CN102068468B - Method for treating traditional Chinese medicinal extraction solution before preparation - Google Patents
Method for treating traditional Chinese medicinal extraction solution before preparation Download PDFInfo
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Abstract
The invention provides a method for treating traditional Chinese medicinal extraction solution before preparation. The method comprises the following steps: 1) mixing traditional Chinese medicinal extraction solution and medicinal active ingredient poor solvent which is 1-10 times of the traditional Chinese medicinal extraction solution by weight or volume, standing, separating to obtain solid matter and supernatant; and 2) concentrating the supernatant in the step 1) to prepare sugarless paste, and collecting the solid matter and the sugarless paste. The invention also provides a preparation method of a traditional Chinese medicinal preparation. The method is that the solid matter and sugarless paste prepared by the method of the invention are used with common excipient or auxiliary components to prepare the common oral preparation. By adopting the technology of the invention, the problem of the existing traditional Chinese medicinal preparation that the paste yield is higher can be solved, the production cycle can be shortened and the production cost can be reduced.
Description
Technical field
The invention provides the preceding method that Chinese medicine extraction liquid is handled of a kind of preparation, belong to field of pharmaceutical preparations.
Background technology
Chinese medicine preparation requires medicine should have safety, effectiveness, stability and quality controllability, and the pre-treating technology flow process of herbal pharmaceutical is generally at present: extract and--filter--concentrating---clear paste (semi-finished product).In such herbal pharmaceutical pre-treating technology, the notion of a most critical is a paste-forming rate.So-called paste-forming rate is meant that according to the rules extraction process produces fluid extract or the quality of dry extract of the Chinese crude drug institute output of 100 unit masses; It is distinctive noun of Chinese patent medicine pharmaceutical industry abstraction process and important production management's index; In close relations with the quality and the cost of product, always paid attention to by Chinese medicine manufacturing enterprise, workshop even pharmaceutical machine enterprise.The principal element that influences paste-forming rate has multinomial factors such as medical material kind, technology, equipment; Its Chinese crude drug factor affecting is the most obvious; When the prescription medical material has been rich in composition such as polysaccharide, tannin, lymphatic temperament, pectin, natural gum, protein, its water or the prepared clear paste of low concentration alcohol extract, stickiness is bigger; It receives the cream rate generally greater than 70%, it is prepared into the preparation that meets existing Chinese patent medicine quality standard has very big obstacle.
The method for making item of China's Chinese patent medicine quality standard; The pattern of the Chinese medicine quality of the pharmaceutical preparations being controlled on the technology has roughly experienced following evolution: the inventory pattern is simply controlled in (1); Mainly control the quality of product with the inventory of control Chinese medicine preparation, for example: tender always, the powder that pill is to control honey focuses on the relative density of color and luster and homogeneity, unguentum control thick paste etc., is flavour of a drug all to be listed get final product basically in the standard; Supplementary product consumption only indicates that the amplitude of adjuvant gets final product; Do not stipulate the amount of processing yet, adjuvant with discharge amplitude just in order to make preparations shaping, rather than the control amount of processing; (2) decide the pattern that cream is decided powder; Promptly in a cream (medicinal substances extract), add several parts of adjuvants, process granule then, the amount of processing of finished product is by the paste-forming rate decision of medical material; Just allow the finished product amount of processing to change with the fluctuation of paste-forming rate, quality standard does not have controllability to the amount of processing.The adverse consequences that this kind operation brings is the amount of the processing difference of each batch kind of identical recipe quantity, that is to say that the contained effective substance of unit formulation is uncertain, and patient's dosage also just can't be fixed, thereby influences the stability and the safety of pharmaceutical effectiveness.
Existing quality control standard is: the pattern of the regulation prescription amount of processing; The medicine of identical prescription had not only been stipulated processing quantity but also having stipulated to process weight of product; Making the gross weight of processing of different enterprises is determined value; Promptly regulation drops into the certain decoction pieces quantity of prescription, through extract concentrate after, its clear paste all gets into finished product.Can guarantee the contained effective substance substantially constant of each batch kind like this, quality controllable, stability and safety are all secure.
According to common practise; Have only when extractum amount and the ability molding under certain proportion of adjuvant amount; If during the extractum amount of stipulating in the medical material paste volume overgauge of certain recipe quantity, under the certain situation of adjuvant amount, can't prepare satisfactory preparation obviously.Yet the inventor finds that under study for action during compositions such as aforementioned prescription medical material is rich in polysaccharide, the matter of mixing, paste volume is the amount of overgauge regulation usually, be prepared into very difficulty of standard compliant preparation, and enterprise usually is in the dilemma.If the adjuvant amount of stipulating in the standard certainly is enough big, can adopts the addition of regulating adjuvant to reach the amount of processing in the technology, but can cause unnecessary adjuvant waste also to increase dose and cost simultaneously to the patient.
In order to solve the excessive problem of extractum amount, prior art is usually handled extractum through following method:
1. extractum wet granulation: press experience and practice that Chinese medicine is produced, when adjuvant: the weight proportion of clear paste can molding greater than 1.6 the time, adopts this method of granulating, even clear paste solid content weight is disregarded, singly just surpasses the prescription amount of processing with regard to supplementary product consumption;
2. extractum one-step palletizing: the cream amount is big, and the ratio of cream amount and bed material is generally greater than 2: 1, and the cream amount is big, and fluidizing velocity is slow, and production efficiency is low and step on pot easily;
3. extract dry: the exsiccant conventional art of Chinese medical concrete mainly be Electric heat oven dry with the conventional vacuum drying; Because the Chinese medical concrete stickiness is big, breathability is poor; Want to obtain drying effect preferably, the temperature of extractum generally all will reach more than 80 ℃ in the dry run, and drying time is long.
