CN100534469C - Fupo cold granules and preparation method thereof - Google Patents
Fupo cold granules and preparation method thereof Download PDFInfo
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- CN100534469C CN100534469C CNB2007100872128A CN200710087212A CN100534469C CN 100534469 C CN100534469 C CN 100534469C CN B2007100872128 A CNB2007100872128 A CN B2007100872128A CN 200710087212 A CN200710087212 A CN 200710087212A CN 100534469 C CN100534469 C CN 100534469C
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Abstract
The invention discloses producing method of fupoganmao gapsule and the quality control method, which has the cotton rose hibiscus leaf, houpu, dried old orange peel, great burdock achene (fried). The process includes: extracting the naphtha from the dried old orange peel, decocting the dried old orange peel dregs, cotton rose hibiscus leaf, houpu, great burdock achene (fried) in the water, combining the decocting liquid, decompressing and concentrating, depositing by the ethanol, placing, recovering the ethanol, concentrating to the dense cream, making the dense cream and proper amount of accessory to the grains. The inventive fupoganmao gapsule improves the disadvantages in the former craft and has a reliable product quality, a high reservation ratio of the effective component, an obvious curative effect, a high production efficiency, a reasonable producing method and quality control method thereof.
Description
Technical field
What the present invention relates to is that a kind of treatment wind heat or wind heat are held wet flu Chinese patent medicine and preparation method thereof under the arm, and referring in particular to a kind of is the granule that raw material is made with Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Pericarpium Citri Reticulatae, Fructus Arctii, belongs to technical field of traditional Chinese medicine pharmacy.
Background technology
The Chinese medicine Folium Hibisci Mutabilis is the dried leaves of Malvaceae plant Hibisci Mutabilis Hibiscus mutabilis L. or polyphyll Hibisci Mutabilis Hibiscus mutabilis L.cv.Plenus, Cortex Magnoliae Officinalis is dry dried bark, root bark and the branch skin of Magnoliacea plant Cortex Magnoliae Officinalis or magnolia officinalis rehd.et wils.var.biloba rehd.et wils., Pericarpium Citri Reticulatae is the dry mature skin of rutaceae orange Citrus reticulata Blanco and variety thereof, and Fructus Arctii is the dry mature fruit of feverfew Fructus Arctii Arctium lap L..By above-mentioned four Fupoganmao particles formed of flavor compatibilities, have the function that heat-clearing and toxic substances removing, lung qi dispersing sore-throat relieving, alleviating distention in middle-JIAO are regulated the flow of vital energy, cure mainly Chinese medical discrimination and belong to wind heat or wind heat folder wet the catch a cold fever and headache, pharyngalgia, limb aching pain, nasal obstruction, the stomach poor appetite that cause and disease such as move back.
The Fupoganmao electuary is the new drug of my the company's research and development eighties, come from distinguished veteran doctors of TCM Wu scholar unit clinical proved recipe for many years, because prevailing condition is limit, its preparation technology fall behind (adopt that uncovered normal pressure concentrates, wet granulation, thermal cycle oven drying, its complex procedures, production cycle are long, the active ingredient loss is big, and quality control index is low, does not have discriminating and contains the survey project).Produce so far from approval, its prescription and method for making all are not disclosed.
On the basis of Fupoganmao electuary, researched and developed Fupoganmao capsule (producing without competition so far) in 1993, now close at Chinese patent medicine ministry standard (standard numbering WS
3-B-2896-98), because it is full extractum preparation, the easy moisture absorption, shelf-life short (room temperature storage 3 months was moisture absorption degeneration), and when concentrated uncovered normal pressure, still adopt the wet granulation drying, extractum is concentrated into 1.35～1.40 (energy consumption is big), extractum bake out temperature height, drying time are long, and it is more that active ingredient such as magnolol is destroyed, and influences its clinical efficacy.Owing to have above-mentioned deficiency, do not have market sale for many years.
It is the application of 03141807.4 relevant Fupoganmao medicine that the applicant has also submitted a application number on July 22nd, 2003, but because this technical scheme and immature itself, also there are many deficiencies, the applicant proceeds research and inquirement on this basis, found under the situation of taking same preparation method, the optimal parameter selection of each step is confirmed in research by experiment, no matter has all obtained good effect on the product that preparation process still makes.
Fupoganmao particle preparation method of the present invention has been improved the deficiency of existing Fupoganmao process for preparing medicine, not only prolonged the medicine that makes shelf-life, improved its bioavailability, and forming temperature is low, drying time short in the whole process of preparation, active ingredient is lost less, the production efficiency height, is beneficial to very much the big production of industry.
Summary of the invention
It is raw material with Chinese crude drug Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Pericarpium Citri Reticulatae, Fructus Arctii (stir-fry) that the object of the invention is to provide a kind of, further investigate and innovate at the capsular technology of preparing of original Fupoganmao, product quality, clinical efficacy and production efficiency are improved significantly.
The present invention is implemented by following scheme.
