CN104547457A - Sustained-release dropping pill capable of regulating flow of vital energy and activating blood and preparation method of sustained-release dropping pill - Google Patents
Sustained-release dropping pill capable of regulating flow of vital energy and activating blood and preparation method of sustained-release dropping pill Download PDFInfo
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Abstract
The invention discloses a sustained-release dropping pill capable of regulating the flow of vital energy and activating blood and a preparation method of the sustained-release dropping pill. The sustained-release dropping pill is prepared from the following raw materials in parts by weight: 350-600 parts of cinnamomum migao, 4-15 parts of borneol, 250-500 parts of ligusticum wallichii, 25-50 parts of allium macrostemon and auxiliary materials. The preparation method comprises the following steps: firstly, preparing a clathrate compound from extracted cinnamomum migao volatile oil and the borneol by a cyclodextrin fractionation method; with the clathrate compound as parent nucleus, preparing mixed powder from ligusticum wallichii and allium macrostemon extracts and cinnamomum migao and ligusticum wallichii extracts; mixing with a sustained-release material evenly to prepare a spray solution; and spraying on the clathrate compound parent nucleus by virtue of a fluidized bed to prepare sustained-release skeleton particles. The sustained-release dropping pill prepared from the raw materials by the preparation method disclosed by the invention is good in stability; loss of volatile effective components is avoided; the medication frequency can be reduced; stable blood concentration can be maintained; the maintaining time for effectively activating and smoothing by aromatic herbs and promoting circulation of vital energy to relieve pain is prolonged; the side effects are reduced; and the sustained-release dropping pill is long in bioavailability and significant in curative effect.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, be specifically related to a kind of vital energy regualting and blood circulation-promoting slow-release pill preparation and preparation method thereof.
Background technology
" Migaoxinle Drop Pills " is existing is according to Miao ethnic group's medication custom and theory of Chinese medical science reasonable formula with " vital energy regualting and blood circulation-promoting drop pill " by name, the pure Chinese medicinal preparation made with Cinnamoman Migao H.W.Li, Bulbus Allii Macrostemonis, Rhizoma Chuanxiong, Borneolum Syntheticum.This product has effect of aromatic herbs activating YANG, promoting the circulation of QI to relieve pain.Cinnamomum Migao H.W.Li. in side, Xin Wen is nontoxic, temperature logical cold expelling, promoting the circulation of QI to relieve pain, mainly for because of air-cooled pathogen, the visitor stagnation of QI caused by the thoracic dorsal pained, be monarch drug; The pungent temperature of Rhizoma Chuanxiong, blood-activating and qi-promoting, wind dispelling pain relieving, therefore coordinate monarch drug to strengthen the effect of the logical pain relieving of temperature with Rhizoma Chuanxiong; The arduous temperature of Bulbus Allii Macrostemonis, warming YANG eliminating stagnation, circulation of qi promoting intestinal stasis relieving; Blumeae preparatum Tabellae temperature is flat nontoxic, and gas is refrigerant, and acrid in the mouth is cool strong, understand things pain-stopping, can increase the analgesic efficacy of Cinnamomum Migao H.W.Li..Four medicine contracts, play effect of aromatic herbs activating YANG, promoting the circulation of QI to relieve pain altogether, cure mainly and lose warm caused obstruction of qi in the chest and cardialgia (angina pectoris) by stagnation of YIN-cold, gas, disease see uncomfortable in chest, breathe hard, cardiopalmus, fear of cold, very then chest pain radiating to the back, the cold pain of sense are very, hypopnea etc.Clinical in prophylactic treatment type of stagnation of YIN-cold obstruction of qi in the chest and cardialgia acquisition good result.
