is with 50% ethanol extraction, purification; The extraction process of the Radix Astragali is 75% ethanol extraction secondary, extracts 2 hours at every turn; The extraction process of Flos Lonicerae is that whole water temperatures are soaked, precipitate with ethanol.
But, derive from the medical configuration product preparation process of plant at above-mentioned raw material, because materials such as the cellulose in the plant cell wall, hemicellulose, pectic substance form a kind of barrier to the leaching of effective ingredient in the plant cell, the diffusion of composition in the block cell, influence the extraction effect of plant component, the leaching rate of effective ingredient is low; And clinical medicine dose is big, and the patient takes inconvenience, even causes herb resource waste and power consumption cost to occupy high.
Summary of the invention
The present invention is exactly that the effective ingredient rate of transform is low in the extraction process that solves medicine material, the preparation inherent quality has much room for improvement, and the problem of dwindling taking dose, and a kind of preparation method for the treatment of diabetes medicament is provided.
The present invention realizes by following technical scheme.
A kind of preparation method for the treatment of diabetes medicament comprises 10.3 parts of Rhizoma Coptidis by weight ratio, 15.4 parts of the Radixs Astragali, 61.8 parts of Flos Loniceraes, after extracting effective ingredient respectively, add 2～4 parts of adjuvants, make granule, compacting is wrapped film-coat and is made in flakes, and the extraction step of its effective ingredient is:
1. the extraction step of Radix Astragali total saponins extract
A. the Radix Astragali adds the sulphuric acid water of 3～8 times of amount pH3.0～6.0, adds the cellulase of Radix Astragali consumption 0.1～1.0% again, and 35～60 ℃ of enzymolysis are collected enzymolysis solution;
B. after enzymolysis solution transfers to pH neutrality with sodium hydroxide solution, add 60～80% alcohol reflux, collect filtrate, concentrating under reduced pressure;
C. macroporous adsorptive resins with 60～80% ethanol elutions of 5～10 times of resin volumes, is collected the ethanol concentrated solution again with the distilled water eluting of 2～10 times of resin volumes on the concentrated solution;
D. add acetone to nothing and precipitate till the generation in the ethanol concentrated solution, filtration, collection, dry precipitator promptly get the Radix Astragali total saponins extract;
2. the extraction step of Rhizoma Coptidis total alkaloids extract
A. with the Rhizoma Coptidis section of cutting into, add the sulphuric acid water of 3～5 times of amount pH1.0～5.0, add the cellulase of Rhizoma Coptidis consumption 0.1～1.0% again, 30～60 ℃ of warm macerating are collected enzymolysis solution and medicinal residues respectively;
B. medicinal residues soak with 8～16 times 0.1～2.0% aqueous sulfuric acid, the sour water leachate;
C. enzymolysis solution and sour water leachate are merged, filter, concentrate;
D. transfer to pH1～4 with hydrochloric acid, under agitation add Sal, be placed to yellow crystal and separate out;
E. the sucking filtration collecting precipitation distills washing and is precipitated to pH4～6, and oven dry promptly gets Rhizoma Coptidis total alkaloids;
3. the extraction step of Flos Lonicerae extract
A. in Flos Lonicerae, add 8～12 times of citrate buffer solutions of measuring pH4.0～6.0, add the pectase of Flos Lonicerae consumption 0.1～2.0% again, collect enzymolysis solution;
B. Flos Lonicerae adds 8～15 times of water gaging warm macerating extractions behind the enzymolysis, collects warm macerating liquid;
C. enzymolysis solution and warm macerating liquid are merged, filter, 60 ℃ are evaporated to relative density 1.10～1.20;
D. add the ethanol of 2～4 times of amounts in concentrated solution, leave standstill precipitate with ethanol, filter, the supernatant concentrating under reduced pressure promptly gets Flos Lonicerae extract.
The preparation method of described treatment diabetes medicament, the citrate buffer solution that in Flos Lonicerae, adds 8～12 times of amount pH4.0～6.0, the compound enzyme that adds Flos Lonicerae consumption 0.1～2.0% again, collect enzymolysis solution, wherein compound enzyme is made up of in 1: 1,1: 2,2: 1 ratio respectively cellulase and pectase.
The preparation method of described treatment diabetes medicament, the Radix Astragali extractum yield in its Radix Astragali total saponins extract is 10～17%, and it is 65～88% that Radix Astragali total saponins extracts the rate of transform, and wherein Astragaloside content accounts for 5～19%.
The preparation method of described treatment diabetes medicament, the Rhizoma Coptidis total alkaloids crude product yield in its Rhizoma Coptidis total alkaloids extract is 10～25%, and it is 70～90% that Rhizoma Coptidis total alkaloids extracts the rate of transform, and it is 50～90% that berberine hydrochloride extracts the rate of transform.
The preparation method of described treatment diabetes medicament, the Flos Lonicerae extractum yield is 15～40% in its Flos Lonicerae extract, it is 50～90% that chlorogenic acid extracts the rate of transform.
Like this, use the treatment diabetes medicament of the present invention's preparation, its prescription component and dosage form are constant.Because the biological enzymolysis effect can destroy the barrier action that plant component leaches with decomposition such as the cellulose in the plant tissue, hemicelluloses, thereby reaches the purpose that improves the effective ingredient rate of transform; Enzyme reaction has characteristics such as reaction condition gentleness, selectivity are strong, reaction efficiency height.The present invention not only improves the leaching rate of effective ingredient, because reduced the extraction temperature and shortened extraction time, so also reduced the cost that consumes energy in the leaching process.This technological operation is simple, and is safe, is more suitable for commercial production.
Description of drawings
Fig. 1 is the extraction flow chart of Rhizoma Coptidis total alkaloids;
Fig. 2 is the extraction flow chart of Radix Astragali total saponins;
Fig. 3 is the extraction flow chart of chlorogenic acid in the Flos Lonicerae.
The specific embodiment
The present invention will be described in detail below in conjunction with drawings and Examples.
One, prescription is formed and extraction process
1.1 because the present invention is that preparation technology improves, so its prescription dosage remains unchanged, dosage form still is a tablet.Because extract obtained weight change causes the tablet specification to change, according to experimental result, calculate with the former crude drug amount of taking, sheet heavily is about 0.50 gram.Its prescription and technology such as following table.