One aspect of the present invention provides a kind of preparation method of Fupoganmao particle agent, it is characterized in that preparation method comprises the following steps:
(1) gets raw material: Folium Hibisci Mutabilis 900g, Cortex Magnoliae Officinalis 150g, Pericarpium Citri Reticulatae 250g, Fructus Arctii (parched) 250g;
(2) get Pericarpium Citri Reticulatae, extract volatile oil, steam pressure is controlled at 0.05～0.10MP when extracting volatile oil, adds 2～4 times water by weight, extracts 3～5 hours, and the volatile oil of acquisition is standby;
(3) Pericarpium Citri Reticulatae residue and Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Fructus Arctii (parched) are decocted with water secondary, for the first time add by weight that 4～8 times decocting boiled 2 hours, add by weight 3～6 times water 1 for the second time and decoct hour, collecting decoction filters, and concentrates, cooling adds 2 times of amount ethanol, leaves standstill 24 hours;
(4) get supernatant and reclaim ethanol, be condensed into extractum;
(5) get above-mentioned extractum and an amount of sucrose or the spray-dried granulation of brown sugar (Saccharum Sinensis Roxb.) or wet granulation process and make granule, sprayed into the Oleum Citri Reticulatae moistening 4～8 hours, that is,
Wherein in the spray-drying process method of step (5), temperature of charge is 55～65 ℃, and atomisation pressure is 1.0～3.0bar, and the binding agent flow is 5～8Hz; In the wet granulation process, get extractum, make granule, in 50～80 ℃ of oven dry with granulator with the Icing Sugar mixing.
The optional feature of in this preparation method other has:
Wherein, the described decompressed concentrate of step (3), being concentrated into 50 ℃ of survey relative densities is 1.10～1.30.
Wherein, the relative density of the described extractum of step (4) is 80 ℃ of surveys 1.02～1.30.
The Fupoganmao particle that the present invention provides a kind of above-mentioned preparation method to make on the other hand.
The present invention also provides a kind of quality control method of above-mentioned Fupoganmao particle, comprising:
(1) the Pericarpium Citri Reticulatae thin layer is differentiated:
Get this product 30g, add hot water 40ml and make dissolving, put coldly, extract 2 times with 60 ~ 90 ℃ petroleum ether joltings, each 20ml, merge extractive liquid,, water 10ml washing discards water liquid, petroleum ether liquid evaporate to dryness, residue add 60 ~ 90 ℃ petroleum ether 1ml makes dissolving, as need testing solution.Other gets Pericarpium Citri Reticulatae control medicinal material 0.3g, adds 60 ~ 90 ℃ petroleum ether 10ml, and supersound process 10 minutes filters, and filtrate evaporate to dryness, residue add 60 ~ 90 ℃ petroleum ether 1ml makes dissolving, in contrast medical material solution.According to the thin layer chromatography test,, draw need testing solution 10 μ l, control medicinal material solution 2 μ l referring to an appendix VI of Chinese Pharmacopoeia version in 2005 B, put respectively on same silica gel g thin-layer plate, with benzene-acetone is developing solvent at 10: 2, launches, and takes out, dry, spray is put ultra-violet lamp and is inspected under 365nm, in the test sample chromatograph with 5% aluminum chloride alcoholic solution, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
(2) the Fructus Arctii thin layer is differentiated:
Get this product 30g, add methanol 60ml, supersound process 30 minutes filters, and filtrate is put on the neutral alumina post of having handled well, the condition of post is 100 ~ 200 orders, 5g, internal diameter 10 ~ 15mm, with 40% methanol 50ml eluting, collect eluent, put evaporate to dryness in the water-bath, residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the arctigenin reference substance, adds methanol and makes the solution that every 1ml contains 3mg, in contrast product solution.Test according to thin layer chromatography, referring to appendix VIB of Chinese Pharmacopoeia version in 2005, draw need testing solution 2 μ l, reference substance solution 6 μ l, put respectively on same silica GF254 lamellae, with lower floor's solution of 15: 4: 1 of chloroform-methanol-water is developing solvent, launches, and takes out, dry, put ultra-violet lamp and under 254nm, inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color; Spray with 10% ethanol solution of sulfuric acid, it is clear to be heated to speckle colour developing in 110 ℃ again.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(3) arctigenin content assaying method
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Acetonitrile-water is a mobile phase at 30: 70; The detection wavelength is 280nm, and number of theoretical plate calculates by the arctigenin peak should be not less than 5000;
The preparation of reference substance solution: it is an amount of that precision takes by weighing in phosphorus pentoxide desiccator 24 hours arctigenin reference substance of drying under reduced pressure, makes the solution that every 1ml contains 0.25mg with methanol, promptly;
The preparation of need testing solution: get this product 1g, the accurate title, decide, and puts in the conical flask.The accurate methanol 10ml that adds, it is fixed to claim.Supersound process 20 minutes is put and is chilled to room temperature and claims surely again, supplies the weight that subtracts mistake with methanol.Shake up, filter.Get subsequent filtrate, with the microporous filter membrane filtration of 0.45 μ m, promptly;
Algoscopy: the accurate reference substance solution 5 μ l that draw, need testing solution 5 ~ 10 μ l inject chromatograph of liquid, measure, and calculate, promptly.
The preparation method of Fupoganmao particle of the present invention has been improved the deficiency of existing Fupoganmao process for preparing medicine, the optimal parameter selection of each step is confirmed in research by experiment, not only prolonged the medicine that makes shelf-life, improved its bioavailability, and forming temperature is low, drying time short in the whole process of preparation, active ingredient is lost less, the production efficiency height, is beneficial to very much the big production of industry.
Because the capsular preparation method of Fupoganmao that drug standard is announced and application number are that the preparation method of putting down in writing in the patent application of 03141807.4 relevant Fupoganmao medicine is basic identical, so be referred to as former technology, simultaneously preparation method of the present invention be called new technology.Though new technology is the research of on the basis of former technology the method for the parameter of each step and use being carried out, but our effort and constantly trial have been passed through, find that some specific parameter will make whole preparation method more optimize, be more suitable for commercial production in each step, the product that makes simultaneously has long shelf-life, advantage that bioavailability is high.
