CN101518554A - Oral medicinal preparation of hairy holly root total aglycon, preparation method and application thereof - Google Patents
Oral medicinal preparation of hairy holly root total aglycon, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an oral medicinal preparation of hairy holly root total aglycon, a preparation method and an application thereof, pertaining to the field of traditional Chinese medicine. Total glycosides extracted from hairy holly roots are hydrolyzed to obtain total aglycon which is then added with special auxiliary materials for preparing a highly efficient preparation, thereby greatly increasing the bioavailability of the hairy holly root total aglycon. The preparation has significant curative effects in the treatment of coronary arteriosclerotic cardiopathy, acute myocardial infarction, thromboangitis obliterans, central retinitis, tonsillitis, pharyngolaryngitis, child pneumonia, chilblain, burn and scald, hypertension, hyperlipemia, hyperglycemia and other diseases.
Description
Technical field
The present invention relates to a kind of Chinese medicine Radix Ilicis Pubescentis extract, especially a kind of extract of Radix Ilicis Pubescentis total aglycones, and the medicinal usage of this extract.Belong to the field of Chinese medicines.
Background technology
Radix Ilicis Pubescentis is the dry root of holly plant Radix Ilicis Pubescentis Ilex pubescens Hook.et Arm, originate in ground such as China Guangdong, Guangxi, Fujian, Jiangxi, Zhejiang, Taiwan, it is China's south Chinese crude drug commonly used, effect with blood circulation and channel invigorating, reducing swelling and alleviating pain, heat-clearing and toxic substances removing, be widely used in treatment coronary heart disease, angina pectoris and thromboangiitis obliterans clinically, central serous chorioretinopathy, tonsillitis, pharyngolaryngitis, disease such as infantile pneumonia and chilblain, burn and scald, have curative effect preferably, Chinese scholars is paid much attention to.
Modern study shows that the main chemical compositions of Radix Ilicis Pubescentis is Radix Ilicis Pubescentis total saponins and total flavonoid glycoside, and main component is a triterpene saponin in the Radix Ilicis Pubescentis.Up to the present, from Radix Ilicis Pubescentis, separated and the saponin component that identifies has: Vanguerolic acid (Ilexodic acid), Radix Ilicis Pubescentis saponin first (IlexsaponinA, II), Peltatin glucoside (Pedunculoside, III), Radix Ilicis Pubescentis saponin B
1(Ilexsaponin B, V), Radix Ilicis Pubescentis saponin B (Ilexsaponin B, VI) and rotundicacid (Rotundicacid, VII), pedunculoside etc., Radix Ilicis Pubescentis also contains phenols, aminoacid, tannin, steroidal and reducing sugar.
Research report about Radix Ilicis Pubescentis is more, Xiong Youxiang etc. are at " chemical constituent of Radix Ilicis Pubescentis, Advance on Pharmacological Activities " (" Chinese crude drug ", in May, 2002, the 25th the 5th phase of volume) in the nearly 10 years pharmacological research of Radix Ilicis Pubescentis, clinical practice and composition Study are summarized and summed up; Yang Xin etc. are at " separation of iridoid glycosides compound and evaluation in the Radix Ilicis Pubescentis " (" Chinese pharmaceutical chemistry magazine ", in June, 2007, the 17th the volume the 3rd phase) and Yin Wenqing at " extraction process of Radix Ilicis Pubescentis total saponins and purification identification research " (" Chinese crude drug ", in JIUYUE, 2007, the 30th the 9th phase of volume) respectively the extraction and purification process of iridoid glycoside in the Radix Ilicis Pubescentis and total saponins is studied in, obtained simple and easy to do method for extraction and purification; Wang Lanlan and Zhang Fanglin etc. have carried out experimental study to antiinflammatory and the anti thrombotic action of Radix Ilicis Pubescentis respectively; Patent CN1049123C, CN1628832A, CN1686251A and CN1301098C etc. have reported the preparation method and the main uses of Radix Ilicis Pubescentis related preparations (compound Ilex pubescens injection, Radix Ilicis Pubescentis injectable powder, hairy holly root soft capsule and hairy holly drop pills etc.) respectively; As seen in technical field of Chinese medicines, Radix Ilicis Pubescentis is one of focus of present Chinese scholars primary study.
But existing technology has been placed on research emphasis on the Radix Ilicis Pubescentis glycoside material, has all ignored the research to the Radix Ilicis Pubescentis total aglycones, and its effect and applicable cases are in space state always.
Summary of the invention
It is the oral drugs of active component with the Radix Ilicis Pubescentis total aglycones that first purpose of the present invention is to provide a kind of.
Second purpose provides the dosage form of this medicine, particularly a kind of high-efficiency preparation;
The 3rd purpose provides the preparation method of this medicine high-efficiency preparation;
Provide this medicine at last in treatment coronary atherosclerotic heart disease, acute myocardial infarction, thromboangiitis obliterans, central serous chorioretinopathy, the application in the diseases such as tonsillitis, pharyngolaryngitis, infantile pneumonia, chilblain, burn and scald and vascular hypertension, hyperlipidemia and hyperglycemia.
The object of the invention first purpose is achieved in that
The inventor provides a kind of oral medicine, and this medicine is an active component with the Radix Ilicis Pubescentis total aglycones.
The inventor finds, the glycoside material is the lower chemical compound of biological activity that produces in plant in fact, as on chemical compound, adding polar group, the aglycon of biologically active and sugar combined form the lower glycoside of physiologically active and stored, make it easier and excrete.Equally, these glycosides compounds are also lower in the intravital bioavailability of people, oral glycosides compound is difficult to absorb in intestinal, bioavailability is low, majority is metabolism and incomplete in vivo, that have even external with prototype (glycoside form) eliminating fully, have only a spot of glycosides compound after intestinal bacteria, enzyme are decomposed into aglycon, just to give play to curative effect; Non-oral glycosides compound, the glycosides that is absorbed by the body also need to be transported to liver through blood, and again by the liver sausage circulation, glycosides is hydrolyzed to aglycon is absorbed into blood again and brings into play curative effect, but because step is more, so can not bring into play curative effect rapidly.
Thereby at the medical value of Radix Ilicis Pubescentis, the inventor proposes a kind of new medical substance, i.e. Radix Ilicis Pubescentis total aglycones.It is to extract from the Radix Ilicis Pubescentis medical material by prior art to obtain the Radix Ilicis Pubescentis total glycosides, and this effective site is hydrolyzed, and makes glycoside material wherein slough glycosyl, generates to have more bioactive aglycon, promptly becomes Radix Ilicis Pubescentis total aglycones provided by the present invention.The inventor confirms that after deliberation because the lipotropy of glycoside material is strong, the absorption by human body permeability is good more, owing to do not had glycosyl on the aglycon that obtains of hydrolysis, its lipotropy strengthens, thereby aglycon is absorbed than the easier intestinal mucosa that sees through of glycosides; Simultaneously, the molecule of medicine is more little also easy more to be absorbed, the glycosides hydrolysis fall with glycan molecule become aglycon after, molecular change gets littler, also can easier absorption.In addition, directly as medical substance, overcome in the past glycoside material long operational time, factor such as transformation efficiency is low, conversion results is uncertain in vivo, improved the bioavailability of medicine greatly, saved drug resource with aglycon.
In medicine provided by the invention, the Radix Ilicis Pubescentis total aglycones can use separately, also can unite use with the other drug composition, that is: in active constituents of medicine, can have only the pure product of Radix Ilicis Pubescentis total aglycones, also can be Radix Ilicis Pubescentis total aglycones crude product, can also be the mixture of Radix Ilicis Pubescentis total aglycones and other drug.The present invention preferably uses Radix Ilicis Pubescentis total aglycones crude product, promptly extracts the Radix Ilicis Pubescentis total glycosides from medical material, hydrolysis in a suitable manner again, and make with extra care as required, obtain required purity.