1.2 in the extraction process of this preparation, Rhizoma Coptidis has the clearing away heat-fire remuval of damp and hot, effect such as quench one's thirst is a monarch drug in the prescription.Pharmacological evaluation proves, berberine and alkaloid thereof are by suppressing the glycogen heteroplasia and promoting that glycolysis produces blood sugar reducing function in the Rhizoma Coptidis, the effect of blood fat reducing is arranged simultaneously, serve as to investigate index with berberine, jateorhizine, palmatine content in this research, adopt orthogonal experiment method, the preferred extraction process of Rhizoma Coptidis total alkaloids has also been carried out preferably the condition of enzymolysis simultaneously.Adopted enzymolysis one sour water normal temperature dipping method, the more former technology Rhizoma Coptidis powder of this method dosage dwindles greatly.The comparable simple sour water infusion process of berberine and total alkaloids extraction ratio improves 20～40%.
The Radix Astragali has invigorating QI to consolidate the body surface resistance, and effects such as diuresis poison holding are used for treatments such as interior-heat is quenched one's thirst, diabetes.Containing compositions such as Radix Astragali saponin, flavone in the Radix Astragali has and improves body to effects such as the sensitivity of insulin and enhancing human body immunity function, blood sugar regulation.So, be content's index with astragaloside and Radix Astragali total saponins in this research, adopted orthogonal experiment, preferred enzymolysis and extraction process condition.New extraction process makes the extraction ratio of Radix Astragali total saponins exceed 30～50% than not enzyme-added matched group.
Flos Lonicerae has heat-clearing toxin-expelling functions, materials such as the chlorogenic acid that contains, flavone, and modern pharmacology experiment shows: except antibiotic, antiinflammation, can also blood fat reducing, protection B cells of pancreas and hypoglycemic activity.Because above-mentioned effective ingredient is responsive to heat, so consider to reduce the principle of extracting temperature and not reducing chlorogenic acid content.With the chlorogenic acid content is index, has screened enzymolysis and extraction conditions by orthogonal experiment, owing to increase the enzymolysis processing step, more conventional water temperature is soaked method, and the chlorogenic acid yield has improved 30～50% in the Flos Lonicerae.All take to extract by the Flos Lonicerae in the prescription, and in conjunction with the step of precipitate with ethanol, make existing technology reduce than the extractum yield of former technology, chlorogenic acid content improves 15～50%.
Above-mentioned each medical material has all adopted the method for enzyme assisted extraction, has weakened plant cell to the barrier action that effective ingredient leaches, and not only improves the leaching rate of effective ingredient, because reduced the extraction temperature and shortened extraction time, extracts the power consumption cost so also reduced.This technological operation is simple, and is safe, is more suitable for commercial production.
2.1 the extraction step of Rhizoma Coptidis total alkaloids extract:
A. Rhizoma Coptidis is selected and removes earth, foreign material, after the oven dry, the suitable section of cutting into;
B. add the sulphuric acid water of 3～5 times of amounts, pH1.0～5.0 in Rhizoma Coptidis, add cellulase again, its consumption is 0.1～1.0% of a Rhizoma Coptidis weight, in 30～60 ℃ of following warm macerating 0.5～4 hour, collects enzymolysis solution and medicinal residues respectively;
C. the medicinal residues after enzymolysis processing soak 2～4 times with 0.1～2.0% aqueous sulfuric acid, and each 12～48 hours, the aqueous sulfuric acid addition was 8～16 times of medical material, collect the sour water leachate;
D. enzymolysis solution and sour water leachate are merged, filter, the extracting solution after filtering is concentrated into 1/4～1/2 of original volume;
E. transfer pH1～4 with hydrochloric acid, make sulfate transfer the less hydrochlorate of dissolubility to, under agitation add Sal, its addition is 6～15% of an extracting liquid volume, places 12～48 hours, till separating out fully to yellow crystal;
F. the sucking filtration collecting precipitation is precipitated to pH4～6 with a small amount of distillation washing, and 50～80 ℃ of oven dry down that are deposited in after the washing promptly get the Rhizoma Coptidis total alkaloids product.
2.2 Radix Astragali total saponins extract:
A. Radix Astragali rhizome raw material is suitably rolled, add the sulphuric acid water of 3～8 times of amounts, pH3.0～6.0, add cellulase again, its consumption was 0.1～1.0% of a crude drug weight, in 35～60 ℃ of following enzymolysis 0.5～4 hour;
B. after above-mentioned enzymolysis solution being transferred to pH neutrality with sodium hydroxide, add ethanol to containing alcohol amount 60～80%, reflux, extract, 2 times each 2 hours, is filtered concentrating under reduced pressure;
C. AB-8 or D-101 macroporous adsorptive resins on the concentrated solution with the water-solubility impurities such as distilled water eluting saccharide of 2～10 times of resin volumes, again with 60～80% ethanol elutions of 2～10 times of resin volumes, are collected ethanol liquid and are carried out suitably concentrated earlier;
D. in the ethanol concentrated solution, add acetone and do not produce, filter, collect dry precipitator, promptly get the Radix Astragali total saponins extract to there being precipitation.
2.3 Flos Lonicerae extract (Flos Lonicerae extracting method 1) is the standard of representative composition as investigation technology with the chlorogenic acid, it may further comprise the steps:
A. the citrate buffer solution that adds 8～12 times of amounts, pH4.0～6.0 in Flos Lonicerae adds 0.1～2.0% pectase of Flos Lonicerae weight again, in 30～60 ℃ of following warm macerating 0.5～4 hour, collects enzymolysis solution;
B. medical material adds water in 40～70 ℃ of warm macerating extractions twice behind the enzymolysis, and each 1～3 hour, amount of water was 8～15 times of amounts of medical material weight, collected and extracted warm macerating liquid;
C. enzymolysis solution and warm macerating liquid are merged, filter, 60 ℃ of filtrate decompression are concentrated into relative density 1.10～1.20;
D. the ethanol that adds 2～4 times of amounts in the above-mentioned concentrated solution leaves standstill and carried out precipitate with ethanol in 12～48 hours, filter, supernatant through concentrating under reduced pressure, be drying to obtain the effective site of Flos Lonicerae.