Therefore above-mentioned technology all exist yield poorly, energy consumption is high, production efficiency is low and the not high shortcoming of product quality.The exsiccant new technique of Chinese medical concrete mainly comprises spray drying and vacuum lyophilization etc.; Novel dried technology is existing certain applying in the dry run of Chinese medical concrete, but still have certain defective and limitation for the Chinese medical concrete that viscosity is high, sugar content is high, and it is big to receive the cream amount; For the ease of preparation; Usually can add a large amount of adjuvants, can cause taking dose to strengthen like this, difficult quality control.
In the face of huge paste volume like this, take to reduce the paste volume that extracts link at present or increase concentrating degree and solve.Reducing the main means of paste volume is refining and edulcorations, if take refining means such as adsorption clarification, centrifugal remove impurity, macroporous resin, must cause the great change of material base, increases operating procedure, has increased cost; If adopt vacuum concentration mode commonly, owing to receive the restriction of equipment capacity, thick extractum is difficult to reach the relative density of pharmacopeia regulation; And thick extractum is when being concentrated into to a certain degree deeply; Water evaporates is slow especially, and when taking a lot of work, and the concentration tank tank skin has the medicinal liquid gelatinizing and sticks; Cause breeze occurring after the finished particle dissolving, so reduce the change that the thinking of paste volume may cause material base.
Therefore, be badly in need of a kind of method, neither influence drug quality and can conveniently handle extractum again, with the requirement of preparation conformance with standard, stay-in-grade pharmaceutical preparation.
Summary of the invention
In order to overcome above-mentioned defective, technical scheme of the present invention has provided a kind of new technique Chinese medicine extraction liquid concentration technique of herbal pharmaceutical, and it can solve the excessive problem of extractum amount, also can shorten the production cycle simultaneously, reduce production costs.
The invention provides a kind of method of before preparation, Chinese medicine extraction liquid being handled, it is characterized in that: it comprises the following steps:
A, get Chinese medicine extraction liquid and mix, leave standstill, separate obtaining solid content and supernatant with the effective ingredient poor solvent of 1～10 times of weight or volume; The poor solvent that the present invention is alleged is meant in this kind solvent, and effective ingredient is insoluble or dissolubility is low for certain in the extracting solution or several kinds.
B, the supernatant concentration of a step is processed clear paste, collect solid content and clear paste.
Wherein, described Chinese medicine extraction liquid is middle liquid medicine or aquiferous ethanol extracting solution.
Further, the concentration of alcohol of described aquiferous ethanol extracting solution is greater than 0, is less than or equal to 50%v/v.
Wherein, the relative density of described Chinese medicine extraction liquid is 1.05～1.20.
Wherein, the described effective ingredient poor solvent of a step is: acetic acid, acetone, methoxybenzene, n-butyl alcohol, sec-butyl alcohol, butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxine, ethanol, ethyl acetate, ether, Ethyl formate, formic acid, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid butanols, butanone, methyl iso-butyl ketone (MIBK), isobutanol, pentane, n-amyl alcohol, normal propyl alcohol, isopropyl alcohol or propyl acetate.
Further, described effective ingredient poor solvent is ethanol, ethyl acetate or n-butyl alcohol.
Further, described effective ingredient poor solvent is a 50%-95%v/v ethanol.
Further preferably, described effective ingredient poor solvent is a 95%v/v ethanol.
Wherein, the described hybrid mode of a step is: Chinese medicine extraction liquid is sprayed in the effective ingredient poor solvent of 1～10 times of weight or volume.
Further; The described method of spraying into is to use conventional sprayer unit; Pressure is not less than 0.2MPa, and the fogdrop diameter of ejection is 200-500 μ m, the sprayer unit that the present invention is alleged; Be meant commercially available conventional sprayer unit at present, comprise devices such as hand spray (like pesticide sprayer), the spraying of high pressure self-action (like the pneumatics aerosol apparatus), centrifugal spraying (like the sprayer unit of centrifugal spray drying), ultrasonic atomizatio.
Wherein, the described hybrid mode of a step is: the effective ingredient poor solvent that extracting solution is slowly added 1～10 times of weight or volume.
Wherein, the described hybrid mode of a step is: the effective ingredient poor solvent is slowly added extracting solution.
Wherein, the described time of repose of a step is 30min～2hr.
The present invention also provides a kind of Chinese medicine preparation, and it is solid content and clear paste by the preparation of Chinese medicine extraction liquid concentration technique, is prepared into preparation commonly used with adjuvant or complementary composition pharmaceutically commonly used.
The present invention also provides a kind of method for preparing Chinese medicine preparation, and it is to adopt wet granulation, and clear paste density is: 1.2～1.5 (heat is surveyed); With solid content mix with the adjuvant of preparation prescription pulverize after, add after wet granulator stirs 1～5min, add clear paste and do binding agent system soft material, soft material is put is granulated on the oscillating granulator, fluid bed drying promptly gets.
The present invention also provides a kind of method for preparing Chinese medicine preparation, and it is to adopt one-step palletizing, gets the clear paste of relative density 1.05～1.30 (heat is surveyed); Solid content is mixed the pulverizing back add one-step-granulating method with the adjuvant of preparation prescription, the 10～30min of ventilation drying earlier adds the clear paste fluidized granulation, and after spraying was accomplished, dry 30～60min promptly got.
The present invention also provides a kind of method for preparing Chinese medicine preparation, and it is to adopt spray drying, and solid content is mixed pulverizing after drying powder 1 with an amount of adjuvant subsequent use; It is subsequent use that the clear paste spray drying of relative density 1.05～1.30 (heat survey) is promptly got powder 2; Two parts pressed powder is mixed the dried cream powder that promptly gets prescription drug.
Chinese medicine extraction liquid of the present invention is to be the extracting solution that raw material is processed with Chinese crude drug, the prepared slices of Chinese crude drugs or Chinese medicine compound, comprised medical material pre-treatment, adopt solvent to extract (comprising squeezing), operation such as concentrated.The solvent that the present invention adopts is water or aquiferous ethanol.