Above-mentioned method for hydrolysis has comprised acid hydrolysis, enzyme hydrolysis or microbial hydrolysis, and the inventor is through screening, and following several concrete method for hydrolysis is provided respectively: acid hydrolysis can be hydrolyzed with hydrochloric acid, sulphuric acid, acetic acid and the formic acid etc. of 1～10mol/L; Enzyme hydrolysis can be hydrolyzed with emulsin, maltase, conversion carbohydrase, hesperidinase etc.; Microorganism can be hydrolyzed with escherichia coli, enterococcus, lactobacillus, clostridium, lopsided thalline, bifidus bacillus and human body intestinal canal normal flora etc.
Second purpose of the present invention provides the pharmaceutical preparation of above-mentioned Radix Ilicis Pubescentis total aglycones, especially a kind of high-efficiency preparation.Owing to solved the absorption problem of medicine in first purpose of the present invention,, be prepared into various conventional formulations so those skilled in the art can cooperate Radix Ilicis Pubescentis total aglycones of the present invention with suitable adjuvant easily.But the inventor is also noted that another problem, and promptly because aglycon fat-soluble stronger relatively, thereby after its preparation was applied to human body, aglycon composition wherein was difficult for wetted and stripping, if can not address this problem, also can influence the absorption of aglycon.So at this problem, the inventor provides a kind of new solution, can guarantee the Radix Ilicis Pubescentis total aglycones is made high-efficiency preparation, this technical scheme is:
Scheme one: a kind of is the efficient pharmaceutical preparation of active component with Radix Ilicis Pubescentis total aglycones of the present invention, contain bio-adhesive agent and wetting agent in its adjuvant, can also contain the conventional adjuvant on dispersant and other pharmaceuticss, and oral formulations such as the sheet that is made into, capsule, granule, powder, ball.
The core of this technical scheme is the Radix Ilicis Pubescentis total aglycones is used for pharmaceutical preparation, and guarantees the efficient utilization of Radix Ilicis Pubescentis total aglycones by special adjuvant.Thereby; embody in the concrete pharmaceutical preparation; can have only Radix Ilicis Pubescentis total aglycones of the present invention in its active constituents of medicine; also can be used with other medicinal or non-medical substances; as long as its objective is contained Radix Ilicis Pubescentis total aglycones is utilized bio-adhesive agent and wetting agent, can also utilize dispersant, carry out moistening, dispersion; to make oral high-efficiency preparation, all should be in the scope of the present patent application protection.In like manner, technical solution of the present invention is selected bio-adhesive agent and wetting agent for use, can also be with dispersant as main adjuvant, and purpose is to make the Radix Ilicis Pubescentis total aglycones to be able to fully, to disperse uniformly, is beneficial to absorption; In actual applications; can also add other conventional adjuvants and molding adjuvant as required; as starch, microcrystalline Cellulose, carboxymethylstach sodium, citric acid, sodium bicarbonate, low-substituted hydroxypropyl methylcellulose, lactose, mannitol, citric acid, Aspartane, dextrin, magnesium stearate etc.; these all should be considered as the work finished on the basis of the technology of the present invention, also should be subjected to the protection of the present patent application.
In this technical scheme, the bio-adhesive agent is preferably chitosan, carbomer, polyvinylpyrrolidone or the mixture between them; Wetting agent is preferably lecithin, poloxamer or its mixture; Dispersant is preferably micropowder silica gel, cyclodextrin or its mixture.
Wherein, chitosan, carbomer have the bio-adhesive performance as the bio-adhesive agent, but prolong drug significantly improves bioavailability of medicament in the gastrointestinal holdup time.Surfactant such as lecithin, poloxamer has the effect of moistened surface to the Radix Ilicis Pubescentis total aglycones, reduces surface tension, increases the dissolubility of fat-soluble Radix Ilicis Pubescentis total aglycones, promotes it to absorb rapidly, is beneficial to rapid performance curative effect.Micropowder silica gel, cyclodextrin be as dispersant, and itself possess hydrophilic property is beneficial to moistening, the dispersion of aglycon, strengthens stability of drug.Radix Ilicis Pubescentis total aglycones of the present invention and above-mentioned adjuvant are used, and fully mix homogeneously can strengthen wherein dispersibility, the wettability of Radix Ilicis Pubescentis total aglycones, improves its bioavailability.
In the preferred case, each composition proportion is preferably active component 20～60% in the medicine of the present invention, bio-adhesive agent 1～10%, wetting agent 5～20%, dispersant 0～30%, other adjuvants 0～50%.Other adjuvants wherein are meant other adjuvants of preparation some in forming process, as: starch, microcrystalline Cellulose, carboxymethylstach sodium, citric acid, sodium bicarbonate, low-substituted hydroxypropyl methylcellulose, lactose, mannitol, citric acid, Aspartane, dextrin, magnesium stearate etc.
Technique scheme is mainly used in oral formulations, and optimum dosage form is tablet, capsule, granule, powder and pill.
Scheme two: a kind of is the efficient pharmaceutical preparation of active component with Radix Ilicis Pubescentis total aglycones of the present invention, contain dispersant and wetting agent in its adjuvant, can also contain the conventional adjuvant on bio-adhesive agent and other pharmaceuticss, and oral formulations such as the soft capsule that is made into, liquid hard capsule, drop pill.
The core of this technical scheme is the Radix Ilicis Pubescentis total aglycones is used for pharmaceutical preparation, and guarantees the efficient utilization of Radix Ilicis Pubescentis total aglycones by special adjuvant.Thereby; embody in the concrete pharmaceutical preparation; can have only Radix Ilicis Pubescentis total aglycones of the present invention in its active constituents of medicine; also can be used with other medicinal or non-medical substances; as long as its objective is contained Radix Ilicis Pubescentis total aglycones is utilized dispersant and wetting agent, can also utilize the bio-adhesive agent, carry out moistening, dispersion; to make oral high-efficiency preparation, all should be in the scope of the present patent application protection.In like manner, technical solution of the present invention is selected dispersant and wetting agent for use, can also be with the bio-adhesive agent as main adjuvant, and purpose is to make the Radix Ilicis Pubescentis total aglycones to be able to fully, to disperse uniformly, is beneficial to absorption; In actual applications; can also add other conventional adjuvants and molding adjuvant as required; as glycerol, glycine, citric acid, ethyl hydroxybenzoate, Cera Flava etc., these all should be considered as the work finished on the basis of the technology of the present invention, also should be subjected to the protection of the present patent application.
In this technical scheme, dispersant is preferably vegetable oil or Polyethylene Glycol; Wetting agent is preferably lecithin, poloxamer, propylene glycol or the mixture between them; The bio-adhesive agent is preferably chitosan, carbomer or its mixture.
Wherein, surfactants such as lecithin, poloxamer, propylene glycol have the effect of moistened surface to the Radix Ilicis Pubescentis total aglycones, reduce surface tension, increase the dissolubility of fat-soluble Radix Ilicis Pubescentis total aglycones, promote it to absorb rapidly, are beneficial to rapid performance curative effect.Vegetable oil, Polyethylene Glycol can be uniformly dispersed the Radix Ilicis Pubescentis total aglycones as dispersant.Chitosan, carbomer have the bio-adhesive performance as the bio-adhesive agent, but prolong drug significantly improves bioavailability of medicament in the gastrointestinal holdup time.Radix Ilicis Pubescentis total aglycones of the present invention and above-mentioned adjuvant are used, and fully mix homogeneously can strengthen wherein dispersibility, the wettability of Radix Ilicis Pubescentis total aglycones, improves its bioavailability.
In the preferred case, each composition proportion is preferably active component 10～40% in the medicine of the present invention, bio-adhesive agent 0～10%, wetting agent 5～20%, dispersant 50～80%, other adjuvants 0～5%.Other adjuvants wherein are meant other adjuvants of preparation some in forming process, as: glycerol, glycine, citric acid, ethyl hydroxybenzoate, Cera Flava etc.
Technique scheme is mainly used in oral formulations, and optimum dosage form is liquid hard capsule, soft capsule and drop pill.
The 3rd purpose of the present invention provides the preparation method of above-mentioned high-efficiency preparation, core technology wherein is with behind Radix Ilicis Pubescentis total aglycones and any method mix homogeneously during required adjuvant mixes by fusion, dissolving, stirring, grinding or micronizing, add required conventional formulation adjuvant again, technology is made preparation routinely.And the blended method of the preferred vibromill micronizing of the mixed method here.