2.4 Flos Lonicerae extract (Flos Lonicerae extracting method 2) is the standard of representative composition as investigation technology with the chlorogenic acid, it may further comprise the steps:
A. the citrate buffer solution that in Flos Lonicerae, adds 8～12 times of amounts, pH4.0～6.0,0.1～1.0% compound enzyme that adds Flos Lonicerae weight again, described compound enzyme is by cellulase and pectase, form in 1: 1,1: 2,2: 1 ratio respectively, in 30～60 ℃ of following warm macerating 0.5～4 hour, collect enzymolysis solution;
B. medical material adds water in 40～70 ℃ of warm macerating extractions twice behind the enzymolysis, and each 1～3 hour, amount of water was 8～15 times of amounts of medical material weight, collected warm macerating liquid;
C. enzymolysis solution and warm macerating liquid are merged, filter, filtrate decompression is concentrated into relative density 1.10～1.20 (60 ℃);
D. the ethanol that adds 2～4 times of amounts in above-mentioned concentrated solution leaves standstill and carried out precipitate with ethanol in 12～48 hours, filter, supernatant through concentrating under reduced pressure, be drying to obtain the effective site of Flos Lonicerae.
Two. preparation and quality standard
1, preparation
Three kinds of medical materials are all taked the form molding of extract among the present invention, wherein Rhizoma Coptidis is to be used as medicine with total alkaloids, Radix Astragali total saponins extract, Flos Lonicerae are the form tablettings with extract powder, so selected mobile strong, pharmaceutic adjuvant that compressibility is good for use, are beneficial to the disintegrate problem of tablet.According to document and former prescription, selected for use adjuvants such as microcrystalline Cellulose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, magnesium stearate to carry out the proportioning screening, determine preparation.
Take by weighing Rhizoma Coptidis total alkaloids by the preparation of weight portion proportioning separately, Radix Astragali total saponins extract, Flos Lonicerae extractum powder three's mixture 6～8 weight portions, add 2～4 parts of adjuvants again, make granule, compacting in flakes, the bag film-coat, promptly.Above-mentioned adjuvant is 0.7～1.5 part of pregelatinized Starch, 1.0～1.8 parts of microcrystalline Cellulose, 0.1～0.2 part of cross-linking sodium carboxymethyl cellulose, 0.1～0.3 part of carboxymethyl starch sodium, 0.1～0.2 part of composition of magnesium stearate.
2, quality standard
2.1 raw material, adjuvant quality
Raw material, adjuvant quality are according to " 2005 editions standards of Chinese pharmacopoeia, the quality of Flos Lonicerae, Radix Astragali raw material is according to " 2005 editions standards of Chinese pharmacopoeia, the quality of Rhizoma Coptidis raw material is measured content to make the HPLC method by oneself, wherein Radix Astragali total saponins selection ultraviolet method mensuration.
2.2 intermediate quality standard
According to experimental result, carry out each raw material respectively and extract the relative density of the Radix Astragali, Flos Lonicerae extractum in the pilot process, the yield detection and the content limit inspection of index effective ingredient.
2.3 end product quality standard
Differentiate: with berberine hydrochloride, Jatrorrhizine chloride, palmatine hydrochloride, chlorogenic acid, astragaloside is contrast, finished product is TLC differentiates, compares above-mentioned detection composition basically identical with the TLC of former handicraft product.
Check: heavy metal detects according to " appendix inspection of 2005 editions standards of Chinese pharmacopoeia.Lead content＜5ppm in 5 batch samples as a result, arsenic content＜2ppm meets the requirement of conventional oral formulations, so these 2 are not included in the routine examination standard.
Assay: detect with the content of HPLC method to the index components berberine in the Rhizoma Coptidis in the finished product, the Radix Astragali, the Flos Lonicerae, jateorhizine, palmatine, chlorogenic acid, astragaloside.
Rhizoma Coptidis, the Rhizoma Coptidis of proper mass standard are directly to be used as medicine with the crude drug powder, only the content of berberine are measured, and in the new technology Rhizoma Coptidis have been carried out the sour water dipping, and its quality standard has also been done corresponding adjustment.Adopt the HPLC method to measure berberine, jateorhizine, 3 kinds of alkaloidal content of palmatine respectively, the content limit of formulation is: the content of every berberine is not less than 15mg.
The Radix Astragali, the finished product of the present invention's preparation are also according to " quality standard of 2005 editions Milkvetch Roots of Chinese pharmacopoeia adopts the HPLC method to measure the content of astragaloside, also Radix Astragali total saponins is detected at the pilot process of producing.The content limit of formulating is: the content of every astragaloside is not less than 0.20mg.
Flos Lonicerae, chlorogenic acid is responsive to heat in the Flos Lonicerae, thus in investigating, extraction process reduces temperature as far as possible, to improve the stability of chlorogenic acid.The finished product of the present invention's preparation is also according to " quality standard of 2005 editions Chinese medicine honeysuckles of Chinese pharmacopoeia adopts the HPLC method to measure chlorogenic acid contents, and the content limit of formulation is: every chlorogenic acid contents is not less than 20mg.
The present invention is owing to increased the process of the auxiliary leaching of enzymolysis in extraction process, the cell wall barrier action that effective ingredient leaches weakens, make that extracting temperature reduces, time shortens, therefore make index components content in the medical material of respectively distinguishing the flavor of that in various degree raising is all arranged, therefore, the quality standard of formulating finished product also improves thereupon, thereby the new technology preparation has improved than the inherent quality of former handicraft product.
Three, use the pharmacodynamic experiment of the treatment diabetes medicament tablet (JINQI JIANGTANG PIAN) of the present invention's preparation:
1. the JINQI JIANGTANG PIAN of two kinds of prepared is to the influence of alloxan diabetes mouse blood sugar
1.1 the foundation of alloxan diabetes mouse model
With Kunming mouse (♂ ♀ dual-purpose is provided by PLA Military Medical Science Institute Experimental Animal Center, 24 ± 2g, the credit number SCXK-2002-001 of army), raised for 1 week at 22 ± 2 ℃ of room temperatures, relative humidity 65%～70% before the experiment, conform.Fasting then, can't help the about 12h of water after, (dosage is 70mg/kg to the alloxan of the new preparation of tail vein injection for Sigma company, A17413) solution (1.4mg/mL).Fasting 12h again behind 60h, the vena ophthalmica clump is got blood, centrifugalize serum.Adopting blood glucose test kit (middle north control bio tech ltd, 240181 of giving birth to) to survey blood glucose value with glucoseoxidase (GOD) method, is qualified tissue of experimental diabetic mice model greater than 11.1mmol/l.