In prior art, Chinese patent CN03135734.2 discloses " Chinese medicine preparation for the treatment of coronary heart diseases and angina pectoris and preparation method thereof ", its preparation method is: Cinnamomum Migao H.W.Li. steam method extracts ethereal oil, Rhizoma Chuanxiong, Bulbus Allii Macrostemonis obtain extractum with alcohol reflux respectively, by obtained Rhizoma Chuanxiong total alkaloids extractum and the mixing of obtained Bulbus Allii Macrostemonis extractum slight fever, add in molten polyethylene glycol, adding Cinnamoman Migao H.W.Li and Borneolum Syntheticum, mixing, dripping becomes drop pill; Chinese patent CN201010562944.X discloses " one treats treating coronary heart disease and angina pectoris compositions and its preparation method and preparation ", and preparation method is: Cinnamomum Migao H.W.Li. adopts the method for soak with ethanol, ultrasonic assistant to extract ethereal oil; Rhizoma Chuanxiong adopts alcohol heat reflux method, carries out purifies and separates after macroporous adsorptive resins to effective ingredient alkaloid; Medicinal residues after Cinnamomum Migao H.W.Li. extracts ethereal oil and the medicinal residues after Rhizoma Chuanxiong alcohol extraction adopt water boiling and extraction further; The method adopting alcohol reflux to extract Bulbus Allii Macrostemonis is extracted; The extract mixing finally obtained, add in molten polyethylene glycol, adding Cinnamoman Migao H.W.Li and Borneolum Syntheticum, mixing, dripping becomes drop pill.The method makes effective ingredient be fully used, and improves the extraction ratio of medical material, the dropping pill formulation made, and active constituent content is higher, thus enhances curative effect.
But, still there are some problems in the obtained vital energy regualting and blood circulation-promoting dropping pill formulation of existing preparation method: dry and cracked, the easy moisture absorption of being easily heated when storing of (1) drop pill is glued the problem such as ball, distortion and easily causes volatility active ingredient to lose, stability of drug products is poor, and long term storage affects drug quality; (2) obtained drop pill is rapid-action, but drug bioavailability is low, and the half-life is short, and the fluctuation of blood medicine peak valley is large, and drug metabolism in vivo is too fast, and blood drug level is difficult to maintain lastingly, and administering mode is inconvenient and be not suitable with the shortcomings such as long term administration; (3) existing vital energy regualting and blood circulation-promoting drop pill specification is the heavy 25mg of every ball.Usage and dosage is: oral or sublingual administration.10 balls, 3 times on the one 4 weeks is a course for the treatment of.Namely daily amount is 750mg, takes quantity many (30 ball), and little being not easy of ball is controlled, and takes number of times and measures all more.
Cyclodextrin inclusion technique uses day by day extensive in recent years.Its application pharmaceutically mainly concentrate on increase medicine dissolution, improve bioavailability, the stability improving medicine, liquid medicine powdered, prevent drug volatilization, cover the bad stink of medicine and reduce the rate of releasing drug of zest, regulating drug; The slow releasing preparation energy long period makes blood drug level maintain certain level.Therefore, use cyclodextrin inclusion technique and slow release method that existing vital energy regualting and blood circulation-promoting drop pill is made slow releasing preparation will be significant.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of vital energy regualting and blood circulation-promoting sustained-release dropping pill is provided.This sustained-release dropping pill can reduce medicining times, maintain blood drug level steadily, extend effective aromatic herbs activating YANG, promoting the circulation of QI to relieve pain are held time, the untoward reaction that reduces side effect, reduce medicine.
Technical scheme of the present invention is: a kind of vital energy regualting and blood circulation-promoting sustained-release dropping pill, according to listed as parts by weight, be prepared from by following crude drug and ratio of adjuvant: Cinnamomum Migao H.W.Li. 350-600 part, Borneolum Syntheticum 4-15 part, Rhizoma Chuanxiong 250-500 part, Bulbus Allii Macrostemonis 25-50 part, 40% alcoholic solution 200-300 part, cyclodextrin 60-100 part, slow-release material 30-60 part, Polyethylene Glycol substrate 60-90 part.