At present in conventional Chinese medicine material, Chinese medicine compound water or the low concentration alcohol extract; Be rich in compositions such as polysaccharide, tannin, lymphatic temperament, pectin, natural gum, protein, for the later stage preparation has brought inconvenience, technology of the present invention does not adopt the remove impurity operation to above-mentioned water or low concentration alcohol extract; All effective ingredient of medical material have been kept; On the basis that has guaranteed former preparation drug effect, solved the bigger problem of paste volume in the existing Chinese medicine preparation, reduced the use amount of adjuvant in the moulding process; Also shorten the production cycle of preparation finished product simultaneously, greatly practiced thrift production cost.
Below the specific embodiment through instance, foregoing of the present invention is remake further detailed description.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
The process chart of Fig. 1 the present invention preparation " Dioscorea nipponica bony spur tablet "
The specific embodiment
The technology of embodiment 1 the present invention preparation " BAZHEN KELI "
[prescription] Radix Codonopsis 45kg Radix Paeoniae Alba 45kg Rhizoma Atractylodis Macrocephalae 45kg Radix Rehmanniae Preparata 68kg
Poria 45kg Radix Angelicae Sinensis 68kg Rhizoma Chuanxiong 31kg Radix Glycyrrhizae 22.5kg
The preparation of [method for making] a, Chinese medicine extraction liquid: above eight flavors, get Radix Angelicae Sinensis 68kg, Rhizoma Chuanxiong 31kg, Rhizoma Atractylodis Macrocephalae 45kg respectively once with 95% ethanol, 50% alcohol heating reflux, each 2 hours, filter, filtrating merges, and reclaims ethanol, filtration, filtrate for later use; The five tastes (Radix Codonopsis 45kg, Radix Paeoniae Alba 45kg, Poria 45kg, Radix Rehmanniae Preparata 68kg, Radix Glycyrrhizae 22.5kg) decocte with water secondaries such as medicinal residues and all the other Radix Codonopsis, each 1.5 hours, filter, filtrating merges, and adds above-mentioned reserve liquid, is condensed into the extractum 272kg of relative density 1.2.
Concentrating of b, extracting solution: it is subsequent use 1. to get 95% ethanol, and wherein consumption of ethanol is: extractum: ethanol=1: 4g/g); 2. (this step is also referred to as spray and coagulates) in 95% ethanol with 4 times of weight of extractum spraying adding wherein, adopted the hand spray device, and atomisation pressure is not less than 0.2MPa, and fogdrop diameter is 200-500 μ m; 3. after leaving standstill 30min, draw supernatant and solid-liquid separation, get solid content and supernatant; (ethanol is the effective ingredient poor solvent of indication of the present invention in the present embodiment)
Solid content is centrifugal through tripod pendulum type batch centrifugal, obtain semi-solid 91kg and centrifugal liquid; Centrifugal liquid is added in the supernatant, and reclaiming ethanol again and being evaporated to relative density is 1.35～1.4 thick paste 74kg;
C, preparation of granules:, add an amount of soluble starch, stevioside with the thick paste of b step; Process soft material 2; The semisolid of b step is added soluble starch, be prepared into soft material 1; Soft material 1 and soft material 2 are mixed, and granulation, drying are prepared into finished particle agent 225.8kg.Wherein, soft material 1 used soluble starch is 1% of a finished weight, and soft material 2 used soluble starches are 65% of finished weight, and stevioside is 0.3%.
The technology of embodiment 2 the present invention preparations " Dioscorea nipponica bony spur tablet "
[prescription] Rhizoma Dioscoreae Nipponicae 27Kg Herba Epimedii 32.4Kg Rhizoma Cibotii 43.2Kg
Radix Cyathulae 43.2Kg Radix Rehmanniae Preparata 27Kg Fructus Lycii 16.2Kg
[method for making] preparation technology sees Fig. 1.Wherein, adopt the high pressure automatic sprayer, atomisation pressure is 1-2MPa, and fogdrop diameter is 200-500 μ m.(ethanol is the effective ingredient poor solvent of indication of the present invention in the present embodiment)
The investigation of embodiment 3 spray coagulation parameters
[screening of poor solvent kind]
In theory, as long as can change the polarity of extractum and all can not realize preparation technology of the present invention with the solvent of water formation azeotropic mixture.But consider that solvent exists potential safety hazard, toxicity etc. when pilot scale and big production, investigated three kinds of solvents that allow use in the Chinese medicine preparation large-scale production process: the influence to testing of ethanol, ethyl acetate and n-butyl alcohol.
In the experiment with the preparation " BAZHEN KELI " be example, poor solvent is investigated:
Get a step gained eight delicacies extractum among the embodiment 1 of 1/5 prescription, relative density 1.18 (60 ℃) sprays into respectively in 4 times of ethanol, ethyl acetate and n-butyl alcohol, investigates and to separate out the dry weight of solid content, dried cream amount and both sums of supernatant after spray is coagulated.The result sees table 1:
Table 1
Can know that by last table the eight delicacies extractum of equivalent sprays in three kinds of solvents, and total solid content is not had appreciable impact.Experimental selection ethanol is that cost is also minimum because ethanol uses the most extensively, the safest in commercial production, and is also minimum to the influence of workman's health, and therefore, we unify to have selected ethanol for use in experimentation is solvent.
[ethanol adds the screening of parameter]
The result can know by " screening of poor solvent kind ", and poor solvent of the present invention is good with ethanol, therefore, is example with preparation " BAZHEN KELI ", and the spray coagulation parameter is done further screening.
Back solid content weight serves as to investigate index to spray with fixed attention, because the solid content that forms after the spray with fixed attention is many more, solid content residual in the supernatant is just few more, concentrates and just carries out more easily, and follow-up granulation is just easier to be successful.Adopt L
9(3
4) orthogonal table arranges the level of concentration of alcohol, amount of ethanol and time of repose, inquire into.Factor level table such as table 2:
Table 2: factor level table
The mensuration of total solid weight: use L
9(3
4) orthogonal table arrangement test, take by weighing the extractum that standard prescription 1/10 is measured, spray by the setting scheme and coagulate, the dry weight of separating out solid content after coagulating with spray is an evaluation index.The result sees table 3, table 4.