1.2 grouping administration
Select 140 of qualified model mices, evenly be divided into 10 groups by blood glucose value, every group 14, be respectively high dose group (4.20 crude drug g/kg), middle dosage group (2.10 crude drug g/kg), low dose group (1.05 crude drug g/kg), normal administration group (2.10 crude drug g/kg), normal control group and the model group (tap water 10ml/kg) of the present invention's (extraction of embodiment 5 methods) and former technology JINQI JIANGTANG PIAN.Other gets 30 tablets of phenformin (25mg/ sheet), grinds, and with the dissolved in distilled water that boiled, is made into the aqueous solution of 7.5mg/ml, as phenformin positive controls (75mg/kg), every day irritating stomach once, successive administration 14 days.
1.3 blood glucose test result
Fasting after the last administration (can't help water) 12 hours.The vena ophthalmica clump is got blood, centrifugalize serum.The GOD method is measured dextrose equivalent, and carries out the t check, the results are shown in Table 1, table 2.
Table 1 JINQI JIANGTANG PIAN of the present invention is to the influence of blood glucose in diabetic mice due to the alloxan (x ± S)
* compare p＜0.05 with model group; * and model group be p＜0.01 relatively;
△ △Compare p＜0.01 with the normal control group;
Know that from table 1 each group of alloxan diabetes mice after 14 days, is compared the decline (25.25%～-40.33%) that all has in various degree through JINQI JIANGTANG PIAN treatment of the present invention than fasting glucose before the administration.After the administration, each dosage group of JINQI JIANGTANG PIAN of the present invention and model group relatively fasting glucose also significantly reduce (P＜0.05, P＜0.01), and each administration group presents certain dose-effect relationship and time-effect relationship on hypoglycemic activity.
Normal mouse administration group illustrates that with normal control group and more equal not statistically significant before the administration on the same group JINQI JIANGTANG PIAN of the present invention does not exert an influence to the blood sugar level of normal mouse.
Two kinds of technology JINQI JIANGTANG PIAN of table 2 are to the comparison of alloxan diabetes mouse blood sugar (x ± S)
Annotate: * and model group be P＜0.05 relatively; * and model group be P＜0.01 relatively;
▲JINQI JIANGTANG PIAN of the present invention and former technology JINQI JIANGTANG PIAN compare P＜0.05 with the dosage group;
Know from table 2, each group of alloxan diabetes mice is after administration, two kinds of each dosage groups of technology JINQI JIANGTANG PIAN and model group relatively fasting glucose all significantly reduce (P＜0.05, P＜0.01), and each administration group presents certain dose-effect relationship and time-effect relationship on hypoglycemic activity.Two kinds of technology JINQI JIANGTANG PIAN respectively low, in relatively have significant difference (P＜0.05) with the dosage fasting glucose, know that by blood glucose value JINQI JIANGTANG PIAN of the present invention blood sugar decreasing effect when low, the middle dosed administration is better than former technology, and when high dose the product of two kinds of extraction processes to the fasting glucose there was no significant difference of alloxan diabetes mice.
2. two kinds of technology JINQI JIANGTANG PIAN are induced the influence of blood glucose in diabetic rats, blood fat to STZ
2.1 the foundation of diabetes rat model
The SD male rat, the SPF level, 220-240g is provided by PLA Military Medical Science Institute Experimental Animal Center, 140-170g, credit number SCXK-(army) 2002-001.Fed 5 days with the normal diet adaptability, be divided into normal control group and modeling group at random by body weight.Wherein the normal control group gives the normal feedstuff nursing, and high glucose and high fat feedstuff (being provided by Medical University Of Tianjin zoopery center), continuous 8 weeks are provided the modeling group.After 8 weeks, fasting, can't help water 12h, the modeling group is pressed the injection of 30mg/kg dosage disposable vein, and (053K3869) solution is set up the type 2 diabetes mellitus model for STZ, Sigma company to give low dose of 2% streptozotocin.After STZ injects a week, survey animal fasting glucose (FBG), selecting the animal of fasting glucose 〉=11.1mmol/L is qualified animal pattern.
2.2 grouping administration
Select the qualified rat of modeling, evenly be divided into 10 groups by blood glucose value and body weight.Be respectively two kinds of technology JINQI JIANGTANG PIAN high doses (3.6 crude drug g/kg), middle dosage (1.8g crude drug/kg), low dose group (0.9g crude drug/kg), metformin hydrochloride (new medicinal liquid Group Plc in the Tianjin, 4105478) positive controls (92.5mg/kg), model control group and normal control group and normal administration group, the normal control group gives distilled water (10ml/kg), normal administration group (the 1.8g crude drug/kg), 11 every group.Below respectively organize and irritate stomach every day 1 time, 10 weeks of continuous irrigation stomach.Respectively organize diabetes rat during the medication treatment and raise with the high glucose and high fat feedstuff every day, normal control group and normal administration group give normal diet.
Treated for the 10th week in medication, 12h after the last administration, fasting (can't help water), the vena ophthalmica clump is got blood, and behind the centrifugal 10min, separation of serum is sub-packed in the 1.5ml centrifuge tube, and related biochemical indicator such as-20 ℃ of cold storage of refrigerator blood glucose to be checked and blood fat the results are shown in Table 3～table 6.
2.3 test result
2.3.1 two kinds of technology JINQI JIANGTANG PIAN influence the experimental diabetic rats fasting glucose
Utilize the One Touch Ultra of U.S. Johnson ﹠ Johnson type blood glucose meter, can't help water 12h, detect change of blood sugar respectively at 4 weeks, 6 weeks, 8 weeks, the back fasting of 10 weeks before the administration, after the administration, adopt the SPSS16.0 statistical software, the utilization one factor analysis of variance carries out comparing between each group, and calculating data the results are shown in Table 2.