Have only by effective hybrid mode, could guarantee that contained Radix Ilicis Pubescentis total aglycones and special adjuvant fully are uniformly dispersed in the extract, moistening rapidly, stripping, absorption when being applied to human body, performance is effect efficiently.Through inventor's checking, modes such as fusion, dissolving, stirring, grinding or micronizing mixing can both realize the object of the invention, and micronizing mode effect wherein are the most outstanding.
Though superfine communication technique occurs already, the application in technical field of Chinese medicines stays in the conceptive of " pulverizing " always, do not break through all the time, thereby its scope is limited to very much.The inventor finds in practice, superfine communication technique has been not only crushing technology, a kind of especially high efficient mixed technology, it can make aglycon be subjected to intensive forward extrusion power and the tangentially effect of shearing force with adjuvant, utilization at a high speed, high-energy is pulverized, mix, resulting powder medium particle diameter is reduced to below the 10 μ m by 75 original μ m, the granularity exquisiteness, evenly, surface area increases, porosity increases, drug particle is fully contacted with the adjuvant particle, mix, both improved the dispersion of drug particle, guaranteed its rapid moistening and stripping again, improved the absorbance and the bioavailability of medicine greatly, its advantage is that present conventional mixed method is incomparable.At this wherein, vibromill micronizing mode is to realize the best approach of the object of the invention.
Beneficial effect
Radix Ilicis Pubescentis total aglycones of the present invention, has blood circulation and channel invigorating, reducing swelling and alleviating pain, the effect of heat-clearing and toxic substances removing, can be used for treating coronary atherosclerotic heart disease, acute myocardial infarction, blood post thromboangiitis obliterans, central serous chorioretinopathy, diseases such as tonsillitis, pharyngolaryngitis, infantile pneumonia, chilblain, burn and scald and vascular hypertension, hyperlipidemia and hyperglycemia.Cooperate high-efficiency preparation means of the present invention, more can give full play to its effect.The inventor illustrates outstanding effect of the present invention by following zoopery.
One, analgesic activity drug effect comparative test
1 test material
1.1 experimental animal
Kunming mouse, the SPF level, ♀, 18～22g, Anhui Province's Experimental Animal Center provides.
1.2 test apparatus
Hot-plate instrument: self-control;
Electric-heated thermostatic water bath: Shanghai Medical Apparatus and Instruments Factory produces.
1.3 be subjected to the reagent thing
Radix Ilicis Pubescentis 6kg is got in preparation for test agent, and coarse pulverization adds 60% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, water liquid is added on the D101 macroporous adsorptive resins, with water, 30% ethanol, 70% ethanol elution, collects 70% ethanol elution respectively, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepare Radix Ilicis Pubescentis total glycosides ordinary preparation; The alcoholic acid water liquid of all the other recovery of 3/4 was with 2mol/L sulphuric acid hydrolysis 5 hours, it is an amount of that hydrolyzed solution adds calcium oxide, filter, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, 1/3 dry thing prepares Radix Ilicis Pubescentis total aglycones ordinary preparation, and 2/3 dry thing prepares Radix Ilicis Pubescentis total aglycones high-efficiency preparation in addition.
Radix Ilicis Pubescentis total glycosides ordinary preparation group: get the dry thing of Radix Ilicis Pubescentis total glycosides, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones ordinary preparation group: get the dry thing of 1/3 Radix Ilicis Pubescentis total aglycones, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones high-efficiency preparation group: get the dry thing of 2/3 Radix Ilicis Pubescentis total aglycones, add carbomer 10g, lecithin 10g, micropowder silica gel 50g, and add starch to 200g, micronizing was mixed 50 minutes.Get wherein that 30g is suspended to 100ml as the aglycon high dose group with water, other gets 15g and is suspended to 100ml as the aglycon low dose group with water.
2 test methods
The reference literature method, get 50 of ♀ Kunming mouses, preceding mice is put on the hot plate of administration (is adjusted to 55 ± 0.5 ℃ with water bath with thermostatic control, put into the sheet iron beaker of 1000ml, the bottom contact water surface), with stopwatch record mice from drop into hot plate to the time that metapedes occurs licking (s) as the administration of this Mus before pain threshold, should select 5～30s with interior person for qualified.Filter out 45 of the satisfactory mices of pain threshold after getting the survey pain threshold, be divided into 5 groups at random by pain threshold and body weight.Be respectively blank group, Radix Ilicis Pubescentis total glycosides ordinary preparation group, total aglycones ordinary preparation group, total aglycones low dose group and total aglycones high dose group, dosage is 10ml/kg, and blank group filling stomach gives the normal saline with volume.Successive administration 5 days, 30min, 60min put into mice on the hot plate after the last administration, measure pain threshold and pain threshold and improve percentage rate, and make t check, comparable group differences significance.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
Table 1 pair mice is because of the table as a result that influences of pain threshold due to the hot plate
Annotate: through the t check, each group is compared * P＜0.05, * * P＜0.01, * * * P＜0.001 with the blank group.
Above-mentioned result of the test shows, after administration when 30min and 60min, with the blank group relatively, Radix Ilicis Pubescentis total aglycones high-efficiency preparation group can significantly improve because of the pain threshold of hot plate induced mice and pain threshold improve percentage rate, has significant difference (P＜0.01); There is notable difference (P＜0.05) equally in Radix Ilicis Pubescentis total aglycones ordinary preparation group, point out Radix Ilicis Pubescentis total aglycones high-efficiency preparation of the present invention and ordinary preparation all to have analgesic activity preferably, and the pharmacological action of high-efficiency preparation group is better than the ordinary preparation group, and pharmacological action still is not less than the total glycosides ordinary preparation group of normal dose under the situation that the crude drug amount reduces by half.
Two, antiinflammatory action drug effect comparative test
1 test material
1.1 experimental animal
Kunming mouse, the SPF level, ♀, 18～22g, Anhui Province's Experimental Animal Center provides.
1.2 test apparatus
JNB type precision torsion balance: Shanghai Second Balance Factory produces.
1.3 be subjected to the reagent thing
Dimethylbenzene: sell in medication purchasing supply station, Wuxi, produces in chemical plant, the pool, East Lake.
Radix Ilicis Pubescentis 6kg is got in preparation for test agent, and coarse pulverization decocts with water three times, each 2 hours, filter merging filtrate, being evaporated to relative density is 1.10～1.15 (60 ℃), add ethanol and make and contain alcohol amount and reach 70%, left standstill 12 hours, filter, filtrate recycling ethanol, extract three times with water-saturated n-butanol, merge n-butyl alcohol liquid, water bath method, residue is dissolved in water, be added on the D101 macroporous adsorptive resins, respectively with water, 30% ethanol, 70% ethanol elution is collected 70% ethanol elution, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepare the total glycosides formulation of Radix Ilicis Pubescentis; The alcoholic acid water liquid of all the other recovery of 3/4 was with 5mol/L hydrochloric acid hydrolysis 5 hours, it is an amount of that hydrolyzed solution adds calcium oxide, filter, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, 1/3 dry thing prepares the general preparation of Radix Ilicis Pubescentis total aglycones, and 2/3 dry thing prepares Radix Ilicis Pubescentis total aglycones high-efficiency preparation in addition.
Radix Ilicis Pubescentis total glycosides ordinary preparation group: get the dry thing of Radix Ilicis Pubescentis total glycosides, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones ordinary preparation group: get the dry thing of 1/3 Radix Ilicis Pubescentis total aglycones, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones high-efficiency preparation group: get the dry thing of 2/3 Radix Ilicis Pubescentis total aglycones, add chitosan 5g, lecithin 20g, micropowder silica gel 80g, and add starch to 200g, micronizing was mixed 80 minutes.Get wherein that 30g is suspended to 100ml as the aglycon high dose group with water, other gets 15g and is suspended to 100ml as the aglycon low dose group with water.