Table 3: back solid content orthogonal test table and range analysis result are coagulated in spray
Table 4: back solid content orthogonal test analysis of variance table is coagulated in spray
*P＜0.05
Can know by table 2, extractum sprayed in the 50-95% ethanol of 4-10 times of extractum weight and leave standstill 0.5-1.5h, can from extractum, isolate and be insoluble to alcoholic acid effective ingredient in a large number, reduce the paste-forming rate of extractum significantly.Can be known that by range analysis and The results of analysis of variance the A factor is the significance influence factor (P=0.0287＜0.05) of this experiment, and the A value is the bigger the better, therefore, the optimum level of confirming the A factor is 95%.B, C factor do not have the significance influence to experimental result, and actual in conjunction with producing, amount of ethanol is confirmed as 4 times, and time of repose is confirmed as 30min, and therefore, the best experimental program that filters out is A
1B
3C
3, promptly the ethanol with 4 times of amounts 95% leaves standstill 30min.
[ethanol adds the checking of parameter] is used for preparation " Dioscorea nipponica bony spur tablet " with above-mentioned ethanol adding method, whether can satisfy the production needs of different prescription drugs with checking the present invention spray technology of coagulating.
Dioscorea nipponica bony spur tablet extractum with 1/5 prescription sprays in 1 times, 2 times, 3 times, 4 times, 5 times, 6 times 95% ethanol respectively, leaves standstill 30 minutes, separates out the dry weight of solid content after coagulating with spray, dried cream amount and both sums of supernatant is that evaluation index is estimated.Result of the test such as table 5:
Table 5
Can know by last table, when the consumption of etoh solvent reaches 4 times, the dry weight substantially constant of the solid content that spray is separated out after coagulating; Guaranteed the deposition molding of most of active ingredient, and be beneficial to the carrying out of follow-up granulation, when amount of ethanol more after a little while; Form semi-solid less coagulated in spray, and the extractum after the supernatant concentration is more, is unfavorable for pelletizing forming; Consider from the angle of energy savings, in experimentation, selected for use 4 times of solvents as optimal dose.
In each parameter that spray is coagulated, the relative density of extractum is not the major influence factors of experiment, and the pharmacy relative density is controlled at 1.20 with interior (60 ℃), all can guarantee good flowability, and spray is carried out with fixed attention smoothly.
Can know according to above result of the test; Chinese traditional medicine water extract is sprayed into 95% ethanol of 4 times of weight or volumes, leave standstill 30 minutes after, can greatly reduce the paste-forming rate in the extracting solution; Consider production cost and to the influence of later stage preparation, preferred 4 times of amount 95% ethanol; When spraying into the water extract, can adopt the sprayer unit of present commercially available routine, atomisation pressure is controlled at more than the 0.2MPa, fogdrop diameter is controlled at 200-500 μ m, all can reach good technical effect.
Below, specify the beneficial effect of the inventive method through comparison to the inventive method products obtained therefrom and existing product active constituent content, drug effect, processing parameter.
The comparison of Test Example 1 the inventive method preparation " BAZHEN KELI " and existing method
One, existing preparation technology (standard numbering: WS3-B-3130-98)
[prescription] Radix Codonopsis 60g Radix Paeoniae Alba (stir-fry) 60g Rhizoma Atractylodis Macrocephalae (stir-fry) 60g Radix Rehmanniae Preparata 90g
Poria 60g Radix Angelicae Sinensis 90g Rhizoma Chuanxiong 45g Radix Glycyrrhizae 30g
Eight distinguish the flavor of more than [method for making], and Radix Angelicae Sinensis, Rhizoma Chuanxiong, the Rhizoma Atractylodis Macrocephalae with 95% ethanol, 50% alcohol heating reflux respectively once each 2 hours, filter filtrating merging, recovery ethanol, filtration, filtrate for later use; Five tastes decocte with water secondaries such as medicinal residues and all the other Radix Codonopsis, each 1.5 hours, filter, filtrating merges, and adds above-mentioned reserve liquid, is condensed into thick paste.Get thick paste and add an amount of soluble starch and correctives, mixing is granulated, and drying is processed 300g, promptly gets.
Two, technology products obtained therefrom of the present invention and former particulate comparison
[active constituent content relatively]
" " content assaying method under carries out BAZHEN KELI with reference to 2010 editions Pharmacopoeias of the People's Republic of China (an one).
Instrument and equipment: U.S. DIONEX company auto injection high performance liquid chromatograph, UVD-170U detector, Chromeleon work station, quaternary pump; Welcohrom C18 chromatographic column (200mm * 4.6mm, 5 μ m); The automatic dual pure water distillator of SZ-93 (Shanghai Yarong Biochemical Instrument Plant); The letter CQ-250 supersound process ripple washer in Shanghai.
Reagent reagent: acetonitrile (chromatographically pure, TEDIDA COMPANY.INC); Triethylamine (analytical pure, the Long Huagongshijichang of Chengdu section); Phosphoric acid (analytical pure, the Long Huagongshijichang of Chengdu section); Methanol (analytical pure, the Long Huagongshijichang of Chengdu section); Redistilled water (self-control); The peoniflorin reference substance (Nat'l Pharmaceutical & Biological Products Control Institute, 110736-200828); BAZHEN KELI (self-control).
Chromatographic condition: with the C18 post is immobile phase, is mobile phase with acetonitrile-0.1% phosphoric acid solution-triethylamine (13: 87: 0.04); The detection wavelength is 230nm.Theoretical cam curve is no less than 3000 in peoniflorin.
The preparation of reference substance solution: get the peoniflorin reference substance, the accurate title, decide, and adds 50% methanol and process the solution that every 1ml contains 30.09 μ g, promptly gets.