Preferably, aforementioned base materials medicine consists of: Cinnamomum Migao H.W.Li. 450 parts, Borneolum Syntheticum 9 parts, Rhizoma Chuanxiong 360 parts, Bulbus Allii Macrostemonis 36 parts.
Preferably, aforementioned adjuvant consists of: 40% alcoholic solution 230-280 part, cyclodextrin 70-90 part, slow-release material 40-50 part, Polyethylene Glycol substrate 70-80 part.
More preferably, aforementioned adjuvant consists of: 40% alcoholic solution 250 parts, cyclodextrin 80 parts, slow-release material 45 parts, Polyethylene Glycol substrate 75 parts.
Cyclodextrin inclusion compound material of the present invention is: one or more mixing of beta-schardinger dextrin-, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin, Sulfobutyl ether β _ cyclodextrin, carboxymethyl-beta-cyclodextrin.Preferred: HP-β-CD and Sulfobutyl ether β _ cyclodextrin (1:1) are as enclose material.
Slow-release material of the present invention is: one or more mixing of hypromellose (HPMC), Carboxymethyl cellulose sodium (CMC-Na), ethyl cellulose (EC); Preferred: CMC-Na:EC=4:1 mixing slow-release material.
Polyethylene Glycol substrate of the present invention is: Macrogol 4000: polyethylene glycol 6000=1:1.5 mixed-matrix.
Another object of the present invention is to provide the preparation method of this vital energy regualting and blood circulation-promoting sustained-release dropping pill, and the method comprises the following steps:
Raw material extraction process:
(1) get Cinnamomum Migao H.W.Li. by formula proportion to pulverize, add 8 times amount 75% soak with ethanol 7 hours, ultrasonic echography extracts 80 minutes, sucking filtration, and filtrate water vapor method steams solvent, and obtain Cinnamoman Migao H.W.Li A, medicinal residues are for subsequent use;
(2) get Rhizoma Chuanxiong power by formula proportion and be broken into coarse powder, extract 3 times with 10 times amount 75% alcohol heating reflux, reclaim ethanol, concentrated, after thick paste adds suitable quantity of water heating for dissolving, sucking filtration, filtrate crosses macroporous adsorptive resins, and the reaction first washed with water to sugar is negative, then uses ethanol elution, reclaim ethanol, concentrated, filter, obtain total extract B for subsequent use, collect medicinal residues, for subsequent use;
(3) medicinal residues getting (1) and (2) decoct with water, and extracting solution filters, and is condensed into extractum C;
(4) get Bulbus Allii Macrostemonis by formula proportion to pulverize, add the alcohol dipping 36 hours of 75%, heating and refluxing extraction, merge, reclaim ethanol, be condensed into extractum, add extract B, extractum C fully mixes, dry, pulverize, obtain fine powder D, for subsequent use.
Sustained release drop pill preparation technology:
(1) Borneolum Syntheticum of Cinnamoman Migao H.W.Li A and formula proportion amount is mixed, add 40% alcoholic solution of formula proportion amount, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450 parts 50-60 DEG C is taken in heat-preserving container, the cyclodextrin taking formula proportion amount again stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40-50 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, get fine powder D, add the ethanol of 95% and whitewashing is made in the slow-release material mixing of formula proportion amount, make concentration of slurry be 0.12-0.18g/ml, adopt fluid bed side spray to spray into, injection flow velocity is 15-25ml/min, temperature is 70-90 DEG C, and atomization air pressure is 0.1-0.3Mpa, obtained granule;
(4) take the substrate of formula proportion amount, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
Described condensed fluid is: one or more mixture of liquid paraffin, methyl-silicone oil, vegetable oil, preferable methyl silicone oil.