2 test methods
The reference literature method is got 50 of Kunming mouses, is divided into 5 groups at random, and grouping and dosage are the same, irritates stomach respectively and gives 0.1ml/10g corresponding test liquid, continuous 7 days, does experiment when last gives behind the medicine 30min.The every Mus of 30min is used etherization after the last administration, the scorching liquid of caused by dimethylbenzene xylene is coated in two sides, ear front and back, a mice left side, every about 0.025ml, be total to the every ear of 0.05ml/, auris dextra compares, behind the 1h, with the mice sacrificed by decapitation, cut two ears along the auricle baseline, lay round auricle at same position respectively, weigh with torsion balance with 9mm diameter card punch.The increase percentage rate that the left auricle weight of every Mus deducts auris dextra sheet weight is the swelling degree.Calculate and respectively organize the average and the standard deviation of swelling degree, and make t check, comparable group differences significance.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
Table 2 pair mice is because of the table as a result that influences of auricle swelling degree due to the dimethylbenzene
Annotate: through the t check, each group is compared * P＜0.05, * * P＜0.01 with the blank group.
Above-mentioned result of the test shows, after Mice Auricle gives dimethylbenzene, can cause the auricle edema inflammatory model.Compare with the blank group, Radix Ilicis Pubescentis total aglycones high-efficiency preparation group can significantly alleviate the mice auricle swelling inflammation, has significant difference (P＜0.01); There is notable difference (P＜0.05) equally in Radix Ilicis Pubescentis total aglycones ordinary preparation group, point out Radix Ilicis Pubescentis total aglycones high-efficiency preparation of the present invention and ordinary preparation all to have antiinflammatory action preferably, and the pharmacological action of high-efficiency preparation group is better than the ordinary preparation group, and pharmacological action still is not less than the total glycosides ordinary preparation group of normal dose under the situation that the crude drug amount reduces by half.
Three, the comparative test of Chinese People's Anti-Japanese Military and Political College Mus venous thrombosis
1 test material
1.1 experimental animal
50 of Wister rats, male and female half and half, body weight 200 ± 20g.Provide by Shandong University's Experimental Animal Center.
1.2 be subjected to the reagent thing
Radix Ilicis Pubescentis 6kg is got in preparation for test agent, and coarse pulverization decocts with water three times, each 2 hours, filter merging filtrate, being evaporated to relative density is 1.10～1.15 (60 ℃), add ethanol and make and contain alcohol amount and reach 70%, left standstill 12 hours, filter, filtrate recycling ethanol, extract three times with water-saturated n-butanol, merge n-butyl alcohol liquid, water bath method, residue is dissolved in water, be added on the D101 macroporous adsorptive resins, respectively with water, 30% ethanol, 70% ethanol elution is collected 70% ethanol elution, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepares total glycosides formulation; The alcoholic acid water liquid of all the other recovery of 3/4 was with 5mol/L hydrochloric acid hydrolysis 3 hours, and it is an amount of that hydrolyzed solution adds calcium oxide, filtered, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, dry thing (55% glycosides is hydrolyzed to aglycon) is standby.
The Radix Ilicis Pubescentis glycosides formulation: get the dry thing of glycosides, add chitosan 2.5g, poloxamer 10g, cyclodextrin 30g, and add carboxymethylstach sodium to 100g, micronizing was mixed 80 minutes, and getting wherein, 30g is suspended to 100ml with water;
The general preparation of Radix Ilicis Pubescentis aglycon: get the dry thing of 1/3 aglycon, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis aglycon high-efficiency preparation: get the dry thing of 2/3 aglycon, add chitosan 5g, poloxamer 20g, cyclodextrin 60g, and add carboxymethylstach sodium to 200g, micronizing was mixed 80 minutes.Get wherein that 30g is suspended to 100ml as the aglycon high dose group with water, other gets 15g and is suspended to 100ml as the aglycon low dose group with water.
2 test methods
Get 50 of Wistar rats, male and female half and half, body weight 200 ± 20g, be divided into 5 groups at random, every group 10: aglycon low dose group, aglycon high dose group, the general preparation group of aglycon, the total glycosides formulation group of Radix Ilicis Pubescentis, blank group, gastric infusion every day 1 time, dosage is respectively 10ml/kg, the blank group is irritated stomach and is given with the volume normal saline continuous 7 days.Behind the last administration 6h, be that the capillary glass tube of 1mm inserts Mus angular vein clump and gets blood, reach 5cm to the capillary blood post with internal diameter, every fracture one section in capillary tube of 30s, inspection has or not and clotting strands occurs, and the calculating capillary tube is taken a blood sample to and the blood clotting silk time occurred, is clotting time.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
The thrombotic table as a result that influences of table 3 pair rat vein
Annotate: compare * P＜0.05 with model group; * P＜0.01; * * P＜0.01.
Above result of the test shows that Radix Ilicis Pubescentis total aglycones preparation group can obviously prolong clotting time, relatively has significant difference (P＜0.01 with the blank group; P＜0.001), Radix Ilicis Pubescentis total aglycones high-efficiency preparation group is more obvious than the effect of ordinary preparation group simultaneously, points out total aglycones preparation of the present invention to have anti thrombotic action preferably.
Four, antihypertensive function drug effect comparative test
1 test material
1.1 test material
The SD rat, 220g ± 30g, ♂ is provided by Shandong Traditional Chinese Medicine University zoopery center.
1.2 be subjected to the reagent thing
Radix Ilicis Pubescentis medical material 3kg is got in preparation for test agent, and coarse pulverization adds 70% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, water liquid extracts three times with water-saturated n-butanol, and n-butyl alcohol liquid evaporate to dryness is got 1/3 dry thing and prepared the total glycosides formulation of Radix Ilicis Pubescentis; All the other dry things of 1/3 are dissolved in water, 115 ℃ of sterilization 20min, with lactic acid bacteria culturers hydrolysis fermentation 72 hours, hydrolyzed solution is added on the D101 macroporous adsorptive resins, with water, 30% ethanol, 80% ethanol elution, collect 80% ethanol elution, decompression recycling ethanol respectively, drying under reduced pressure, dry thing (80% glycosides is hydrolyzed to aglycon) preparation total aglycones preparation.
The total glycosides formulation group of Radix Ilicis Pubescentis: get the dry thing of Radix Ilicis Pubescentis total glycosides, add carbomer 2g, poloxamer 3g, cyclodextrin 30g, and add dextrin to 100g, micronizing was mixed 30 minutes, and getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones ordinary preparation group: get the dry thing of 1/2 total aglycones, add dextrin to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
Radix Ilicis Pubescentis total aglycones high-efficiency preparation group: get the dry thing of 1/2 total aglycones in addition, add carbomer 4g, poloxamer 6g, cyclodextrin 40g, and add dextrin to 100g, micronizing was mixed 30 minutes.Getting wherein, 30g is suspended to 100ml with water.
Positive drug (captopril): the sharp 10g of card taking Top is suspended to 100ml with water, promptly.
2 test methods
Get 60 of healthy male rats, body weight 220g ± 30g, be divided into 6 groups at random, every group 10: Radix Ilicis Pubescentis total aglycones high-efficiency preparation group, Radix Ilicis Pubescentis total aglycones ordinary preparation group, the total glycosides formulation group of Radix Ilicis Pubescentis, positive controls, the blank group, model group, adopt the electric shock vola rat to be carried out stress stimulation as single stressor, stimulus intensity is 30～48.5V, frequency 0.5Hz, rat is put in self-control cellular electric shock Mus case, and connection stressor, except that the normal control group, all the other experimental group rat every morning 8:00～10:00, afternoon, 2:00～4:00 respectively accepted stress stimulation 1 time, totally 4 weeks, impose for the last time behind the stress stimulation in 2～5h with tail cover method and measure the arteria caudalis systolic pressure (after being about to rat and placing soft cotton pad to go up, the afterbody heating, to press the arteries and veins condom to the rat tails proximal part, transducer places 1/3 place, Mus tail middle and upper part, open recording system, after regular pulse appearance, utilize inflatable ball to make the cover internal pressure be elevated to the complete obiteration of beating, slowly venting then, examine and read pulse wave pairing force value from do not having to beginning to occur the time, this is rat systolic pressure (mmHg), repeats 3 times, averages).