The preparation of need testing solution: get former BAZHEN KELI and each 5g of self-control BAZHEN KELI, porphyrize, each accurate title, decided 0.5g, puts in the tool plug conical flask; The accurate 50% methanol 25ml that adds, close plug claims to decide weight, supersound process (120W; 59kHz) 30min is put coldly, claims to decide weight again, supplies the weight of loss with 50% methanol; Shake up, filter, get subsequent filtrate, promptly get.
Algoscopy: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject high performance liquid chromatograph, measure, promptly get.
Measure the result: the content that is respectively that records peoniflorin in 0.5g self-control granule and the source granule is 0.6339mg and 0.6347mg; Be that the homemade BAZHEN KELI paeoniflorin content of laboratory is 1.269mg/g; Both content is suitable, and every bag of 3.5g granule of the Sugarless type BAZHEN KELI paeoniflorin content that has reached the pharmacopeia regulation is no less than the requirement of 4.0mg.
[drug effect relatively]
BAZHEN KELI after utilizing former BAZHEN KELI and improving technology has carried out the main pharmacodynamics experiment to the peripheral hemogram and the spleen coefficient of blood deficiency mice induced by cyclophosphamide, investigates its drug effect difference to syndrome of deficiency of blood.Experimental result confirms that before and after the BAZHEN KELI process modification, its main pharmacodynamics does not have notable difference, and this has proved that the improvement of technology does not cause the change of main pharmacodynamics material base.
1, experiment material
1.1 animal KM mice (male and female half and half, 18～22g, cleaning level, the quality certification number: SCXK (river) 2004-15, purchase in Sichuan Academy of Medical Sciences institute of lab animals).
1.2 (pharmaceutical Co. Ltd of Sichuan standing grain nation provides the BAZHEN KELI that the reagent prior art makes; The accurate word Z51022270 of traditional Chinese medicines), the BAZHEN KELI that the inventive method makes (embodiment of the invention 1 prepares), batilol (20mg; The dark pharmaceutical Co. Ltd of Chongqing China, the accurate word H50021226 of traditional Chinese medicines); Cyclophosphamide for injection (0.2g, Hengrui Medicine Co., Ltd., Jiangsu Prov., the accurate word H32020857 of traditional Chinese medicines); Normal saline.
1.3 the full-automatic blood counting instrument of instrument (MEK-6318, Nihon Kohden Corporation); Electronic analytical balance (BP211D, Sartorius AG).
2, experimental technique
2.1 group technology is divided into 5 groups at random with 50 mices, is respectively blank control group, model group, BAZHEN KELI group, self-control BAZHEN KELI group, 10 every group.
2.2 administration and modeling method mice began the prospective adaptation environment 3 days in experiment, normally gave diet and water.The prevention gastric infusion is 3 days before modeling.All the other each groups were worked as daily weight intraperitoneal injection of cyclophosphamide 100mg/kgd-1 by mice, for three days on end except that the blank control group abdominal cavity gives the equal-volume normal saline in the 4th day.Continued gastric infusion 6 days the same day from modeling.
2.3 experimental technique is eye socket blood sampling in the 7th day after modeling, adopts full-automatic blood counting instrument to detect the peripheral blood conventional parameter, comprises leukocyte WBC number, erythrocyte RBC, and Hb H GB, platelet PLT gets spleen simultaneously and weighs, and calculates the spleen coefficient.
2.4 the statistical method experimental result adopts the SPSS13.0 statistical software to carry out one factor analysis of variance between many groups.
3, experimental result
BAZHEN KELI is seen table 6 with the self-control BAZHEN KELI to the influence that the caused by cyclophosphamide murine interleukin reduces disease peripheral hemogram and spleen coefficient.
Table 6 BAZHEN KELI and of the influence (
n=10) of self-control BAZHEN KELI to leukopenia mice peripheral hemogram and spleen coefficient
Compare with model group: * P＜0.05, * * P＜0.01; Compare with blank control group: △ P＜0.05, △ △ P＜0.01.
Mouse peritoneal injection cyclophosphamide can make PBL, erythrocyte, hemoglobin and platelet count obviously reduce, and the spleen coefficient obviously reduces, and with blank control group significant difference is arranged relatively.Compare with model group, BAZHEN KELI group, self-control BAZHEN KELI group and Batilol tablet be leukocyte increasing number, platelet count, raising spleen coefficient obviously.BAZHEN KELI has trend of rising with the self-control BAZHEN KELI to RBC number, but does not have significant difference.BAZHEN KELI, self-control BAZHEN KELI and Batilol tablet are little to the content of hemoglobin influence, and trend of rising is also only arranged.To sum up, BAZHEN KELI and homemade BAZHEN KELI do not have significant difference to the influence of caused by cyclophosphamide mice syndrome of deficiency of blood model.This has also proved the change that the improvement of technology does not bring main pharmacodynamics.
[parameter relatively]
Existing preparation technology of BAZHEN KELI and preparation technology's of the present invention relevant parameter compares, and the result sees table 7.
Table 7: existing preparation technology of BAZHEN KELI and preparation technology's of the present invention relevant parameter relatively
[conclusion]
The experimental result of assay and main pharmacodynamics shows that BAZHEN KELI takes spray to coagulate its effective substance of technology back not to be had to take place obviously to change, simultaneously; Solved the difficulty in process that the paste-forming rate height causes; Shorten the production cycle, improved production efficiency, reduced production cost.Proved that preparation technology of the present invention is feasible.
The comparison of Test Example 2 prepared of the present invention " Dioscorea nipponica bony spur tablet " and existing technology
One, existing preparation technology's (965 pages of 2010 editions Pharmacopoeias of the People's Republic of China (an one))
[prescription] Rhizoma Dioscoreae Nipponicae 270g Herba Epimedii 324g Rhizoma Cibotii 432g
Radix Cyathulae 432g Radix Rehmanniae Preparata 270g Fructus Lycii 162g
[method for making] above Six-element, Rhizoma Dioscoreae Nipponicae is pulverized, and it is subsequent use to get the 180g fine powder; Residue Rhizoma Dioscoreae Nipponicae powder is made solvent with 70% ethanol, carries out percolation, collects the about 600ml of percolate, and reclaiming ethanol and being concentrated into relative density is 1.20～1.25 (70 ℃); Five tastes decocte with water such as all the other Herba Epimedii three times, collecting decoction filters, and filtrating is concentrated into relative density 1.20-1.25 (70 ℃); Merge with Dioscorea nipponica Mak. Ningpo Yam Rhizome extract, be concentrated in right amount, with Rhizoma Dioscoreae Nipponicae fine powder mixing, granulate, drying is pressed into 1000, promptly gets.