To pharmacodynamics and the clinical comparative study that we did be described below, prove that new technology is better than former technology, the product that new technology makes also is better than the product that former technology makes, and concrete condition is as follows, at first is that the innovation performance of new technology is as follows:
1, granulates with spray drying method
Spray drying method (one-step palletizing) is a kind of novel granulating process technology that spray drying technology and fluidization are combined as a whole, binding agent (Chinese medical concrete) is atomized into fine drop from nozzle under compressed-air actuated effect, be sprayed on the powder that is fluidized state in the fluidized bed granulation chamber, make it glued agglomerating, make granule.In the former technology and the concrete grammar of unmatchful granulation describe, we find that in numerous granulations spray drying method is granulated and are best suited for, therefore, have selected this method.Conventional use be wet granulation, we contrast it.
One-step palletizing and wet granulation ratio have following advantage:
A, granule molten loose fast, no breeze: need not stir, can in 1min, dissolve automatically, and be uniformly dispersed;
B, with short production cycle: wet granulation needed more than 72 hours, and adopted one-step palletizing only to need 3 hours;
C, production capacity are big, the automaticity height;
Granulate is polluted less, be need not to D, process.
2, improved the extract dry method, the concrete parameter in the dry run has been carried out preferably.
Former technology is used Steam Heating volatilization moisture, baking temperature height (more than 80 ℃), and drying time long (needing more than 72 hours), active ingredient losses such as magnolol, Arctiin, Folium Hibisci Mutabilis total flavones are big, and productivity ratio is imitated low.
New technology is used spray drying, baking temperature low (below 60 ℃), and drying time short (only needing 3 hours), the active ingredient relative loss factor is few, and productivity ratio is imitated high.
3, substitute normal pressure with concentrating under reduced pressure and concentrate, the concrete parameter in the concentration process is carried out preferably.
Former process using normal pressure concentrates (100 ℃ of temperature), and it is more than 1.35 that technological requirement is concentrated into relative density, is unfavorable for that active ingredient keeps, operative employee's duration, and productivity ratio is imitated low.
New technology adopts triple effect energy-saving pressure-reduction concentration technology, thickening temperature low (under vacuum condition, the medicinal liquid boiling point is lower than 65 ℃), and weak point consuming time (concentration time shortens 3～5 times), the active ingredient loss is few, energy savings, productivity ratio is imitated high.
4, adjuvant is selected rationally
The product that former technology makes is full extractum preparation, is adjuvant with amount of starch only, and its resistance to water soak is poor; Having selected brown sugar (Saccharum Sinensis Roxb.) in the new technology for use is adjuvant, and mouthfeel is good, the flu treatment for diseases is had synergism.Taking granule must use water dissolution, moisturizes additionally to be beneficial to that sb.'s illness took a favorable turn.
5, concentrate the control of density
The density of extractum is concentrated into and is used for drying more than 1.35 in the former technology, and the density of extractum only need be controlled at 1.02～1.30 and gets final product in the new technology, is preferably 1.15～1.20.This helps energy savings, minimizing active ingredient loss and enhances productivity.
6, increased and differentiate and contain the survey project
Have only the routine examination of character and capsule in the quality standard of drug standard, be unfavorable for controlling product quality; The present invention has increased Pericarpium Citri Reticulatae and the Fructus Arctii thin layer is differentiated, has increased Arctiin HPLC and has contained the survey item.
For verify granule that new technology of the present invention makes have steady quality, evident in efficacy, technology is reasonable, the applicant has carried out series of experimental research, and is specific as follows:
1. the particulate stability and the granular mass comparative study that make of the granule that makes of new technology and former technology
Adopt the accelerated stability test method, the steadiness of granule under experiment condition that granule that the investigation new technology makes and former technology make.Under the accelerated test condition, preserve (40 ℃ ± 2 ℃ of temperature, 75% ± 5%RH), examine its character, moisture and Arctiin content January, February, March, June.The result shows: the easy moisture absorption degeneration of the granule that former technology makes (seeing Table 1.1), the granular mass that new technology makes excellent (seeing Table 1.2).
The granule stability comparative study that granule that table 1.1 new technology makes and former technology make
The granular mass comparative study that granule that table 1.2 new technology makes and former technology make
2. new technology and former technology are to the comparison of magnolol content and production efficiency
Get Folium Hibisci Mutabilis 90kg, Cortex Magnoliae Officinalis 15kg, Pericarpium Citri Reticulatae 25kg, Fructus Arctii (stir-fry) 25kg, make thick paste, get 1/5 oven dry (former technology), get 4/5 spray drying (new technology), relatively both magnolol content rates of transform by technology.The result shows: the new technology magnolol content rate of transform higher (seeing Table 2.1), and with short production cycle, less energy consumption (seeing Table 2.2).
Table 2.1 new technology and former process forming technology are to the influence of magnolol content
The comparison of table 2.2 new technology and former process forming explained hereafter efficient
3. the pharmacodynamic study of new technology and former technology relatively
3.1 separate heat test
Get 50 of rats, body weight 80 ± 10g, male and female half and half.Laboratory temperature is 24 ± 1 ℃.Tested preceding 2 days, respectively survey body temperature once morning and afternoon every day, rejects the body temperature that records for the first time, and experiment day surveys once as stated above again, the body temperature fluctuation is rejected the rat more than 0.3 ℃, with the meansigma methods of four body temperature as basal body temperature.After measuring basal body temperature, be divided into five groups at random by body temperature, in subcutaneous injection 15% fresh yeast normal saline suspension 1ml/100g pyrogenicity on same day experiment day, and press table 3 dosage gastric infusion respectively simultaneously, the administration volume is 1.5ml/100g.Negative control group is given equal-volume water, and the granule that granule that new technology makes and former technology make divides height two kinds of dosage, 0.5,1,2,4,6,8,10 and 12 hour body temperature after the mensuration administration.The result shows: the rat fever that the granule that new technology makes causes yeast has tangible refrigeration function, and is better than the granule (seeing Table 3.1) that former technology makes.