Get 10 the healthy male rats respectively organizing Hypertensive Rats and normal control group after modeling becomes, irritate stomach and give corresponding test sample 10ml/kg, normal control group and model group give isopyknic normal saline, every day 1 time, behind the successive administration 3 days, with 1% pentobarbital intraperitoneal anesthesia (5mg/kg), the carotid artery intubate is got blood, measures systolic pressure.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
Table 4 pair Hypertensive Rats systolic pressure influence table as a result
Annotate: compare * P＜0.05, * * P＜0.01 with model group.
Above result of the test shows that model group and blank group compare, and systolic pressure increases significant difference, shows the modeling success.Radix Ilicis Pubescentis total aglycones high-efficiency preparation group and positive controls can obviously reduce the systolic pressure of Hypertensive Rats, relatively has significant difference (P＜0.01 with the blank group, P＜0.01), the total glycosides formulation group of Radix Ilicis Pubescentis total aglycones ordinary preparation group has hypotensive effect preferably simultaneously, and above-mentioned prompting total aglycones preparation of the present invention has ideal antihypertensive function.
Five, to the comparative test of diabetic mice glycolipid metabolism
1 test material and instrument
1.1 test material
Kunming mouse, male, 25 ± 2g, the Medical University Of Anhui animal testing center provides; The injection alloxan is the Sigma product, purchases in magnificent biotech firm; Glucose, fructosamine (FA), T-CHOL (TC), serum high-density LP-cholesterol (HDL-C), triglyceride (TG) test kit are all purchased the glad biotechnology research institute in Shanghai section.
1.2 test apparatus
TGL-16B high speed tabletop centrifuge; It beautiful UV-1100 spectrophotometer.
1.3 be subjected to the reagent thing
Radix Ilicis Pubescentis medical material 2kg is got in preparation for test agent, and coarse pulverization adds 60% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, water liquid is added on the D101 macroporous adsorptive resins, with water, 30% ethanol, 70% ethanol elution, collects 70% ethanol elution respectively, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepare the total glycosides formulation of Radix Ilicis Pubescentis; The alcoholic acid water liquid of all the other recovery of 3/4 was with 2mol/L sulphuric acid hydrolysis 5 hours, it is an amount of that hydrolyzed solution adds calcium oxide, filter, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, 1/3 dry thing prepares the general preparation of Radix Ilicis Pubescentis total aglycones, and 2/3 dry thing prepares Radix Ilicis Pubescentis total aglycones high-efficiency preparation in addition.
The A group: get the dry thing of Radix Ilicis Pubescentis total glycosides, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
The B group: get the dry thing of 1/3 Radix Ilicis Pubescentis total aglycones, add starch to 100g, mixing, getting wherein, 30g is suspended to 100ml with water;
The C group: get the dry thing of 2/3 Radix Ilicis Pubescentis total aglycones, add carbomer 2g, lecithin 4g, micropowder silica gel 6g, and add starch to 200g, micronizing was mixed 50 minutes.Get wherein that 30g is suspended to 100ml as the aglycon high dose group with water, other gets 1.5g and is suspended to 100ml as the aglycon low dose group with water.
2 test methods
Get Kunming mouse, begin experiment after one week in laboratory rearing.10 mices of elder generation's random choose are as the normal control group.Behind all the other mice fasting 18h, tail vein injection alloxan (45mg/kg) was surveyed fasting blood sugar after 4 days.Select blood sugar concentration 50 of the mices of 25.00～30.00mmol/L, be divided into 5 groups at random, every group 10, be respectively: blank group, model group, the total glycosides formulation group of Radix Ilicis Pubescentis (A group), Radix Ilicis Pubescentis total aglycones ordinary preparation group (B group) and Radix Ilicis Pubescentis total aglycones high-efficiency preparation group (C group).Dosage is 10ml/kg, and blank group and model group are irritated stomach respectively and given normal saline with volume.Regularly detect body weight and blood sugar level, administration adopted related kit to detect to blood glucose, FA, TC, TG, HDL-C in the serum after 30 days.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
Table 5 pair blood glucose in diabetic mice influence table as a result
Annotate: compare with the blank group: #P＜0.05, ##P＜0.01; Compare with model group: * P＜0.05, * * P＜0.01.
Result of the test shows that model group and medicine group mouse blood sugar do not have significant difference before the administration, but all organizes comparing difference significantly (P＜0.01) with blank, illustrates that it is successful that diabetes model is set up.After the administration, the medicine group is along with the increase of experimental period, blood glucose is descending gradually, along with the rising of dosage, blood glucose descends more and more obvious simultaneously, and the blood glucose of high-efficiency preparation medicine group descends the most obvious, compare with model group, significant difference (P＜0.01), and the model group mouse blood sugar still maintains higher level, points out aglycone preparation of the present invention to have the effect of comparatively ideal blood sugar lowering.
Table 6 couple diabetic mice TC, TG and HDL-C influence table as a result
Annotate: compare with the blank group: #P＜0.05, ##P＜0.01; Compare with model group: * P＜0.05, * * P＜0.01.
Experimental result shows that animals administer detects diabetic mice serum TC, TG and HDL-C level after 30 days.Compare with the blank group, model group serum TC, TG level significantly raise (P＜0.01), and HDL-C obviously descends (P＜0.05), and the blood lipid level that diabetic mice is described illustrates that obviously than normal group height it is successful that diabetes model is set up; The medicine group is compared TC with model group, the TG level descends gradually, the HDL-C level raises gradually, relative other medicines group, aglycon ordinary preparation group has similar pharmacological action to aglycon high-efficiency preparation group, but the effect of the blood fat reducing of high-efficiency preparation medicine group is the most obvious, points out aglycone preparation of the present invention to have the effect of blood fat reducing preferably.
Six, the comparative test that mouse cardiac muscle cell hypoxic-ischemic is damaged
1 test material and instrument
1.1 test material
The SD neonatal rat, Anhui Province's Experimental Animal Center provides; MEM culture medium, sugar-free MEM culture medium: GIBCO company product; Nadide, trypsin: Sigma company product; Superfine calf serum: the cell company's product that grows directly from seeds; Malonaldehyde (MDA), superoxide dismutase (SOD) test kit: build up bio-engineering research institute available from Nanjing.
1.2 test apparatus
Constant incubator, aseptic clean bench etc.
1.3 be subjected to the reagent thing
Radix Ilicis Pubescentis medical material 500g is got in preparation for test agent, pulverizes, and adds 80% ethanol percolation and extracts, percolate reclaims ethanol, and water liquid adds 0.5% activated carbon decolorizing, filter, filtrate is crossed the D101 macroporous resin column, and water, 30% ethanol, 60% ethanol elution are collected 60% ethanol elution respectively, reclaim ethanol, get 1/3 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepare Radix Ilicis Pubescentis total glycosides ordinary preparation; The alcoholic acid water liquid of all the other recovery of 2/3 was used the beta-glycosidase hydrolysis 24 hours, and hydrolyzed solution filters, and crossed the D101 macroporous resin column, and water, 70% ethanol elution are collected 70% ethanol elution respectively, reclaimed ethanol, and drying under reduced pressure is standby.
Radix Ilicis Pubescentis total glycosides ordinary preparation group (A group): the total glycosides formulation of Radix Ilicis Pubescentis is for getting the dry thing of Radix Ilicis Pubescentis total glycosides, add starch to 10g promptly;
Radix Ilicis Pubescentis total aglycones ordinary preparation group (B group): the general preparation of Radix Ilicis Pubescentis total aglycones adds starch to 10g for getting the dry thing of 1/2 Radix Ilicis Pubescentis total aglycones, mixing, promptly;
Radix Ilicis Pubescentis total aglycones high-efficiency preparation group (C group): Radix Ilicis Pubescentis total aglycones high-efficiency preparation adds chitosan 0.5g, lecithin 0.5g, cyclodextrin 1.5g, and adds starch to 10g for getting the dry thing of 1/2 Radix Ilicis Pubescentis total aglycones, and micronizing was mixed 60 minutes, promptly.
2 test methods
The reference literature method is got newborn 3 days 50 of SD neonatal rats (male and female all can), gets its ventricular muscles and shred under aseptic condition, becomes single cell suspension through 0.1% trypsinization, and after the centrifugal collection, making concentration with the MEM culture medium that contains 20% calf serum is 5 * 10
5/ mL cell suspension inoculation places 37 ℃ of constant incubators to cultivate in culture bottle.