Know from table 3, each organizes diabetes rat after JINQI JIANGTANG PIAN of the present invention is treated 4 weeks, 6 weeks, high dose group, positive controls and model group are relatively, fasting glucose all has obvious decline (P＜0.05), to administration 8,10 during week, each dosage group of JINQI JIANGTANG PIAN of the present invention, positive controls and model group comparison fasting glucose significantly reduce (P＜0.01, P＜0.05), and each group of administration to present certain dosage on hypoglycemic activity relevant.Normal rat administration group is compared with the normal control group, and relatively there are no significant before and after self administration difference, illustrate that JINQI JIANGTANG PIAN of the present invention influences not obvious to the blood sugar level of normal rat.
Know that from table 4 each organizes diabetes rat after JINQI JIANGTANG PIAN of the present invention treated for 4 weeks, only high dose group and model group compare, and fasting glucose all has obvious decline (P＜0.05); To administration 8,10 during week, each dosage group of JINQI JIANGTANG PIAN of the present invention, positive controls and model group relatively fasting glucose all significantly reduce (P＜0.01, P＜0.05), and only middle and high dosage of former technology JINQI JIANGTANG PIAN and model group are relatively, fasting glucose obviously descend (P＜0.05, P＜0.01); Two kinds of technology JINQI JIANGTANG PIAN low dosage fasting glucose relatively have significant difference (
▲P＜0.05), illustrate that JINQI JIANGTANG PIAN of the present invention blood sugar decreasing effect when low, middle dosed administration is better than former technology, and when high dose the product of two kinds of technologies to the fasting glucose there was no significant difference of the diabetes rat of high sugar, high fat.
The comparison that two kinds of technology JINQI JIANGTANG PIAN of table 4 influence the experimental diabetic rats fasting glucose (x ± S)
* compare p＜0.05 with model group; * and model group be p＜0.01 relatively;
▲JINQI JIANGTANG PIAN of the present invention and former technology JINQI JIANGTANG PIAN compare P＜0.05 with the dosage group;
2.3.2 the blood fat of two kinds of technology JINQI JIANGTANG PIAN experimental diabetic rats influence
According to T-CHOL (TC), triglyceride (TG), high density lipoprotein (HDL-C), the concrete operations of low density lipoprotein, LDL (LDL-C) test kit (the middle north control bio tech ltd of giving birth to) description detect TC, TG, HDL-C, LDL-C content in the rat blood serum.The results are shown in Table 5, table 6.
Table 5 JINQI JIANGTANG PIAN of the present invention is to the influence of experimental diabetic rats blood fat (x ± S)
| Group | ??n | ??TC ??(mmol/L) | ??TG ??(mmol/L) | ??LDL-C ??(mmol/L) | ??HDL-C ??(mmol/L) |
| The blank group | ??10 | ??1.98±0.28** | ??1.36±0.48** | ??0.51±0.07** | ??0.89±0.19** |
| Normal administration group | ??10 | ??2.03±0.31** | ??1.41±0.46** | ??0.46±0.08** | ??1.04±0.16** |
| Model control group | ??9 | ??5.65±0.84 △△ | ??2.35±0.87 △△ | ??0.94±0.50 △△ | ??0.54±0.29 △△ |
| Low dose group of the present invention | ??10 | ??4.61±1.23* △△ | ??1.56±0.65** △ | ??0.79±0.24* △△ | ??0.66±0.19** △△ |
| Dosage group among the present invention | ??10 | ??4.02±0.63* △△ | ??1.59±0.39** △ | ??0.61±0.25** △△ | ??0.79±0.21** |
| High dose group of the present invention | ??10 | ??3.86±0.71** △△ | ??1.29±0.45** | ??0.53±0.19** | ??0.86±0.23** |
| Positive controls | ??10 | ??3.89±1.26** △△ | ??1.35±0.58** | ??0.55±0.24* | ??0.94±0.24** |
* compare p＜0.05 with model group; * and model group be p＜0.01 relatively;
△Compare p＜0.05 with the blank group;
△ △Compare p＜0.01 with the blank group;
Know that by table 5 after 10 weeks of administration, the T-CHOL (TC) of each dosage group of JINQI JIANGTANG PIAN of the present invention and triglyceride (TG) concentration and model group significantly reduce, and significant difference (P＜0.01, P＜0.05) is arranged; And along with the increase of JINQI JIANGTANG PIAN dosage of the present invention, the average of total cholesterol level presents the trend that progressively reduces, and effect for reducing blood fat presents certain dose-effect dependency.It is unusual that each administration group can partly be corrected the triglyceride levels that diabetes cause, and makes the triglyceride concentration of diabetes rat reach the level of normal rat.Normal administration group rat is compared there was no significant difference with the blank group, illustrates that JINQI JIANGTANG PIAN of the present invention is not obvious to the T-CHOL and the triglyceride levels influence of normal rat.
Know that from table 5 result of the test after 10 weeks of administration, the LDL-C concentration of each dosage group of JINQI JIANGTANG PIAN of the present invention and model group significantly descend, and significant difference (P＜0.05, P＜0.01) is arranged; Along with the increase of JINQI JIANGTANG PIAN dosage of the present invention, its LDL-C level progressively reduces.And JINQI JIANGTANG PIAN high dose group LDL-C concentration of the present invention and blank group be there was no significant difference (P＜0.05) relatively, illustrate that JINQI JIANGTANG PIAN of the present invention can correct the LDL-C horizontal abnormality that diabetes cause, make the LDL-C concentration of diabetes rat reach the level of normal rat.
The HDL-C concentration of each dosage group of JINQI JIANGTANG PIAN of the present invention and model group more all show significant difference (P＜0.05, P＜0.01), and the effect of each dosage group rising HDL-C presents certain dose-effect dependency.And each dosage group HDL-C concentration of JINQI JIANGTANG PIAN of the present invention and blank group be there was no significant difference (P＜0.05, P＜0.01) relatively, illustrates that JINQI JIANGTANG PIAN of the present invention can make the HDL-C concentration of diabetes rat reach the level of normal rat.Normal administration group illustrates that with blank group LDL-C, HDL-C relatively there are no significant difference JINQI JIANGTANG PIAN of the present invention is not obvious to the LDL-C and the HDL-C level affects of normal rat.