The analgesic experiment of granule that granule that table 3.1 new technology makes and former technology make (unit: ℃, n=10, X ± SD)
Annotate: compare * * * P＜0.001**P＜0.01*P＜0.05 with matched group
Analgesic test 3.2 (hot plate method)
Get female 60 of mice, each one is placed on the hot plate (in advance with hot plate temperature transfer at 55 ± 1 ℃), and mice is from being placed on the hot plate to the pain threshold of metapedes required time (second) as this Mus occurring licking, i.e. response latency bitterly.Allly lick the metapedes time less than 5 seconds or give it up greater than 30 seconds or leaper.Qualified mice is divided into 5 groups at random, repeats to survey its normal pain threshold, the meansigma methods of getting two subnormal pain thresholds is as the pain threshold before this Mus administration (pain response latency).Pressed table 3 in preceding 16 hours in experiment, 2 dosage are administered once earlier, and experiment day is administered once again, and the administration volume is 0.15ml/10g.30min, 60min, 90min survey the pain threshold (pain response latency) of mice respectively after administration.Still reactionless as 60 seconds, mice is taken out, in order to avoid scald, calculated with 60 seconds its threshold of pain.The result shows: the granule that new technology makes causes pain to hot plate analgesic activity preferably, and is better than the granule (seeing Table 3.2) that former technology makes.
The granule that granule that table 3.2 new technology makes and former technology make to the analgesia of mice influence (X ± SD, n=10)
Annotate: compare with matched group
*P＜0.01
*P＜0.05
3.3 antiinflammatory test (rat paw edema method)
Get 50 of SD rats, body weight 135 ± 25g is divided into five groups at random, and 10 every group, press table 3.3 dosage gastric infusion, matched group is given the equal-volume normal saline.The administration volume is 1.5ml/100g, experiment proxima luce (prox. luc) be administered once earlier (Pm17:00), after testing the volume of the right back sufficient sole of the foot of daily capillary tube measurement by magnification method survey rat, be administered once again, after the administration 30 minutes, right back sufficient plantar subcutaneous injection 10% fresh albumen 0.06ml/ only caused inflammation in rat, measured right back sufficient sole of the foot volume in 0.5,1,2,4,6 hour respectively at causing scorching back, with administration front foot sole of the foot volume ratio, calculate swelling degree (administration metapedes sole of the foot volume-administration front foot sole of the foot volume).The result shows: the granule that new technology makes has significant inhibitory effect to the rat paw inflammation that Ovum Gallus domesticus album causes, and is better than the granule (seeing Table 3.3) that former technology makes.
The granule that granule that table 3.3 new technology makes and former technology make to Ovum Gallus domesticus album cause rat paw edema influence (X ± SD, n=10)
Annotate: compare with matched group,
* *P＜0.001
*P＜0.01
*P＜0.05
4. the clinical comparison of granule (matched group) that makes of the granule (test group) that makes of new technology and former technology
4.1 physical data: select all Chinese medical discriminations that meets to belong to that wind heat or wind heat are held wet flu under the arm, Western medicine diagnose is patient's 100 examples of upper respiratory tract infection, wherein test group 50 examples, matched group 50 examples.Each organizes that situations such as the state of an illness (syndrome integrated value) before the sex, age, treatment, TCM Syndrome Type see Table 4.1 more respectively, table 4.2, table 4.3, table 4.4, table 4.5.
Table 4.1 liang group sex situation relatively
Two groups of age distribution situations of table 4..2 comparison sheet
The state of an illness (syndrome integrated value) comparison sheet before two groups of treatments of table 4..3
Table 4.4 liang group TCM Syndrome Type distribution comparison sheet
The result shows: situations such as the state of an illness (syndrome integrated value), TCM Syndrome Type before the sex of each group, age, the treatment, compare with matched group respectively, and no significant difference has comparability (P＞0.05).
4.2 result of the test
In test group 50 examples, clinical recovery 11 examples (22.0%), produce effects 26 examples (52.0%), effective 11 examples (22.0%), invalid 2 examples (4.0%), total obvious effective rate is 74.0%, total effective rate is 96.0%.
Integration changes relatively before and after each the symptom and sign treatment of table 4.5 test group
The result shows: each symptom integral of treatment back all has highly significant decline, P＜0.05～0.01.
In matched group 50 examples, clinical recovery 8 examples (16.0%), produce effects 10 examples (20.0%), effective 23 examples (46.0%), invalid 9 examples (18.0%), total obvious effective rate is 36.0%, total effective rate is 82.0%.
Integration changes relatively before and after each the symptom and sign treatment of table 4.6 matched group
The result shows: treatment back each symptom (except the feeling of oppression over the chest and nausea) integration all has highly significant decline, P＜0.05～0.01.
4.3 two groups relatively
Table 4.7 liang group general curative effect
The result shows: two groups of general curative effects have significant difference, P＜0.05 through the Ridit check.
4.4 safety evaluatio
Test group 5 routine patients make security inspections such as blood, urine, stool routine, hepatic and renal function and electrocardiogram respectively before and after treatment, the result shows: show no obvious abnormalities change, zero difference (P＞0.05) before and after the treatment.
Table 4.8 safety indexes testing result
5. the research of new preparation process
5.1 Pericarpium Citri Reticulatae is carried the amount of water of volatile oil, and jar internal pressure control and extraction time are studied, the result shows: the water that adds 3 times of amounts is more conducive to the extraction of volatile oil; The jar internal pressure is controlled at 0.05～0.10MP, keeps little boiling, and the volatile oil extraction ratio obviously improves; With the oil yield is index, extracts 4 hours oil yields and reaches more than 90%.