The reference literature method causes hypoxic-ischemic damage to myocardial cell, be about to cultivate the myocardial cell that 3d beats synchronously and use the saturated sugar-free MEM culture medium of high pure nitrogen instead, and in culture bottle inflated with nitrogen 30s, air displacement in the bottle is gone out.37 ℃ of airtight cultivations of constant incubator cause the damage of myocardial cell hypoxic-ischemic, the cellular morphology behind observation damage 6, the 12h, and carry out each biochemical indicator and measure.
Cardiac muscle cells is divided into six groups at random: normal group, hypoxic-ischemic group, hypoxic-ischemic+A group (1mg/g), hypoxic-ischemic+B group (1mg/g), hypoxic-ischemic+C low dose group (0.5mg/g), hypoxic-ischemic+C high dose group (1mg/g).Every group of 10 bottles of cells, each group is taken out 5 bottles of cells respectively and is surveyed SOD and MDA content according to kit method behind damage 6h and the 12h.
3 result of the tests
(x ± s) expression, group difference relatively adopts the t check to experimental data with mean ± standard deviation.Concrete result of the test sees the following form.
The table 7 different experiments time is respectively organized cell MDA Determination on content table as a result
Annotate: compare * P＜0.001 with matched group; Compare * * P＜0.01 with the hypoxic-ischemic group.
The above results shows, MDA (lipid peroxide) content of different experiments time hypoxic-ischemic group is also apparently higher than corresponding normal group, difference highly significant (P＜0.001).Aglycone preparation of the present invention has not only reduced MDA content; and its effect becomes positive correlation with formulation concentrations; the effect of aglycon high-efficiency preparation group points out aglycone preparation of the present invention to have the effect that the protection cell prevents lipid peroxidation and oxygen free radical injury significantly better than aglycon ordinary preparation group simultaneously.
The table 8 different experiments time is respectively organized the active measurement result table of cell SOD
Annotate: compare * P＜0.001 with matched group; Compare * * P＜0.01, * * * P＜0.001 with the hypoxic-ischemic group.
The above results shows that the SOD activity of different experiments time hypoxic-ischemic group is obviously low than corresponding normal group, difference highly significant (P＜0.001).Aglycone preparation of the present invention can be in the activity that improves cell SOD in varying degrees; the effect of aglycon high-efficiency preparation group is significantly better than aglycon ordinary preparation group simultaneously; point out aglycone preparation of the present invention to have the active ability of the SOD in cardiac muscle cells of raising, can play the effect that the protection cell prevents lipid peroxidation.
The specific embodiment
Enumerate embodiment below, further specify the present invention, each embodiment only is used to illustrate the present invention, does not limit the present invention:
Embodiment 1
Get Radix Ilicis Pubescentis total aglycones 50g, add chitosan 20g, polyvinylpyrrolidone 20g, carbomer 10g, poloxamer 50g, lecithin 50g, micropowder silica gel 50g, betacyclodextrin 100g, starch 150g, the vibromill micronizing was mixed 30 minutes, and powder is made in packing.
Embodiment 2
Get Radix Ilicis Pubescentis total aglycones 50g, Radix Puerariae Lobatae total flavonoid glycoside 10g, add chitosan 5g, carbomer 5g, poloxamer 14g, lecithin 10g, micropowder silica gel 10g, betacyclodextrin 20g, carboxymethylstach sodium 6g, microcrystalline Cellulose 70g, the weight formula was ground ultra micro machine micronizing 30 minutes, added 70% ethanol and closed and stick together 10 minutes, pill bar, gradation and round, dry, polishing, pill is made in packing.
Embodiment 3
Get Radix Ilicis Pubescentis total aglycones 50g, add chitosan 1g, lecithin 5g, add dextrin 43g, Aspartane 1g again, stir, dry-pressing is granulated, and granule is made in packing.
Embodiment 4
Get Radix Ilicis Pubescentis total aglycones 40g, add chitosan 10g, polyvinylpyrrolidone 10g, poloxamer 8g, lecithin 12g, betacyclodextrin 20g, starch 100g, the mix homogeneously that sieves is granulated, and the dress enteric coated capsule is made capsule.
Embodiment 5
Get Radix Ilicis Pubescentis total aglycones 30g, add chitosan 3.6g, polyvinylpyrrolidone 1.5g, poloxamer 1.8g, lecithin 1.5g, micropowder silica gel 5g, betacyclodextrin 10g, add carboxymethylstach sodium 3g, starch 145g, the vibromill micronizing was mixed 50 minutes, granulate, tabletting, coating is made tablet.
Embodiment 6
Get Radix Ilicis Pubescentis total aglycones 40g, Folium Ginkgo total flavonoid aglycone 20g, add polyvinylpyrrolidone 3.6g, carbomer 0.3g, poloxamer 1.7g, soybean phospholipid 1g, micropowder silica gel 6g, low-substituted hydroxypropyl methylcellulose 46g, microcrystalline Cellulose 120g, air-flowing type ultra micro machine micronizing 60 minutes, granulate, tabletting is made dispersible tablet.
Embodiment 7
Get Radix Ilicis Pubescentis total aglycones 20g, add chitosan 2g, carbomer 0.2g, poloxamer 1g, micropowder silica gel 4g, betacyclodextrin 12g, add citric acid 50g, sodium bicarbonate 55g again, the vibromill micronizing was mixed 70 minutes, its height mixing is disperseed, dry-pressing is granulated, tabletting is made effervescent tablet.
Embodiment 8
Get Radix Ilicis Pubescentis total aglycones 80g, erythromycin 3g, gentamycin 5g adds propylene glycol 8g, poloxamer 2g, ethyl hydroxybenzoate 1g, and adds the stirring of 300g PEG400, and the mixing that sieves is pressed into soft capsule, promptly.
Embodiment 9
Get Radix Ilicis Pubescentis total aglycones 100g, add propylene glycol 10g, poloxamer 10g, lecithin 10g, Cera Flava 15g, and add soybean oil 200g, vibromill ultra micro 20 minutes makes mix homogeneously, makes liquid hard capsule, promptly.
Embodiment 10
Get 250g Macrogol 4000 heating and melting, add Radix Ilicis Pubescentis total aglycones 100g, chitosan 1g, lecithin 8g, vibromill ultra micro 40 minutes makes mix homogeneously, drips to make drop pill, promptly.
Embodiment 11
Get Radix Ilicis Pubescentis medical material 2kg, coarse pulverization decocts with water three times, each 2 hours, filter merging filtrate, being evaporated to relative density is the clear paste of 1.10～1.15 (60 ℃), add ethanol, make to contain the alcohol amount and reach 70%, left standstill 12 hours, filter, decompression filtrate recycling ethanol, water liquid are added on the D101 macroporous adsorptive resins, respectively with water, 20% ethanol, 70% ethanol elution, collect 70% ethanol elution, decompression recycling ethanol, surplus water liquid add sulphuric acid makes acid content reach 2mol/L, heating hydrolysis 3 hours, put cold, filter, residue is extremely near neutral with water washing, drying under reduced pressure, obtain the Radix Ilicis Pubescentis general aglycone extract and (contain the Radix Ilicis Pubescentis total aglycones more than 60%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add carbomer 15g, chitosan 5g, lecithin 10g, poloxamer 10g, glycerol 30g, and add the 450g Macrogol 600, vibromill ultra micro 80 minutes, make mix homogeneously, make liquid hard capsule, promptly.
Embodiment 12
Get Radix Ilicis Pubescentis medical material 4kg, pulverize, add 60% alcohol reflux three times, each 1.5 hours, filter, filtrate recycling ethanol, surplus water liquid is added on the D101 macroporous adsorptive resins, the difference water, 70% ethanol elution, collect 70% ethanol elution, reclaim ethanol, surplus water liquid adds hydrochloric acid makes acid content reach 2mol/L, heating hydrolysis 4 hours, hydro-oxidation sodium is regulated pH to neutral, is added on the D101 macroporous adsorptive resins, respectively water, 20% ethanol, 80% ethanol elution, collect 80% ethanol elution, reclaim ethanol, drying under reduced pressure obtains the Radix Ilicis Pubescentis general aglycone extract and (contains the Radix Ilicis Pubescentis total aglycones more than 65%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add propylene glycol 2g, glycerol 30g, ethyl hydroxybenzoate 1g, and add 200g PEG400, stirring and evenly mixing, be pressed into soft capsule, promptly.