Two, technology products obtained therefrom of the present invention and former comparison
[active constituent content relatively]
Content assaying method with reference under 2010 editions Pharmacopoeias of the People's Republic of China (an one) " Dioscorea nipponica bony spur tablet " item carries out.
Instrument and equipment: U.S. DIONEX company auto injection high performance liquid chromatograph, UVD-170U detector, Chromeleon work station, quaternary pump; Welcohrom C18 chromatographic column (200mm * 4.6mm, 5 μ m); The automatic dual pure water distillator of SZ-93 (Shanghai Yarong Biochemical Instrument Plant); The letter CQ-250 supersound process ripple washer in Shanghai.
Reagent reagent: acetonitrile (chromatographically pure, TEDIDA COMPANY.INC); Triethylamine (analytical pure, the Long Huagongshijichang of Chengdu section); Phosphoric acid (analytical pure, the Long Huagongshijichang of Chengdu section); Methanol (analytical pure, the Long Huagongshijichang of Chengdu section); Redistilled water (self-control); The diosgenin reference substance (Nat'l Pharmaceutical & Biological Products Control Institute, 110736-200828); Dioscorea nipponica bony spur tablet (embodiment 2 makes).
Chromatographic condition: with the C18 post is immobile phase, is mobile phase with acetonitrile-water (90: 10); The detection wavelength is 203nm.Theoretical cam curve is no less than 3000 in diosgenin.
The preparation of reference substance solution: get the diosgenin reference substance, the accurate title, decide, and adds mobile phase and process the solution that every 1ml contains 0.21mg, promptly gets.
The preparation of need testing solution: get original product and each 10 of self-control Dioscorea nipponica bony spur tablets respectively, porphyrize, the accurate title, decided 2.0g, puts in the tool plug conical flask, accurate methanol 50ml, the close plug of adding; Claim decide weight, reflux 1h is put coldly, and weight decided in title again, supplies the weight of loss with 5 methanol, shakes up; Filter, precision is measured subsequent filtrate 25ml, puts in the tool plug conical flask, and evaporate to dryness, residue add 3mol/L hydrochloric acid solution 20ml makes dissolving, reflux 1h; Take out, put coldly, extract 4 times each 25ml, merging chloroform liquid with the chloroform jolting; Reclaim solvent to doing, residue adds mobile mutual-assistance dissolving and is transferred in the 25ml volumetric flask, adds mobile phase to scale, shakes up, and promptly gets.
Algoscopy: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject high performance liquid chromatograph, measure, promptly get.
Measure the result: the content that records diosgenin in the 2g self-control tablet is 5.232mg; Diosgenin content is 5.018mg in the 2g Dioscorea nipponica bony spur tablet; Be that the homemade Dioscorea nipponica bony spur tablet of laboratory diosgenin content is 2.616mg/g; Be converted to every and contain diosgenin 1.308mg, both content is suitable, and every of the Dioscorea nipponica bony spur tablet that has reached the pharmacopeia regulation contains the requirement that diosgenin is no less than 1.0mg.
[drug effect relatively]
Utilize former Dioscorea nipponica bony spur tablet and improve Dioscorea nipponica bony spur tablet after the technology and main pharmacodynamics has been carried out contrast investigate, comprise to glacial acetic acid cause influence that mouse writhing reacts, diagonal angle again dish glue cause the influence of rat paw edema, to the influence of stasis syndrome rat model WBV, plasma viscosity and packed cell volume and to the effect of rabbit experiment property knee hyperplasia.Experimental result confirms that before and after the Dioscorea nipponica bony spur tablet process modification, its main pharmacodynamics does not have notable difference, and this has proved that the improvement of technology does not cause the change of main pharmacodynamics material base.
1, experiment material
1.1 animal KM mice (male and female half and half, 18～22g, cleaning level, the quality certification number: SCXK (river) 2004-15, purchase in Sichuan Academy of Medical Sciences institute of lab animals).The SD rat (male and female half and half, 180～220g, cleaning level, the quality certification number: SCXK (river) 2004-15, purchase in Sichuan Academy of Medical Sciences institute of lab animals).Japan large ear rabbit (1.6～2.0kg, regular grade are purchased the Experimental Animal Center in Chengdu University of Traditional Chinese Medicine).
1.2 the Dioscorea nipponica bony spur tablet that the reagent prior art makes (pharmaceutical Co. Ltd of Sichuan standing grain nation provides, the accurate word Z51021346 of traditional Chinese medicines), the Dioscorea nipponica bony spur tablet that the inventive method makes (embodiment 2 makes), Aspirin Enteric-coated Tablets (25mg/ sheet; Taiyuan, Shanxi Province Jin Yang pharmaceutical factory, the accurate word H14023041 of traditional Chinese medicines), Rotundine Tablets (60mg/ sheet, Ha Gaoke Jiamusi Chinese medicine company limited; The accurate word H23022282 of traditional Chinese medicines), prednisone acetate tablets (5mg/ sheet, Beijing Kangdini Pharmaceutical Co., Ltd., the accurate word H20058375 of traditional Chinese medicines); Anti-bone regeneration sheet (every substrate 0.3g, Tonghua Golden Horse Pharmaceutical Group Plc, 20053070), glacial acetic acid (Long Huagongshijichang of Chengdu section); Carrageenin (Sigma company), heparin sodium (Sigma company), epinephrine (1ml: 1mg; Kunming Medicine Group Stock Co., Ltd, the accurate word H53020781 of traditional Chinese medicines), pentobarbital sodium (happy reagent company limited is thought in Guangzhou); Penicillin sodium (4.8g (8,000,000 unit), Sichuan Pharmaceutical, Inc., the accurate word 20066128 of traditional Chinese medicines); Paraformaldehyde (Nanjing state chemical plant in morning), paraffin, normal saline.