Beneficial effect of the present invention is as follows: first the Cinnamomum Migao H.W.Li. ethereal oil extracted and Borneolum Syntheticum are mixed, adopt cyclodextrin to carry out enclose to its mixture and obtain clathrate, improve the stability of drop pill volatile ingredient, improve the water solublity of slightly solubility volatile oil simultaneously, the bioavailability of medicine is improved; Then using clathrate as parent nucleus, Rhizoma Chuanxiong is extracted extractum, Bulbus Allii Macrostemonis extracts extractum, Cinnamomum Migao H.W.Li. and the Rhizoma Chuanxiong fine powder made of extract again, mix with slow-release material and make whitewashing solution, adopt fluid bed side spray on clathrate parent nucleus, make sustained-release matrix granule, not only increase the mixing homogeneity of prescription drug, make the drop pill mass uniformity made good, in whitewashing, add slow-release material simultaneously, granule skin is made to form a sustained-release matrix, drug release is played to the effect of slow control, blood drug level can be maintained lastingly.Adopt raw material of the present invention and preparation method, obtained sustained release drop pill good stability, avoid the loss of volatile effective component, medicining times can be reduced, maintain blood drug level steadily, extend effective aromatic herbs activating YANG, the holding time of promoting the circulation of QI to relieve pain, reduce side effect, bioavailability is high, evident in efficacy.
Below by way of experimental example, the present invention is further illustrated.
The Selection experiment of experimental example 1, preparation technology:
1.1 cyclodextrin inclusion compound Material selec-tion tests:
According to the method for aforementioned sustained release drop pill step of preparation process 2, select enclose temperature 40 DEG C, enclose time 60min, adopt the different enclose material of following table to Cinnamomum Migao H.W.Li. ethereal oil and Borneolum Syntheticum mixture enclose, with the loss rate of volatile ingredient under inclusion rate, clathrate yield, hot and humid intense light conditions for index, investigate enclose material to the impact of technique, Data Processing in Experiment result is as following table 1, table 2:
Table 1 enclose Material selec-tion experimental result
Table 2: enclose Material selec-tion experimental result:
| Hydroxy propyl-Beta CD: sulphur butyl-β CD | Enclose material usage | Inclusion rate % | Clathrate yield % | Loss rate % |
| 1:1 | 80 parts | 81.7 | 86.7 | 5.8 |
| 1:2 | 80 parts | 74.4 | 79.3 | 7.6 |
| 1:3 | 80 parts | 72.5 | 78.6 | 8.1 |
| 2:1 | 80 parts | 71.3 | 81.2 | 6.9 |
| 3:1 | 80 parts | 69.4 | 76.6 | 7.8 |
From upper table 1,2: adopt above-mentioned enclose material, consumption is 60-100 part, carries out enclose to Cinnamomum Migao H.W.Li. ethereal oil and Borneolum Syntheticum mixture, and all can touch the mark requirement; The clathrate wherein adopted is that HP-β-CD and Sulfobutyl ether β _ cyclodextrin are by 1:1 mixture, the inclusion rate of sample, clathrate yield and stability are all higher than other enclose materials, therefore preferably HP-β-CD mixes as enclose material by 1:1 with Sulfobutyl ether β _ cyclodextrin.
The test of granule process choice prepared by 1.2 fluid beds:
According to literature research, the impact of fluidized bed granulation paper examines spray concentration of slurry of the present invention, hydrojet flow velocity, intake air temperature, atomization air pressure four factors.
Table 3, factor level table
Adopt L
9(3
4) orthogonal table arrangement test, carry out 9 tests, measure the sieving rate that the obtained granule of each test can cross 45-80 mesh sieve, sieving rate=can granule total amount × 100% of 24-40 mesh sieve grain amount/obtained.Ideal granule degree of the present invention is to cross the particle diameter granule between 24-40 mesh sieve.