Embodiment 13
Get Radix Ilicis Pubescentis medical material 3kg, coarse pulverization decocts with water three times, each 2 hours, filter, merging filtrate, being evaporated to relative density is the clear paste of 1.10～1.15 (60 ℃), adds ethanol, make and contain alcohol amount and reach 60%, left standstill 12 hours, and filtered decompression filtrate recycling ethanol, water liquid extracts three times with water-saturated n-butanol, n-butyl alcohol liquid evaporate to dryness, dry thing is dissolved in water, 115 ℃ of sterilization 20min, with bifidus bacillus strain fermentation hydrolysis 72 hours, concentrating under reduced pressure, drying under reduced pressure obtains the Radix Ilicis Pubescentis general aglycone extract and (contains the Radix Ilicis Pubescentis total aglycones more than 80%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add the 100g polyethylene glycol 6000, the 250g Macrogol 4000, the 20g of Radix Notoginseng total glycosides unit, carbomer 5g, propylene glycol 40g, lecithin 5g, poloxamer 5g, vibromill ultra micro 35 minutes, heating and melting, make mix homogeneously, drip and make drop pill, promptly.
Embodiment 14
Get Radix Ilicis Pubescentis medical material 2.5kg, pulverize, add 10 times of water gagings and decoct 3 times, each 1 hour, filter, merging filtrate concentrates, 70% ethanol precipitation, reclaim ethanol, n-butyl alcohol liquid is reclaimed in n-butanol extraction 3 times of water liquid, 115 ℃ of sterilizations of surplus water liquid 15-20min, the escherichia coli strain is mixed with every milliliter with sterilized water and contains 10
8Individual conidial suspension is that the ratio of 3-10% inserts culture medium with the form of spore suspension in V/W,, shakes incubation time 72-96h under the condition of shaking speed 140-220rpm in 26-30 ℃; After stopping fermentation, filter, filter cake is measured 80% alcohol reflux 2 times with 5 times, and each 30 minutes, merging filtrate, decompression recycling ethanol, surplus water liquid is crossed the D101 macroporous resin column, respectively water, 70% ethanol elution is collected 70% ethanol elution, reclaim ethanol, concentrate, drying obtains the Radix Ilicis Pubescentis general aglycone extract and (contains the Radix Ilicis Pubescentis total aglycones more than 75%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add carbomer 7g, poloxamer 5g, soybean phospholipid 10g, betacyclodextrin 28g, the vibromill micronizing was mixed 20 minutes, granulated, encapsulated, make capsule.
Embodiment 15
Get Radix Ilicis Pubescentis medical material 6kg, coarse pulverization adds 70% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, surplus water liquid merge n-butyl alcohol liquid with n-butanol extraction three times, water bath method, residue are added on the D101 macroporous adsorptive resins with water dissolution, earlier with water, 30% ethanol elution, discard eluent, again with 70% ethanol elution, eluent reclaims ethanol, surplus liquid adds hydrochloric acid makes acid content reach 1mol/L, back hydrolysis 3 hours, put cold, with in the sodium hydroxide and remaining acid, dry, dry thing alcohol reflux, gained ethanol liquid reclaims ethanol, drying, obtain the Radix Ilicis Pubescentis general aglycone extract and (contain the Radix Ilicis Pubescentis total aglycones more than 55%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 25g, poloxamer 25g, lecithin 20g, micropowder silica gel 30g, betacyclodextrin 150g, carboxymethylstach sodium 10g, the vibromill micronizing was mixed 80 minutes, granulate, tabletting, coating is made tablet (0.35g/ sheet).
Embodiment 16
Get Radix Ilicis Pubescentis medical material 6kg, pulverize, add 60% alcohol reflux 3 times, each 1 hour, filter merging filtrate, reclaim ethanol, surplus water liquid is crossed the D101 macroporous resin column, respectively water, 65% ethanol elution is collected 65% ethanol elution, reclaim ethanol, water liquid adds hydrochloric acid 300ml, heating hydrolysis 4 hours, the neutralization of hydrolyzed solution hydro-oxidation sodium, cross the AB-8 macroporous resin column, the difference water, 65% ethanol elution is collected 65% ethanol elution, reclaims ethanol, spray drying, obtain Radix Ilicis Pubescentis general aglycone extract (contain the Radix Ilicis Pubescentis total aglycones more than 90%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 15g, carbomer 15g, poloxamer 5g, soybean phospholipid 10g, the vibromill micronizing was mixed 40 minutes, granulate, the dress enteric coated capsule is made enteric coated capsule.
Embodiment 17
Get Radix Ilicis Pubescentis medical material 3.5kg, pulverize, adding 70% ethanol percolation extracts, percolate, reclaim ethanol, water liquid adds 0.5% activated carbon decolorizing, filters, filtrate is crossed the D101 macroporous resin column, the difference water, 20% ethanol, 60% ethanol elution is collected 60% ethanol elution, reclaims ethanol, use the maltoside enzyme, amygdaloside enzyme hydrolysis 24 hours, hydrolyzed solution is crossed the D101 macroporous resin column, respectively water, 70% ethanol elution is collected 70% ethanol elution, reclaim ethanol, drying obtains Radix Ilicis Pubescentis general aglycone extract (contain the Radix Ilicis Pubescentis total aglycones more than 50%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 7g, polyvinylpyrrolidone 10g, carbomer 5g, poloxamer 5g, soybean phospholipid 10g, carboxymethylstach sodium 5g, the vibromill micronizing was mixed 40 minutes, granulated tabletting, enteric coated, make tablet.
Embodiment 18
Get Radix Ilicis Pubescentis medical material 5kg, pulverize, add 60% alcohol reflux 2 times, each 1 hour, filter, merging filtrate reclaims ethanol, 115 ℃ of sterilizations of water liquid 15-20min, lactic acid bacteria culturers is mixed with every milliliter with sterilized water and contains 10
8Individual conidial suspension is that the ratio of 3-10% inserts culture medium with the form of spore suspension in V/W,, shakes incubation time 72-96h under the condition of shaking speed 140-220rpm in 26-30 ℃; After stopping fermentation, get the filtering fermentation liquor after the fermentation, filtrate is crossed polyamide column, the difference water, 70% ethanol elution, collect 70% ethanol elution, reclaim ethanol, spray drying, obtain Radix Ilicis Pubescentis general aglycone extract (except containing the Radix Ilicis Pubescentis total aglycones, also containing unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 15g, polyvinylpyrrolidone 50g, soybean phospholipid 10g, low-substituted hydroxypropyl methylcellulose 70g, microcrystalline Cellulose 100g, vibromill micronizing 30 minutes, granulate, tabletting is made dispersible tablet (0.5g/ sheet).
Embodiment 19
Get Radix Ilicis Pubescentis medical material 6kg, pulverize, add 8 times of water gagings and decoct each 1 hour 3 times, filter, merging filtrate concentrates 60% ethanol precipitation, reclaim ethanol, water liquid is crossed the D101 macroporous resin column, respectively water, 20% ethanol, 70% ethanol elution is collected 70% ethanol elution, reclaim ethanol, water liquid maltoside enzyme, amygdaloside enzyme hydrolysis 48 hours, hydrolyzed solution filters, peroxidating aluminum post, the difference water, 70% ethanol elution, collect 70% ethanol elution, reclaim ethanol, drying, obtain the Radix Ilicis Pubescentis general aglycone extract (except containing the Radix Ilicis Pubescentis total aglycones, also contain unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add polyvinylpyrrolidone 10g, carbomer 15g, poloxamer 30g, soybean phospholipid 15g, add citric acid 150g again, sodium bicarbonate 180g, the vibromill micronizing was mixed 50 minutes, its height mixing is disperseed, dry-pressing is granulated, and tabletting is made effervescent tablet (0.5g/ sheet).