Table 5.1.1 proposes the research of volatile oil amount of water
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Pericarpium Citri Reticulatae medical material amount (g) | 500 | 500 | 500 |
| Amount of water (g) | 500 | 1500 | 2500 |
| Volatilization oil mass (L) | 6 | 9 | 5 |
| The volatile oil character | Yellow clarification | Yellow clarification | Yellow clarification |
Annotate: amount of water is too much, and volatile oil is suspended in the water, is unfavorable for volatilization.
The research of table 5.1.2 jar internal pressure
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Pericarpium Citri Reticulatae medical material amount (g) | 500 | 500 | 500 |
| Amount of water (g) | 1500 | 1500 | 1500 |
| Jar internal pressure (MP) | 0.03～0.06 | 0.06～0.10 | 0.10～0.20 |
| Volatilization oil mass (L) | 10 | 8 | 7 |
| The volatile oil character | Yellow clarification | Yellow clarification | Yellow clarification |
Annotate: jar internal pressure increases, and the moisture content volatilization is too fast, is unfavorable for that volatile oil extracts, and jar internal pressure is little, will prolong extraction time.
Table 5.1.3 extraction time is studied
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Pericarpium Citri Reticulatae medical material amount (g) | 500 | 500 | 500 |
| Amount of water (g) | 1500 | 1500 | 1500 |
| Jar internal pressure (MP) | 0.05～0.10 | 0.05～0.10 | 0.05～0.10 |
| Extraction time (h) | 4 | 6 | 8 |
| Volatilization oil mass (L) | 10 | 9 | 11 |
| The volatile oil character | Yellow clarification | Yellow clarification | Yellow clarification |
Annotate: extraction time, oil yield did not have obvious raising greater than 4 hours.
5.2 study decocting amount of water, the result shows, first fries in shallow oil and adds 6 times of water gagings, and second to fry in shallow oil the paste-forming rate that adds 4 times of water gagings the most reasonable.
The research of table 5.2 amount of water
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Medical material amount (g) | 100 | 100 | 100 |
| One fries in shallow oil amount of water (g) | 400 | 600 | 1000 |
| Two fry in shallow oil amount of water (g) | 300 | 400 | 800 |
| Paste-forming rate (%) | 24 | 38 | 41 |
| The arctigenin rate of transform (%) | 85 | 92 | 93 |
Annotate: paste-forming rate obviously reduced when amount of water was very few, paste-forming rate and contain and survey index and do not have obvious raising when amount of water is excessive.
5.3 ethanol consumption and method are studied, and the result shows: adding 2 times of amount ethanol is reasonably, and the fluid temperature when adding ethanol should be lower than 50 ℃, should constantly stir when adding ethanol.
Table 5.3 ethanol quantity research
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Extractum is (ml) | 100 | 100 | 100 |
| Ethanol consumption (ml) | 100 | 200 | 300 |
| Go out dried cream amount (g) | 48 | 42 | 40 |
| Alcohol deposit fluid | Muddy | Clarification | Clarification |
Annotate: it is unclear that the ethanol consumption reduces the back alcohol deposit fluid, is unfavorable for removing impurity.
5.4 precipitate with ethanol time of repose method of getting liquor is studied, and the result shows that leaving standstill 24 hours is reasonably, gets liquid and should use siphonage.
The research of table 5.4 time of repose
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Alcohol deposit fluid (ml) | 200 | 200 | 200 |
| Time of repose (h) | 12 | 24 | 36 |
| Alcohol deposit fluid | Muddy | Clarification | Clarification |
5.5 the concentrated solution relative density behind the recovery ethanol is studied, and the result shows that relative density 1.15 is rational.
The research of table 5.5 relative density
| Project | Lot number 1 | Lot number 2 | Lot number 3 |
| Relative density | 1.10 | 1.15 | 1.25 |
| Method of granulating | Spray granulation | Spray granulation | Spray granulation |
| The result | Medicinal liquid is too much, and the granulation time is long | Amount of liquid medicine is suitable, and the granule color and luster is even | Medicinal liquid is very few, and granule has piebaldism |
5.6 to spray-dired technological parameter research
Atomisation pressure helps the flow-like drop is refined into vaporific droplet, increases the area coverage of drop, prevented from caking.But atomisation pressure is excessive, and size droplet diameter is too little, and most of droplet is not striking the surperficial dry powder that just become of powder particle; Atomisation pressure is too small, forms bigger drop easily, and granule is grown up too fast, and inside has little time drying, and moisture content is higher.
Material flow is directly proportional with the particle diameter of drop, and flow velocity increases, and particle diameter increases.Make granule have little time drying but flow velocity is crossed conference, easily form white heart granule; And the too small prolongation spray time of flow velocity, and droplet easily is with to the filter chamber.
Fluidized-bed temperature is too high, and droplet drying is too fast, and owing to the expansion of self, density reduces, and forms hollow particle easily, and is big and unreal in the process that descends; Temperature is crossed low granule caking, the sticking wall of can causing with the bed that causes death.So select atomisation pressure, material flow, fluidized-bed temperature as the investigation factor, select L for use
9(3
4) orthogonal table tests, and the particulate qualification rate of once going is investigated (seeing Table 5.6.1)
Table 5.6.1 factor level table
Annotate: (1) particle grain size requires between 10 ~ 30 orders, greater than 10 orders or all be judged to defective less than 30 purpose granules; (2) moisture≤1.5% be judged to qualified.
Orthogonal test table and result:
By analysis of variance table as can be seen, A, B, three factors of C are to particulate disposable qualification rate influence degree difference, and the influence degree of each factor is followed successively by B＞C＞A, and wherein, B has remarkable influence to the qualification rate of granulating.