1.3 the instrument stopwatch, tape, LG-R-20 type blood viscosity tester (Beijing Steellex Scientific Instrument Company), microscope (Shanghai cosmos pediment is learned instrument plant).
2, experimental technique and result
2.1 glacial acetic acid is caused the influence of mouse writhing reaction
40 male and female half and half of KM mice cleaning level, body weight 18～22g at random, divide equally 4 groups (n=10), the Dioscorea nipponica bony spur tablet 10g/kg that prior art makes, the Dioscorea nipponica bony spur tablet 10g/kg that the inventive method makes, rotundine 30mg/kg group and normal saline matched group.Drug group is administered once every day; Successive administration 5 days; Matched group is then irritated the isopyknic normal saline of stomach; 1 hour every Mus lumbar injection 0.7% glacial acetic acid 0.2ml/ Mus after the last administration, after 5 minutes with mice in the stopwatch record 10 minutes turn round the body number of times, the result is with the significance of t inspection statistics group difference.The result sees table 8.
Table 8 Dioscorea nipponica bony spur tablet causes the influence (
n=10) of mouse writhing reaction to glacial acetic acid
Compare with the normal saline matched group,
※P＜0.05,
※ ※P＜0.01
Compare with the normal saline matched group, what Dioscorea nipponica bony spur tablet, self-control Dioscorea nipponica bony spur tablet and rotundine all can reduce mice turns round the body number of times, and rotundine group effect is best, the Dioscorea nipponica bony spur tablet with make Dioscorea nipponica bony spur tablet effect by oneself and do not have significant difference.
2.2 diagonal angle dish glue again causes the influence of rat paw edema
The SD rat, 40, body weight 150～200g, male and female half and half are divided equally 4 groups (n=10) at random.Dioscorea nipponica bony spur tablet 10g/kg, self-control Dioscorea nipponica bony spur tablet 10g/kg, prednisolone acetate 25mg/kg and normal saline matched group.Drug group is administered once every day; Successive administration 7 days; Matched group is then irritated the isopyknic normal saline of stomach, causes scorching before measurement normal value once, promptly causes inflammation every Mus right hind foot sole of the foot SCI% carrageenin 0.1ml/ Mus after the last administration; With 1,2,3,4,5 hour pedal swelling degree behind the special transparent tape survey medicine, by formula calculate swelling rate and suppression ratio then.Experimental result is with the significance of t check comparable group differences.The result sees table 9.
Table 9 Dioscorea nipponica bony spur tablet on Carrageenan causes the influence (
n=10) of rat paw edema
Compare with the normal saline matched group,
※ ※P＜0.01
Compare with the normal saline matched group, Dioscorea nipponica bony spur tablet, self-control Dioscorea nipponica bony spur tablet and prednisolone acetate all can significantly suppress carrageenin and cause rat paw edema.Dioscorea nipponica bony spur tablet and homemade Dioscorea nipponica bony spur tablet do not have significant significant difference.
2.3 influence to stasis syndrome rat model WBV and plasma viscosity
50 of SD rats, body weight 150～200g male and female half and half, be divided into 5 groups at random.Dioscorea nipponica bony spur tablet 10g/kg, self-control Dioscorea nipponica bony spur tablet 10g/kg, aspirin 50mg/kg, blank group and model group.Drug group gastric infusion every day once, successive administration 7 days.Blank group and model group are then irritated clothes equal-volume normal saline, except that the normal control group, and all the other each groups all after the last administration 1 hour; The epinephrine 0.08ml/100g Mus of subcutaneous injection 1mg/ml, totally 2 times, 2 minor ticks 4 hours; Rat is immersed frozen water caused the stasis syndrome model in 5 minutes for the second time injecting between the epinephrine (front and back 2 hours at interval), the rat femoral blood of not anaesthetizing is got in fasting after the modeling the next morning; Blood is used the heparin sodium anticoagulant; From 3ml anticoagulant blood, get 0.8ml and be used for WBV mensuration, surplus blood is got the mensuration that supernatant 0.8ml is used for plasma viscosity in 650 centrifugal 10min; Test instrunment is a LG-R-20 type blood viscosity tester, and experimental result is with the significance of t check comparable group differences.Experimental result is seen table 10.
Table 10 Dioscorea nipponica bony spur tablet is to the influence (
n=10) of syndrome of blood stasis rat blood viscosity
Compare with model group,
※P＜0.05
Compare with model group, Dioscorea nipponica bony spur tablet, self-control Dioscorea nipponica bony spur tablet and aspirin are all cut under the speed in difference the whole blood viscosity of syndrome of blood stasis rat all has the trend that is lower than matched group, and each group is starkly lower than model group when low shear rate.Aspirin is in the various whole blood viscosity that all can reduce rat under the speed of cutting.Each group is not seen notable difference to plasma viscosity.Dioscorea nipponica bony spur tablet and homemade Dioscorea nipponica bony spur tablet are all close at various WBV and the plasma viscosities of cutting under the speed, do not have significant difference.