Embodiment 20
Get Radix Ilicis Pubescentis medical material 4kg, pulverize, add 70% ethanol percolation and extract, percolate reclaims ethanol, and water liquid adds 0.5% activated carbon decolorizing, filter, filtrate is crossed the D101 macroporous resin column, respectively water, 20% ethanol, 60% ethanol elution, collect 60% ethanol elution, reclaim ethanol, add concentrated sulphuric acid 250ml, heating hydrolysis 60 minutes, the neutralization of hydrolyzed solution adding calcium hydroxide, filter, filter cake is measured 80% alcohol reflux 2 times, each 30 minutes with 5 times, merging filtrate, decompression recycling ethanol, drying obtains the Radix Ilicis Pubescentis general aglycone extract and (contains the Radix Ilicis Pubescentis total aglycones more than 40%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add carbomer 20g, poloxamer 32g, and add starch to total amount 1000g, the vibromill micronizing was mixed 30 minutes, powder is made in packing.
Embodiment 21
Get Radix Ilicis Pubescentis medical material 5kg, pulverize, add 60% alcohol reflux 3 times, each 1 hour, filter, merging filtrate reclaims ethanol, 115 ℃ of sterilizations of water liquid 15-20min, bifidobacterium species is mixed with every milliliter with sterilized water and contains 10
8Individual conidial suspension is that the ratio of 3-10% inserts culture medium with the form of spore suspension in V/W,, shakes incubation time 72-96h under the condition of shaking speed 140-220rpm in 26-30 ℃; After stopping fermentation, filter, filtrate is crossed the D101 macroporous resin column, difference water, 70% ethanol elution, collect 70% ethanol elution, reclaim ethanol, spray drying obtains Radix Ilicis Pubescentis general aglycone extract (contain the Radix Ilicis Pubescentis total aglycones more than 65%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), spray powder adds polyvinylpyrrolidone 2g, poloxamer 33g, lecithin 13g, carboxymethylstach sodium 10g, and adding microcrystalline Cellulose to total amount 1000g, the vibromill micronizing was mixed 30 minutes, granulated, filled capsules is made capsule.
Embodiment 22
Get embodiment 13 made drop pill and treat 54 routine angina pectoris patients.Therapeutic scheme: every day 3 times, each 6, use after 10 days, obvious effective rate is 40.8%, total effective rate is 90.4%.
Embodiment 23
Get embodiment 15 made tablet in treatment thromboangiitis obliterans patient 66 examples.Therapeutic scheme: every day 3 times, each 2,15 days is a course of treatment, and 48 examples are cured in statistical result after 3 courses of treatment, 5 examples that take a turn for the better, and total effective rate is 80.3%.
Embodiment 24
Get embodiment 18 made dispersible tablet treatments and suffer from patient's 134 examples of tonsillitis and pharyngolaryngitis.Therapeutic scheme: every day 3 times, each 2,2 weeks were a course of treatment, added up therapeutic outcome after 2 courses of treatment, and obvious effective rate is 44.8%, and total effective rate is 88.7%.
Embodiment 25
Get embodiment 19 made effervescent tablet auxiliary treatment 58 routine hyperpietics.Therapeutic scheme: every day 2 times, each 3; Use simultaneously and take Nifedipine sustained release tablets, every day 3 times, each 1.After 15 days, obvious effective rate is 74.6%, and total effective rate is 88.3%.
Claims (18)
1, a kind of is the oral drugs of active component with the Radix Ilicis Pubescentis total aglycones.
2, medicine according to claim 1 is characterized in that described Radix Ilicis Pubescentis total aglycones can use separately, also can unite use with the other drug composition.
3, medicine according to claim 2 is characterized in that described Radix Ilicis Pubescentis total aglycones obtains by hydrolysis Radix Ilicis Pubescentis total glycosides.
4, medicine according to claim 3 is characterized in that method for hydrolysis is acid hydrolysis, enzyme hydrolysis or microbial hydrolysis.
5, according to each described medicine in the claim 1 to 4, it is characterized in that acceptable auxiliary is used on active constituents of medicine and the pharmaceutics.
6, medicine according to claim 5 is characterized in that containing in the adjuvant bio-adhesive agent and wetting agent.
7, medicine according to claim 6 is characterized in that also can containing dispersant in the adjuvant.
8, medicine according to claim 7 is characterized in that bio-adhesive agent in the adjuvant is meant any or the compositions more than two kinds in chitosan, carbomer, the polyvinylpyrrolidone; Wetting agent is meant lecithin and/or poloxamer; Dispersant is meant micropowder silica gel and/or cyclodextrin.
9, medicine according to claim 8 is characterized in that the proportion of composing of active constituents of medicine and adjuvant is:
Active component 20～60%,
Bio-adhesive agent 1～10%,
Wetting agent 5～20%,
Dispersant 0～30%,
Other adjuvants 0～50%.
10, medicine according to claim 9 is characterized in that being made into tablet, capsule, granule or pill.
11, medicine according to claim 5 is characterized in that containing in the adjuvant wetting agent and dispersant.
12, medicine according to claim 11 is characterized in that also can containing the bio-adhesive agent in the adjuvant.
13, medicine according to claim 12 is characterized in that wetting agent in the adjuvant is meant any or the compositions more than two kinds in propylene glycol, lecithin, the poloxamer; Dispersant is meant Polyethylene Glycol or vegetable oil; The bio-adhesive agent is meant chitosan and/or carbomer.
14, medicine according to claim 13 is characterized in that the proportion of composing of active constituents of medicine and adjuvant is:
Active component 10～40%,
Bio-adhesive agent 0～10%,
Wetting agent 5～20%,
Dispersant 50～80%,
Other adjuvants 0～5%.
15, medicine according to claim 14 is characterized in that being made into soft capsule, liquid hard capsule or drop pill.
16, the method for preparing each described medicine in the claim 6 to 15, it is characterized in that behind active constituents of medicine and any method mix homogeneously during required adjuvant mixes by fusion, dissolving, stirring, grinding or micronizing, add required conventional formulation adjuvant again, technology is made preparation routinely.
17, preparation method according to claim 16 is characterized in that active constituents of medicine is mixed by the vibromill superfine grinding method with required adjuvant.
18, each described medicine is used for the treatment of application in the medicine of diseases such as coronary atherosclerotic heart disease, acute myocardial infarction, thromboangiitis obliterans, central serous chorioretinopathy, tonsillitis, pharyngolaryngitis, infantile pneumonia, chilblain, burn and scald, vascular hypertension, hyperlipidemia or hyperglycemia in the claim 1 to 4 in preparation.
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| CN200810101021A CN101518554A (en) | 2008-02-27 | 2008-02-27 | Oral medicinal preparation of hairy holly root total aglycon, preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104042720A (en) * | 2014-07-08 | 2014-09-17 | 河南中医学院 | Traditional Chinese medicine for preventing and treating diabetes with depression and application of traditional Chinese medicine |
| CN114939121A (en) * | 2022-04-11 | 2022-08-26 | 枣庄学院 | Application of pubescent holly root saponin A in preparation of ionizing radiation protection medicines |
| EP3871694A4 (en) * | 2019-06-10 | 2022-08-31 | Jing Zhang | Composition |
-
2008
- 2008-02-27 CN CN200810101021A patent/CN101518554A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104042720A (en) * | 2014-07-08 | 2014-09-17 | 河南中医学院 | Traditional Chinese medicine for preventing and treating diabetes with depression and application of traditional Chinese medicine |
| CN104042720B (en) * | 2014-07-08 | 2016-03-30 | 河南中医学院 | There is the Chinese medicine and application thereof of preventing and treating diabetes complicated depression |
| EP3871694A4 (en) * | 2019-06-10 | 2022-08-31 | Jing Zhang | Composition |
| US12036197B2 (en) | 2019-06-10 | 2024-07-16 | Jing Zhang | Composition for improving bioavailability of drugs |
| CN114939121A (en) * | 2022-04-11 | 2022-08-26 | 枣庄学院 | Application of pubescent holly root saponin A in preparation of ionizing radiation protection medicines |
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