Table 2L
9(3
4) orthogonal test table
Table 2 is the result show, what disposable qualification rate was the highest is No. 5 test, and promptly optimum combination is A
2B
2C
3, and the anticipated optimal combination is A
2B
2C
2, difference wherein is the selection difference to horizontal factor C item, by to A
2B
2C
2Same A is tested in combination
2B
2C
3Compare, as a result A
2B
2C
3Make up excellent, so the optimum combination process conditions are: the extractum flow velocity (5～8Hz), thing temperature (55～65), atomisation pressure (1.0～3.0bar).
6. the research of quality control standard
6.1 the Pericarpium Citri Reticulatae thin layer is differentiated
Get this product 30g, add hot water 40ml and make dissolving, put coldly, extract 2 times with petroleum ether (60 ~ 90 ℃) jolting, each 20ml, merge extractive liquid,, water 10ml washing discards water liquid, petroleum ether liquid evaporate to dryness, residue add petroleum ether (60 ~ 90 ℃) 1ml makes dissolving, as need testing solution.Other gets Pericarpium Citri Reticulatae control medicinal material 0.3g, adds petroleum ether (60 ~ 90 ℃) 10ml, and supersound process 10 minutes filters, and filtrate evaporate to dryness, residue add petroleum ether (60 ~ 90 ℃) 1ml makes dissolving, in contrast medical material solution.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2005), draw need testing solution 10 μ l, control medicinal material solution 2 μ l, put respectively on same silica gel g thin-layer plate, with benzene-acetone (10: 2) is developing solvent, launch, take out, dry, spray is put under the ultra-violet lamp (365nm) and is inspected with 5% aluminum chloride alcoholic solution.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
The result shows: method is easy, and collection of illustrative plates is clear, and it is noiseless to lack flavor.
6.2 the Fructus Arctii thin layer is differentiated
Get this product 30g, add methanol 60ml, supersound process 30 minutes filters, filtrate put the neutral alumina post handled well (100 ~ 200 orders, 5g is on the internal diameter 10 ~ 15mm), with 40% methanol 50ml eluting, collect eluent, put evaporate to dryness in the water-bath, residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the arctigenin reference substance, adds methanol and makes the solution that every 1ml contains 3mg, in contrast product solution.Test according to thin layer chromatography (an appendix VI of Chinese Pharmacopoeia version in 2005 B), draw need testing solution 2 μ l, reference substance solution 6 μ l, put respectively on same silica GF254 lamellae, lower floor's solution with chloroform-methanol-water (15: 4: 1) is developing solvent, launch, take out, dry, put under the ultra-violet lamp (254nm) and inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color; Spray with 10% ethanol solution of sulfuric acid, it is clear to be heated to speckle colour developing in 110 ℃ again.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
The result shows: method is feasible, and collection of illustrative plates is clear, and it is noiseless to lack flavor.
6.3 arctiin content assaying method research
6.3.1 instrument and reagent
SSI IV type high performance liquid chromatograph (U.S.), Model 201 UV-detector, Anastar chromatographic work station.
The arctigenin reference substance is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number 819-9401, and purity is 98.1%, and acetonitrile is a chromatographically pure, and reagent is analytical pure.
6.3.2 measure the selection of wavelength
The alcohol extract of arctigenin reference substance solution and Fupoganmao particle all has absorption maximum at the 280nm place, so this assay item selects 280nm as detecting wavelength.Be reported in 270nm as the detection wavelength, but this absworption peak type is sharper, the peak area of measuring at 280nm is higher by 30% than 270nm, so select 280nm comparatively reasonable for detecting wavelength.
6.3.3 chromatographic condition
Chromatographic column: Sumtek C18 (250mm * 4.6mm); Mobile phase: acetonitrile-water (30: 70); Detect wavelength: 280nm, detection sensitivity 0.1AFUS; Room temperature, flow velocity 1.0ml/min, the theoretical cam curve of chromatographic column is pressed the arctigenin peak and is calculated greater than 5000, and separating degree is greater than 2.
Once according to relevant document, this paper has also investigated methanol-water mobile phase system, separating effect is undesirable as a result, also tested the multiple ratio of acetonitrile-water respectively, experimental result shows with acetonitrile-water (30: 70) as mobile phase, obtained comparatively ideal effect, the characteristic peak retention time is about 8min, so this paper has selected acetonitrile-water (30: 70) to be mobile phase.
6.3.4 the selection of extraction conditions
Character and extracting method commonly used according to arctigenin, investigate Fupoganmao particle supersound extraction, backflow and water-soluble pure extracting method, and different solvents and extraction time carried out integrated survey, the result shows that with 20 minutes extracting method of methanol supersound process be the best.
Extracting method and choice of Solvent
The selection of ultrasonic time
6.3.5 linear relationship is investigated
It is an amount of that precision takes by weighing in phosphorus pentoxide desiccator 24 hours arctigenin reference substance of drying under reduced pressure, adds methanol and be made into every ml and contain arctigenin 0.2467mg reference substance solution.Accurate reference substance solution 1,2,4,6,8, the 10 μ l that draw inject high performance liquid chromatograph, measure by above-mentioned chromatographic condition, the results are shown in Table 3.Integrated value with arctigenin absworption peak area is vertical coordinate Y, and sample size X (μ g) is an abscissa, the drawing standard curve.
Linear relationship is investigated
Equation of linear regression: Y=-3988.1+367007.2X R=1 is good linear relationship in 0.2476～2.476 μ g scope.