Two kinds of technology JINQI JIANGTANG PIAN of table 6 are to the comparison of the influence of experimental diabetic rats blood fat (x ± S)
| Group | ??n | ??TC ??(mmol/L) | ??TG ??(mmol/L) | ??LDL-C ??(mmol/L) | ??HDL-C ??(mmol/L) |
| Low dose group of the present invention | ??10 | ??4.61±1.23* | ??1.56±0.65** ▲ | ??0.79±0.24* ▲ | ??0.66±0.19** ▲ |
| Dosage group among the present invention | ??10 | ??4.02±0.63* | ??1.59±0.39** | ??0.61±0.25** | ??0.79±0.21** |
| High dose group of the present invention | ??10 | ??3.86±0.71** | ??1.29±0.45** | ??0.53±0.19** | ??0.86±0.23** |
| Model control group | ??9 | ??5.65±0.84 | ??2.35±0.87 | ??0.94±0.50 | ??0.54±0.29 |
| Former technology low dose group | ??9 | ??4.73±0.81* | ??1.93？±0.32* | ??0.89±0.35 | ??0.56±0.15 |
| Dosage group in the former technology | ??10 | ??3.97±0.78** | ??1.64±0.49** | ??0.68±0.28** | ??0.72±0.23** |
| Former technology high dose group | ??10 | ??4.04±1.06** | ??1.36±0.58** | ??0.64±0.20** | ??0.89±0.29** |
* compare p＜0.05 with model group; * and model group be p＜0.01 relatively;
▲JINQI JIANGTANG PIAN of the present invention and former technology JINQI JIANGTANG PIAN compare P＜0.05 with the dosage group;
Know that from table 6 each organizes diabetes rat after JINQI JIANGTANG PIAN of the present invention treated for 10 weeks, each dosage group and model group compare, and its TC, TG, LDL-C, HDL-C value all have significant difference (P＜0.05, P＜0.01); And each dosage group of former technology JINQI JIANGTANG PIAN and its TC of model group comparison, TG have significant difference (P＜0.05, P＜0.01); But LDL-C, the only middle and high dosage of HDL-C level and model group relatively have significant difference (P＜0.05, P＜0.01).The present invention and former technology JINQI JIANGTANG PIAN relatively, the TG of low dosage, LDL-C, HDL-C level have significant difference (
▲P＜0.05), the product that two kinds of technology is extracted and when middle and high dosed administration is to the metabolism there was no significant difference of the blood fat of diabetes rat.Illustrate that JINQI JIANGTANG PIAN of the present invention lipid-lowering effect when the low dosage administration is better than former technology JINQI JIANGTANG PIAN, just illustrating that also new extraction process also shows lipid-lowering effect preferably on the basis of improving effective ingredient.
To sum up, the present invention is not obvious to the fasting glucose influence of normal mouse with original JINQI JIANGTANG PIAN.JINQI JIANGTANG PIAN under two kinds of technology all can reduce the blood glucose value of the diabetic mice of model induced by alloxan, JINQI JIANGTANG PIAN of the present invention blood sugar decreasing effect when low, middle dosed administration is better than former technology, and when high dose the product of two kinds of technologies to reduce the fasting glucose effect of alloxan diabetes mice suitable.Two kinds of technology JINQI JIANGTANG PIAN are fed high lipid food, and the inductive diabetes rat of injection streptozotocin, by reducing serum TC, TG, LDL-C, rising HDL-C level, the metabolism of blood lipid regulation, the present invention is suitable to the regulating action of the blood fat of diabetes rat with former technology process JINQI JIANGTANG PIAN during middle and high dosed administration, and the blood sugar lowering of JINQI JIANGTANG PIAN of the present invention and effect for reducing blood fat are better than former technology JINQI JIANGTANG PIAN when low dosage.Studies show that blood glucose, blood fat that the prolonged application said preparation can obviously suppress the diabetes model animal raise, and normal body blood glucose, blood fat are not had obvious influence.Blood sugar reducing preparation of the present invention and former technology relatively active constituent content, drug action all strengthen to some extent, and the dosage form of preparation of the present invention dwindles, and are more convenient for producing keeping and take with clinical.
Four, embodiment
Embodiment 1: the extracting method of Radix Astragali total saponins extract.
Take by weighing Chinese crude drug Radix Astragali 1kg, be cut into 2～3cm length after rolling, add the 5g cellulase, the sulphuric acid water that adds 4000ml pH4.5 again in 45 ℃ of enzymolysis 2 hours, transfers pH to neutrality, add 7000ml ethanol (containing alcohol amount about 60%), reflux, extract, twice, each 2 hours.Filter, be evaporated to nothing alcohol flavor, add water 10000ml (about 500g resin) on AB-8 that has handled well or D101 macroporous adsorptive resins, with water-solubility impurities such as 3000ml distilled water eluting saccharides, with the 80% ethanol elution Radix Astragali saponin of 4000ml, collect eluent, be concentrated into original volume 1/4 after, adding acetone does not produce to there being precipitation, filter, drying precipitated, promptly get the Radix Astragali total saponins extract.After measured, the extractum yield of the Radix Astragali is 15% under these process conditions, and the extraction rate of transform of Radix Astragali total saponins is 87%, and wherein astragaloside accounts for 19%.Experiment shows that the Radix Astragali total saponins by the enzymolysis assisted extraction exceeds 35% than not enzyme-added matched group.
Embodiment 2: the extracting method of Rhizoma Coptidis total alkaloids extract.
Take by weighing Chinese crude drug Rhizoma Coptidis 1kg, the section of cutting into, long 2～3cm, add the 3g cellulase, add the sulphuric acid water of 4000ml pH4.5 again, in 35 ℃ of enzymolysis after 2.5 hours, filter, collect filtrate, 8 times of amounts of medicinal residues reuse, 0.3% aqueous sulfuric acid merceration extract twice, each 24 hours, merging filtrate, be evaporated to 3 liters, regulate pH1～2 with hydrochloric acid then, the Sal that under agitation adds liquor capacity 8% is saltoutd, left standstill 12 hours, sucking filtration gets precipitate in 60 ℃ of oven dry down, grinding, can obtain Rhizoma Coptidis total alkaloids hydrochlorate finished product.After measured, the coptisine extract yield reaches 18% under these process conditions, and berberine and total alkaloids extract the transfer yield and be respectively 85% and 87%, compare with traditional cold-maceration, and berberine and total alkaloids extraction ratio have improved 32% and 31% respectively.