Table 4, orthogonal experiments L
9(3
4)
Shown by orthogonal table 4, affect the present invention make microgranule factor primary and secondary order be: A>B>C>D.Wherein A factor has technique affects more significantly, and the present invention is best, and fluidized bed granulation technique is: A3B3C2D3, and concentration of namely whitewashing is 0.18g/ml, and hydrojet flow velocity is 25ml/min, temperature 80 DEG C, atomizing pressure 0.1Mpa.Therefore, determine that fluid bed of the present invention is prepared granule optimum process and is: whitewashing concentration is 0.18g/ml, and hydrojet flow velocity is 25ml/min, temperature 80 DEG C, atomizing pressure 0.1Mpa.
1.3 slow-release material Selection experiment:
(1) investigating the present invention adopts different slow-release materials on the impact of the dropping pill formulation release made.
Adopt Chinese Pharmacopoeia 2010 editions two appendix C X first methods, using alcoholic solution 500ml as dissolution medium, rotating speed is 50 turns/min, according to this law operation, take out solution 3ml(automatic liquid supply at 0.25h, 0.75h, 2h, 3h, 4h, 5h, 6h, 8h, 10h respectively), immediately through 0.22um microporous filter membrane, get filtrate 4ul injection high performance liquid chromatograph to measure, in drop pill, eucalyptol release is as inspection target, and calculate and curve plotting, result is as table 5:
Table 5 slow-release material Selection experiment result
Shown by table 5: hypromellose (HPMC), Carboxymethyl cellulose sodium (CMC-Na), CMC-Na and EC, all meet the requirements as slow release blocker by 4:1 composite material.Wherein EC obtains drop pill as slow release blocker, and release rate is lower, and EC should do not selected separately to make slow release blocker; Wherein CMC-Na and EC obtains drop pill by 4:1 composite material, and during beginning, release is fast, reaches the object of quick acting, and later rate of releasing drug is comparatively steady, and blood drug level more can be made to maintain lastingly; And in bed spray slow-release micro-pill, the obtained micropill uniformity is better, and therefore the preferred slow release blocker of the present invention is: CMC-Na and EC is by 4:1 mixed accessories.
(2) Selection experiment of slow-release material consumption:
Adopt the preparation method of present invention process, add CMC-Na and EC by 4:1 composite material deal number on the impact of drop pill release, result is as following table 6:
Table 6 slow-release material consumption Selection experiment result
Table 6 shows: when adding 20 parts of slow-release auxiliary material, and drag is inadequate, and rate of releasing drug is too fast, and slow release effect is bad; When adding 80 parts of slow-release auxiliary material, drag is bigger than normal, and rate of releasing drug is excessively slow, is difficult to maintain desirable blood drug level.Therefore, the present invention selects 30-60 part adjuvant, preferred 40-50 part adjuvant, most preferably 45 parts of adjuvants.
Experimental example 2: drop pill quality stability is checked:
Matched group: matched group 1, matched group 2 are respectively embodiment 1 disclosed in patent CN03135734.2, embodiment 3 preparation method is prepared and obtained; The drop pill that matched group 3 embodiment 1 preparation method disclosed in patent CN201010562944.X is prepared and obtained.
Test group: be respectively the invention process row 3, drop pill that embodiment 4, embodiment 5 are made.
Investigation mode is: adopt accelerated stability test to measure in dropping pill formulation volatile component content with the situation of change in storage time; The mensuration being wherein the drop pill just prepared and carrying out for 0th month, the mensuration of carrying out after one month for storage for the 1st month, by that analogy, each experimental group dropping pill formulation carrying out testing all adopts identical storage method.Experimental result is as following table 7:
Table 7 Cinnamoman Migao H.W.Li study on the stability is tested:
Shown by table 7: the obtained dropping pill formulation of two kinds of different process is stored into 6th month, traditional handicraft is prepared drop pill eucalyptol content and is on average dropped to 73.8% of eucalyptol content in the dropping pill formulation just prepared, and present invention employs eucalyptol content in the dropping pill formulation that cyclodextrin inclusion technique preparation technology obtains still for just prepared 94.1% of drop pill eucalyptol content.And downward trend tends to be steady.Describe accordingly: the drop pill quality stability adopting the present invention to obtain is good, and preparation technology is greatly better than traditional handicraft and obtains dropping pill formulation.