2.4 effect to rabbit experiment property knee hyperplasia
20 of Japan big-ear white rabbits, body weight 1.5～2.0kg, female dual-purpose.Model production method: after every rabbit ear edge intravenous injection pentobarbital sodium 31mg/kg anesthesia; Be fixed on the operating-table; Select under the left knee joint aseptic condition and perform a surgical operation, layer-by-layer suture otch after excising medial meniscus and cutting off MCL, postoperative rabbit sub-cage rearing; And divide equally 4 groups (n=5) at random by male and female, body weight, i.e. model group, anti-bone regeneration sheet 5g/kg group, Dioscorea nipponica bony spur tablet 5g/kg group, self-control Dioscorea nipponica bony spur tablet 5g/kg group.Intramuscular injection penicillin sodium 400,000 units/only, prevent wound infection are respectively organized for three days on end in operation.Medicine respectively organize every day gastric infusion once, 8 weeks of successive administration.Model group is then irritated stomach equal-volume distilled water; After the last administration 2 hours; Carotid artery sacrificed by exsanguination animal is dissected knee joint immediately, puts in the 10% formaldehyde normal saline fixing, paraffin embedding, section, HE dyeing, light microscopic and observes cartilage down and change situation; With the scoring of cartilage proliferation degree, and evaluate damage.Each treated animal adopts reference differential technique statistical analysis according to the standards of grading integration.The cartilage proliferation standards of grading: osteosclerosis (IV degree) note 4 minutes appears that the fubril pencil becomes that (II degree) note 2 minutes, the obvious fiber bundle-like of cartilage become that (III degree) note 3 minutes, abrasiveness fiber bundle-like become that companion's cartilage exposes and in softening but level and smooth (I degree) note 1 minute of cartilage surface, cartilage attenuation.Experimental result is seen table 11.
Table 11 Dioscorea nipponica bony spur tablet is to the influence of rabbit experiment property knee hyperplasia
Compare with model group,
※ ※P＜0.01
Compare with model group, Dioscorea nipponica bony spur tablet, self-control Dioscorea nipponica bony spur tablet and anti-bone regeneration sheet all have obvious inhibitory action to rabbit experiment property knee hyperplasia.The Dioscorea nipponica bony spur tablet is close to the antagonism of rabbit experiment property knee hyperplasia with homemade Dioscorea nipponica bony spur tablet, does not have significant difference.
[parameter relatively]
Existing preparation technology of Dioscorea nipponica bony spur tablet and preparation technology's of the present invention relevant parameter compares, and the result sees table 12.
Table 12: existing preparation technology of Dioscorea nipponica bony spur tablet and preparation technology's of the present invention relevant parameter relatively
The experimental result of [conclusion] assay and main pharmacodynamics shows that the Dioscorea nipponica bony spur tablet takes spray to coagulate its effective substance of technology back not to be had to take place obviously to change, simultaneously; Solved the difficulty in process that the paste-forming rate height causes; Shorten the production cycle, improved production efficiency, reduced production cost.Proved that preparation technology of the present invention is feasible.
At present in conventional Chinese medicine material and compound recipe water or the low concentration alcohol extract; Be rich in compositions such as polysaccharide, tannin, lymphatic temperament, pectin, natural gum, protein, for the later stage preparation has brought inconvenience, technology of the present invention does not adopt the remove impurity operation to above-mentioned water or low concentration alcohol extract; All effective ingredient of medical material have been kept; On the basis that has guaranteed former preparation drug effect, solved the bigger problem of paste volume in the existing Chinese medicine preparation, reduced the use amount of adjuvant in the moulding process; Also shorten the production cycle of preparation finished product simultaneously, greatly practiced thrift production cost.
Claims (10)
1. method of before preparation, Chinese medicine extraction liquid being handled, it is characterized in that: it comprises the following steps:
A, get Chinese medicine extraction liquid and mix, leave standstill, separate obtaining solid content and supernatant with the effective ingredient poor solvent of 1～10 times of weight or volume;
B, the supernatant concentration of a step is processed clear paste, collect solid content and clear paste;
Described Chinese medicine extraction liquid is middle liquid medicine or aquiferous ethanol extracting solution, and wherein, the concentration of alcohol of described aquiferous ethanol extracting solution is greater than 0, is less than or equal to 50%v/v;
Described effective ingredient poor solvent is ethanol, ethyl acetate or n-butyl alcohol, and wherein, ethanol is 95%v/v ethanol.
2. method according to claim 1 is characterized in that: the relative density of described Chinese medicine extraction liquid is 1.05～1.20.
3. method according to claim 1 is characterized in that: the described hybrid mode of a step is: Chinese medicine extraction liquid is sprayed in the effective ingredient poor solvent of 1～10 times of weight or volume.
4. method according to claim 3 is characterized in that: the described method of spraying into is to use conventional sprayer unit, and atomisation pressure is not less than 0.2MPa, and fogdrop diameter is 200-500 μ m.
5. method according to claim 1 is characterized in that: the described hybrid mode of a step is: the effective ingredient poor solvent that extracting solution is slowly added 1～10 times of weight or volume.
6. method according to claim 1 is characterized in that: the described hybrid mode of a step is: the effective ingredient poor solvent is slowly added extracting solution.
7. method according to claim 1 is characterized in that: the described time of repose of a step is 30min～2hr.
8. the method for preparing of a Chinese medicine preparation; It is that solid content with any preparation of claim 1-7 mixes with the adjuvant of preparation prescription, after the pulverizing, adds wet granulator and stirs 1～5min; Add heat when surveying relative density be that 1.2～1.5 clear paste is done binding agent system soft material; Soft material put on the oscillating granulator granulate, behind the fluid bed drying, further be prepared into oral formulations commonly used again.
9. the method for preparing of a Chinese medicine preparation; It is that solid content with any preparation of claim 1-7 mixes with the adjuvant of preparation prescription and pulverizes the back and add one-step-granulating method; Dry 10～the 30min of ventilation, relative density is 1.05～1.30 clear paste fluidized granulation when adding the heat survey, after spraying is accomplished; Behind dry 30～60min, further be prepared into oral formulations commonly used again.
10. the method for preparing of a Chinese medicine preparation, it is that solid content with any preparation of claim 1-7 mixes with an amount of adjuvant and pulverizes after drying and promptly get subsequent use powder; When heat is surveyed after the clear paste spray drying of relative density 1.05～1.30, promptly get the dried cream powder of prescription drug, further be prepared into oral formulations commonly used again with subsequent use powder mixes.
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