Embodiment 3: the extracting method 1 of Flos Lonicerae extract.
Take by weighing Chinese crude drug Flos Lonicerae 1kg, add pectase 5g, pH6.0 citrate buffer solution 10000ml, in the 40oC enzymolysis after 1.5 hours, collect enzymolysis solution, again the medical material water is carried out warm macerating in 70oC and extract twice, each 1 hour, the consumption of water was followed successively by 8000ml, 6000ml.Merging filtrate, being concentrated into relative density is 1.10～1.20 (60 ℃), treats that temperature is reduced to room temperature, adds 3 times of amount ethanol in concentrated solution, and standing over night is filtered, and concentrating under reduced pressure is drying to obtain Flos Lonicerae extract.After measured, the yield of extract of Flos Lonicerae is 20%, and the extraction rate of transform of chlorogenic acid reaches 73%.Increase the more conventional warm macerating method of enzymolysis assisted extraction process, can make the chlorogenic acid yield improve 27%.
Embodiment 4: the extracting method 2 of Flos Lonicerae extract
Take by weighing Chinese crude drug Flos Lonicerae 1kg, add compound enzyme (cellulase pectase 1: 1) 2g, pH6.0 citrate buffer solution 10000ml, in 40 ℃ of enzymolysis after 1.5 hours, collect enzymolysis solution, again the medical material water being carried out warm macerating in 70oC extracts twice, each 1 hour, the consumption of water was followed successively by 8000ml, 6000ml.Merging filtrate, being concentrated into relative density is 1.10～1.20 (60 ℃), treats that temperature is reduced to room temperature, adds 3 times of amount ethanol in concentrated solution, and standing over night is filtered, and concentrating under reduced pressure is drying to obtain Flos Lonicerae extract.After measured, the yield of extract of Flos Lonicerae is 24%, and the extraction rate of transform of chlorogenic acid reaches 82%.Compare with traditional warm macerating method, the chlorogenic acid yield has improved 34%.
Embodiment 5: the treatment diabetes medicament tablet of using the present invention's preparation
Component and proportioning: Rhizoma Coptidis 343g, Radix Astragali 513g, Flos Lonicerae 2058g, pregelatinized Starch 65g, microcrystalline Cellulose 70g, cross-linking sodium carboxymethyl cellulose 5.5g, carboxymethyl starch sodium 9g, magnesium stearate 2.5g.
Preparation method:
1. Rhizoma Coptidis is selected and removes earth, foreign material, suitably the section of cutting into is grown 2～3cm, in the 343g Rhizoma Coptidis, add 4 times of amount sulphuric acid water (pH4.5) 1372ml, the cellulase 1.715g that adds Rhizoma Coptidis weight 0.5% again in 50 ℃ of following warm macerating enzymolysis 2 hours, collects the warm macerating extracting solution; Medicinal residues behind enzymolysis add 0.1% the sulphuric acid water logging bubble 2 times of 12 times of amounts, and each 24 hours, merge enzymolysis solution and sour water leachate, transfer to neutrality, filtration is concentrated into 1/3 of original volume with filtrate decompression; Transfer pH2 with hydrochloric acid, stir the Sal that adds filtrate volume 8% down, placed 12 hours, till separating out to yellow crystal, filtration, distillation washing are precipitated to pH6, and 80 ℃ of oven dry down promptly get the Rhizoma Coptidis total alkaloids product.
2. Radix Astragali 513g rhizome is rolled, add the sulphuric acid water 2052ml of 4 times of amounts, pH5.0 and the cellulase 5.13g of crude drug amount 1.0%, transfer to neutrality after 2 hours in 40 ℃ of following enzymolysis, add 70% alcohol reflux again twice, each 2 hours, collect filtrate, concentrating under reduced pressure; AB-8 or D-101 macroporous adsorptive resins on the concentrated solution with the distillation washing of 5 times of resin volumes, again with 80% ethanol elution of 5 times of resin volumes, are collected ethanol liquid and are evaporated to 1/5 of original volume earlier; Add acetone and do not produce to there being precipitation, filtration, collecting precipitation, drying promptly get the Radix Astragali total saponins extract.
3. the citrate buffer solution 20580ml that adds 10 times of amounts, pH5 in the 2058g Flos Lonicerae adds 0.2% cellulase and pectase (1: 1) the mixture 4.116g of Flos Lonicerae weight again, 50 ℃ of following warm macerating 2 hours, filtration, collection enzymolysis solution; In medical material, add 10,8 times of water gaging 20580ml, 16464ml more respectively and extract 2 times (2,2 hours), collect extracting solution in 60 ℃ of warm macerating; Merge enzymolysis solution and warm macerating extracting solution, filter, concentrating under reduced pressure filtrate is to relative density 1.10～1.20 (60 ℃); The ethanol that adds 3 times of amounts in above-mentioned concentrated solution (being chilled to 40 ℃) left standstill 12 hours, filtered, and supernatant is standby through concentrating under reduced pressure, drying and crushing, promptly obtains the effective site of Flos Lonicerae.
Get above-mentioned 3 kinds of powder, add pregelatinized Starch 65g, microcrystalline Cellulose 70g, cross-linking sodium carboxymethyl cellulose 5.5g, carboxymethyl starch sodium 9g, the blended adjuvant of magnesium stearate 2.5g is granulated, and is pressed into 1000, and the bag film-coat promptly gets the preparation of the present invention's preparation.