6.3.6 the preparation of reference substance solution and need testing solution
The preparation of reference substance solution: it is an amount of that precision takes by weighing in phosphorus pentoxide desiccator 24 hours arctigenin reference substance of drying under reduced pressure, makes the solution that every 1ml contains 0.25mg with methanol, promptly.
The preparation of need testing solution: get this product 1g, the accurate title, decide, and puts in the conical flask, the accurate methanol 10ml that adds, and it is fixed to claim, supersound process 20 minutes is placed room temperature, and it is fixed to claim again, supplies the weight that subtracts mistake with methanol, shakes up, filter, get subsequent filtrate, filter with microporous filter membrane (0.45 μ m), promptly.
6.3.7 precision test
The accurate need testing solution 10 μ l that draw inject high performance liquid chromatograph, repeat sample introduction 6 times, obtain arctigenin peak area (seeing Table 4), as a result RSD=0.49% (n=6).
The precision test
6.3.8 stability test
The same need testing solution 10 μ l of accurate absorption, every interval certain hour is measured once, measures altogether 6 times, and the result shows that need testing solution is basicly stable in 32 hours, RSD=0.54%, n=6.
Stability test
6.3.9 blank assay
Lack other Chinese crude drug and the adjuvant of Fructus Arctii by prescription proportioning input, make blank preparation, press the test of the stratographic extracting method of test sample and chromatographic condition, the result contrasts the place, peak at arctigenin and chromatographic peak do not occur, so interference measurement not.
6.3.10 repeatability test
Precision takes by weighing 6 parts of same lot number Fupoganmao particles, measures in accordance with the law, and data see Table 6, and RSD is 1.62% (n=6) as a result.
6.3.11 recovery test
Precision takes by weighing the about 0.25g of Fupoganmao particle of known content, and totally 6 parts, the accurate arctigenin reference substance that adds is an amount of, presses the preparation of need testing solution preparation method, measures in accordance with the law.
The response rate of arctigenin in the Fupoganmao particle
The response rate of this assay method is 99.97% (n=6), and RSD is 1.80%.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment, and following each embodiment only is used to illustrate the present invention, but to not restriction of the present invention.
Embodiment one
Take by weighing Folium Hibisci Mutabilis 900g, Cortex Magnoliae Officinalis 150g, Pericarpium Citri Reticulatae 250g, Fructus Arctii (stir-fry) 250g in the prescription ratio, get Pericarpium Citri Reticulatae, add 3 times of water gagings, extracted volatile oil 4 hours, the extraction pot internal pressure is controlled at 0.05～0.10MP, collects and separation volatile oil, and is standby.Pericarpium Citri Reticulatae residue and Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Fructus Arctii (stir-fry) are decocted with water 2 times, 2 hours (adding 6 times of water gagings) of the first time, 1 hour (adding 4 times of water gagings) of the second time, collecting decoction, filter, it is 1.15～1.20 that filtrate is concentrated into relative density, and the ethanol that adds 2 times of amounts carries out precipitate with ethanol, leaves standstill 24 hours, get supernatant, reclaim ethanol, medicinal liquid is concentrated to be become relative density and is about 1.15～1.18 extractum, standby.Get spray granulation behind above-mentioned extractum and the brown sugar (Saccharum Sinensis Roxb.) powder mixing, temperature of charge is 55～65 ℃, and atomisation pressure is 1.0～3.0bar, and the binding agent flow is 5～8Hz, sprays into the Pericarpium Citri Reticulatae volatile oil moistening 4～8 hours, promptly.
Embodiment two
Take by weighing Folium Hibisci Mutabilis 900g, Cortex Magnoliae Officinalis 150g, Pericarpium Citri Reticulatae 250g, Fructus Arctii (stir-fry) 250g in the prescription ratio, get Pericarpium Citri Reticulatae, add 2 times of water gagings, extracted volatile oil 3 hours, the extraction pot internal pressure is controlled at 0.05～0.10MP, and collection and separation volatile oil are standby.Pericarpium Citri Reticulatae residue and Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Fructus Arctii (stir-fry) merging are decocted with water 2 times, 2 hours (adding 4 times of water gagings) of the first time, 1 hour (adding 3 times of water gagings) of the second time, collecting decoction, filter, it is 1.10～1.15 that filtrate is concentrated into relative density, and the ethanol that adds 2 times of amounts carries out precipitate with ethanol, leaves standstill 24 hours, get supernatant, reclaim ethanol, medicinal liquid is concentrated to become relative density be 1.02～1.15 extractum, standby.Get above-mentioned extractum and sucrose fine mixing, make granule,, get granule 1000g in 50～80 ℃ of oven dry with granulator.
Embodiment three
Take by weighing Folium Hibisci Mutabilis 900g, Cortex Magnoliae Officinalis 150g, Pericarpium Citri Reticulatae 250g, Fructus Arctii (stir-fry) 250g in the prescription ratio, get Pericarpium Citri Reticulatae, add 4 times of water gagings, extracted volatile oil 5 hours, the extraction pot internal pressure is controlled at 0.05～0.10MP, and collection and separation volatile oil are standby.Pericarpium Citri Reticulatae residue and Folium Hibisci Mutabilis, Cortex Magnoliae Officinalis, Fructus Arctii (parched) merging are decocted with water 2 times, 2 hours (adding 8 times of water gagings) of the first time, 1 hour (adding 6 times of water gagings) of the second time, collecting decoction, filter, it is 1.20～1.30 that filtrate is concentrated into relative density, and the ethanol that adds 2 times of amounts carries out precipitate with ethanol, leaves standstill 24 hours, get supernatant, reclaim ethanol, medicinal liquid is concentrated to become relative density be 1.18～1.30 extractum, standby.Get spray granulation behind above-mentioned extractum and the cane sugar powder mixing, temperature of charge is 55～65 ℃, and atomisation pressure is 1.0～3.0bar, and the binding agent flow is 5～8Hz, sprays into the Pericarpium Citri Reticulatae volatile oil moistening 4～8 hours, promptly.