Claims (5)
1. preparation method for the treatment of diabetes medicament, comprise 10.3 parts of Rhizoma Coptidis by weight ratio, 15.4 parts of the Radixs Astragali, 61.8 parts of Flos Loniceraes, extract effective ingredient respectively after, add adjuvant, make granule, compacting is wrapped film-coat and is made in flakes, it is characterized in that the extraction step of effective ingredient is:
1. the extraction step of Radix Astragali total saponins extract
A. the Radix Astragali adds the sulphuric acid water of 3～8 times of amount pH 3.0～6.0, adds the cellulase of Radix Astragali consumption 0.1～1.0% again, and 35～60 ℃ of enzymolysis are collected enzymolysis solution;
B. after enzymolysis solution transfers to pH neutrality with sodium hydroxide solution, add 60～80% alcohol reflux, collect filtrate, concentrating under reduced pressure;
C. macroporous adsorptive resins with 60～80% ethanol elutions of 5～10 times of resin volumes, is collected the ethanol concentrated solution again with the distilled water eluting of 2～10 times of resin volumes on the concentrated solution;
D. add acetone to nothing and precipitate till the generation in the ethanol concentrated solution, filtration, collection, dry precipitator promptly get the Radix Astragali total saponins extract;
2. the extraction step of Rhizoma Coptidis total alkaloids
A. with the Rhizoma Coptidis section of cutting into, add the sulphuric acid water of 3～5 times of amount pH 1.0～5.0, add the cellulase of Rhizoma Coptidis consumption 0.1～1.0% again, 30～60 ℃ of warm macerating are collected enzymolysis solution and medicinal residues respectively;
B. medicinal residues soak with 8～16 times 0.1～2.0% aqueous sulfuric acid; Get the sour water leachate;
C. enzymolysis solution and sour water leachate are merged, filter, concentrate;
D. transfer to pH 1～4 with hydrochloric acid, under agitation add Sal, be placed to yellow crystal and separate out;
E. the sucking filtration collecting precipitation distills washing and is precipitated to pH4～6, and oven dry promptly gets Rhizoma Coptidis total alkaloids.
3. the extraction step of Flos Lonicerae extract
A. in Flos Lonicerae, add 8～12 times of citrate buffer solutions of measuring pH4.0～6.0, add the pectase of Flos Lonicerae consumption 0.1～2.0% again, collect enzymolysis solution;
B. Flos Lonicerae adds 8～15 times of water gaging warm macerating extractions behind the enzymolysis, collects warm macerating liquid;
C. enzymolysis solution and warm macerating extracting solution are merged, filter, 60 ℃ are evaporated to relative density 1.10～1.20;
D. add the ethanol of 2～4 times of amounts in concentrated solution, leave standstill precipitate with ethanol, filter, the supernatant concentrating under reduced pressure promptly gets Flos Lonicerae extract.
2. according to the preparation method of the described treatment diabetes medicament of claim 1, it is characterized in that in Flos Lonicerae, adding the citrate buffer solution of 8～12 times of amount pH4.0～6.0, the compound enzyme that adds Flos Lonicerae consumption 0.1～2.0% again, collect enzymolysis solution, wherein compound enzyme is made up of in 1: 1,1: 2,2: 1 ratio respectively cellulase and pectase.
3. according to the preparation method of the described treatment diabetes medicament of claim 1, it is characterized in that the Radix Astragali extractum yield in the Radix Astragali total saponins extract is 10～17%, it is 65～88% that Radix Astragali total saponins extracts the rate of transform, and wherein Astragaloside content accounts for 5～19%.
4. according to the preparation method of the described treatment diabetes medicament of claim 1, it is characterized in that the Rhizoma Coptidis total alkaloids crude product yield in the Rhizoma Coptidis total alkaloids extract is 10～25%, it is 70～90% that Rhizoma Coptidis total alkaloids extracts the rate of transform, and it is 50～90% that berberine hydrochloride extracts the rate of transform.
5. according to the preparation method of the described treatment diabetes medicament of claim 1, it is characterized in that the Flos Lonicerae extractum yield is 15～40% in the Flos Lonicerae extract, it is 50～90% that chlorogenic acid extracts the rate of transform.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102526243A (en) * | 2010-12-07 | 2012-07-04 | 天津中新药业集团股份有限公司隆顺榕制药厂 | Traditional Chinese medicine combination for clearing heat and tonifying qi and preparation method thereof |
| CN101717427B (en) * | 2009-12-04 | 2013-02-27 | 张守力 | Process for extracting astragaloside IV |
| CN103127207A (en) * | 2011-11-23 | 2013-06-05 | 中国科学院长春应用化学研究所 | Method for increasing astragaloside content in radix astragali total extract by acid catalysis |
| CN103417661A (en) * | 2013-08-13 | 2013-12-04 | 吴中区胥口精益生物医药研究所 | Rhizoma coptidis essence and preparation method thereof |
| CN105753859A (en) * | 2016-03-15 | 2016-07-13 | 合肥华方医药科技有限公司 | Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate |
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| CN1294936C (en) * | 2004-03-12 | 2007-01-17 | 天津中新药业集团股份有限公司隆顺榕制药厂 | Medicine for treating diabetes and its preparation method |
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| CN101717427B (en) * | 2009-12-04 | 2013-02-27 | 张守力 | Process for extracting astragaloside IV |
| CN102526243A (en) * | 2010-12-07 | 2012-07-04 | 天津中新药业集团股份有限公司隆顺榕制药厂 | Traditional Chinese medicine combination for clearing heat and tonifying qi and preparation method thereof |
| CN103127207A (en) * | 2011-11-23 | 2013-06-05 | 中国科学院长春应用化学研究所 | Method for increasing astragaloside content in radix astragali total extract by acid catalysis |
| CN103127207B (en) * | 2011-11-23 | 2015-01-14 | 中国科学院长春应用化学研究所 | Method for increasing astragaloside content in radix astragali total extract by acid catalysis |
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| CN105753859A (en) * | 2016-03-15 | 2016-07-13 | 合肥华方医药科技有限公司 | Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate |
| CN108245665A (en) * | 2018-02-22 | 2018-07-06 | 天津中新药业集团股份有限公司隆顺榕制药厂 | Pharmaceutical composition and its preparation method and application |
| CN109464505A (en) * | 2018-12-09 | 2019-03-15 | 林嗣松 | It is a kind of for treating the Chinese medicine composition of diabetes |
| CN109464505B (en) * | 2018-12-09 | 2023-08-18 | 林嗣松 | Traditional Chinese medicine composition for treating diabetes |
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