Claims (5)
1, a kind of preparation method of Fupoganmao particle agent is characterized in that preparation method comprises the following steps:
(1) gets raw material: Folium Hibisci Mutabilis 900g, Cortex Magnoliae Officinalis 150g, Pericarpium Citri Reticulatae 250g, Fructus Arctii (parched) 250g;
(2) get Pericarpium Citri Reticulatae, extract volatile oil, steam pressure is controlled at 0.05～0.10MP when extracting volatile oil, adds 2～4 times water by weight, extracts 3～5 hours, and the volatile oil of acquisition is standby;
(3) Pericarpium Citri Reticulatae residue and pod Rong leaf, Cortex Magnoliae Officinalis, Fructus Arctii (parched) are decocted with water secondary, for the first time add by weight that 4～8 times decocting boiled 2 hours, add by weight 3～6 times water 1 for the second time and decoct hour, collecting decoction filters, and concentrates, cooling adds 2 times of amount ethanol, leaves standstill 24 hours;
(4) get supernatant and reclaim ethanol, be condensed into extractum;
(5) get above-mentioned extractum and an amount of sucrose or the spray-dried granulation of brown sugar (Saccharum Sinensis Roxb.) or wet granulation process and make granule, sprayed into the Oleum Citri Reticulatae moistening 4～8 hours, that is,
Wherein in the spray-drying process method of step (5), temperature of charge is 55～65 ℃, and atomisation pressure is 1.0～3.0bar, and the binding agent flow is 5～8Hz; In the wet granulation process, get extractum, make granule, in 50～80 ℃ of oven dry with granulator with the Icing Sugar mixing.
2, the preparation method of a kind of Fupoganmao particle according to claim 1 is characterized in that: the described decompressed concentrate of step (3), being concentrated into 50 ℃ of survey relative densities is 1.10～1.30.
3, the preparation method of a kind of Fupoganmao particle according to claim 1 is characterized in that: the relative density of the described extractum of step (4) is 80 ℃ and surveys 1.02～1.30.
4, the Fupoganmao particle that makes according to each described preparation method of claim 1-3.
5, the detection method of Fupoganmao particle according to claim 4 is characterized in that this method comprises following content:
(1) the Pericarpium Citri Reticulatae thin layer detects:
Get this product 30g, add hot water 40ml and make dissolving, put coldly, extract 2 times with 60 ~ 90 ℃ petroleum ether joltings, each 20ml, merge extractive liquid,, water 10ml washing discards water liquid, petroleum ether liquid evaporate to dryness, residue add 60 ~ 90 ℃ petroleum ether 1ml makes dissolving, as need testing solution.Other gets Pericarpium Citri Reticulatae control medicinal material 0.3g, adds 60 ~ 90 ℃ petroleum ether 10ml, and supersound process 10 minutes filters, and filtrate evaporate to dryness, residue add 60 ~ 90 ℃ petroleum ether 1ml makes dissolving, in contrast medical material solution.According to the thin layer chromatography test,, draw need testing solution 10 μ l, control medicinal material solution 2 μ l referring to an appendix VI of Chinese Pharmacopoeia version in 2005 B, put respectively on same silica gel g thin-layer plate, with benzene-acetone is developing solvent at 10: 2, launches, and takes out, dry, spray is put ultra-violet lamp and is inspected under 365nm, in the test sample chromatograph with 5% aluminum chloride alcoholic solution, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
(2) the Fructus Arctii thin layer detects:
Get this product 30g, add methanol 60ml, supersound process 30 minutes filters, and filtrate is put on the neutral alumina post of having handled well, the condition of post is 100 ~ 200 orders, 5g, internal diameter 10 ~ 15mm, with 40% methanol 50ml eluting, collect eluent, put evaporate to dryness in the water-bath, residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the arctigenin reference substance, adds methanol and makes the solution that every 1ml contains 3mg, in contrast product solution.Test according to thin layer chromatography, referring to an appendix VI of Chinese Pharmacopoeia version in 2005 B, draw need testing solution 2 μ l, reference substance solution 6 μ l, put respectively on same silica GF254 lamellae, with lower floor's solution of 15: 4: 1 of chloroform-methanol-water is developing solvent, launches, and takes out, dry, put ultra-violet lamp and under 254nm, inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color; Spray with 10% ethanol solution of sulfuric acid, it is clear to be heated to speckle colour developing in 110 ℃ again; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(3) arctigenin content assaying method
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Acetonitrile-water is a mobile phase at 30: 70; The detection wavelength is 280nm, and number of theoretical plate calculates by the arctigenin peak should be not less than 5000;
The preparation of reference substance solution: it is an amount of that precision takes by weighing in phosphorus pentoxide desiccator 24 hours arctigenin reference substance of drying under reduced pressure, makes the solution that every 1ml contains 0.25mg with methanol, promptly;
The preparation of need testing solution: get this product 1g, the accurate title, decide, and puts in the conical flask.The accurate methanol 10ml that adds, it is fixed to claim.Supersound process 20 minutes is put and is chilled to room temperature and claims surely again, supplies the weight that subtracts mistake with methanol.Shake up, filter.Get subsequent filtrate, with the microporous filter membrane filtration of 0.45 μ m, promptly;
Algoscopy: the accurate reference substance solution 5 μ l that draw, need testing solution 5 ~ 10 μ l inject chromatograph of liquid, measure, and calculate, promptly.
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