Experimental example 3: release investigates experiment:
Investigation mode: compare the obtained common vital energy regualting and blood circulation-promoting drop pill of traditional handicraft and the present invention obtains drop pill, investigate its vitro release situation, adopt Chinese Pharmacopoeia 2010 editions two appendix C X first methods, using alcoholic solution 500ml as dissolution medium, rotating speed is operate according to this law, respectively at 0.25h, 0.75h, 2h, 3h, 4h, 5h, 6h takes out solution 3ml(automatic liquid supply), immediately through 0.22um microporous filter membrane, get filtrate 4ul injection high performance liquid chromatograph to measure, in drop pill, eucalyptol release is as inspection target, calculate and curve plotting, result is as following table 8:
Table 8 release investigates experimental result
Shown by watch 9: common drop pill rate of release is very fast, in 2 hours, basic release is complete, and comparatively steadily slowly, just release is complete after 10 hours in the drop pill release that the present invention makes, illustrate that drop pill that the present invention makes is relative to common drop pill, has better slow releasing function.
Experimental example 4: pharmacodynamic study
4.1 experiment materials:
Invention formulation: be prepared into sustained-release dropping pill according to the embodiment of the present invention 1, specification: the heavy 0.1g of every ball.
Contrast medicine: the dropping pill formulation be prepared into according to CN201010562944.X embodiment 1, specification: the heavy 25mg of every ball.
Subjects: Kunming mouse l8 ~ 20g, male and female half and half, Wistar rat, according to different experiments, has 80 ~ 100g, male and female half and half, is purchased from Guiyang Medical College Experimental Animal Center.
4.2 test methods:
A, analgesic activity (hot plate method, writhing method) to mice
Get female KM kind mice, by only putting into G-8402 type hot plate dolorimeter, measuring and recording mice and occur licking metapedes required time (s) as this Mus pain threshold, tie-in three times, average as pain threshold before this Mus normal value or medicine.The mice of pain threshold within 5s ~ 30s 30 is selected to be divided into 3 groups at random, dosage is: experimental group the present invention obtains drop pill 4 ball, matched group is drop pill 10 ball that traditional handicraft obtains, normal saline group gives isometric(al) normal saline, after medicine 30,60,90min measures each Mus pain threshold, if mice hot-plate instrument 60S still analgesia reaction namely take out, pain threshold, by 60s, the results are shown in Table 1.Separately get Kunming mouse 30, be divided into 3 groups at random by table 9 dosage.After administration, lh each Mus lumbar injection 0.7% acetum O.2ml/ only, is observed the writhing response number of times that in 15min, each group mice is caused by acetic acid, be the results are shown in Table 9 respectively.
Table 9 Migaoxinle Drop Pills is to mice analgesic activity (hot plate method writhing method)
n=10)
Shown by table 10 data, show the drop pill group that the present invention obtains all have analgesic activity to the pain that thermostimulation and acetic acid chemical stimulation cause.Experimental group compares with normal saline group, shows drop pill of the present invention and has obvious analgesic activity; Experimental group compares with matched group, and the pain threshold of experimental group when 60min, 90min, 120min is all greater than matched group, and substantially maintains same level, illustrates that the drop pill that the present invention obtains has slow releasing function.
B, Migaoxinle Drop Pills resisting oxygen lack
With the normobaric hypoxia mouse survival time for observation index, get Kunming mouse 30, male and female half and half, body weight 20 ± 2g, is divided into 3 groups at random, often organize 10, dosage is: experimental group is drop pill 4 ball that preparation technology of the present invention obtains, and matched group is drop pill 10 ball that traditional handicraft prepares, and normal saline group gives isometric(al) normal saline, every day 1 time, continuous 3 times.Lh after last medicine, often group gets l0 mice, by only putting into 250m] wide mouthed bottle airtight (bottle puts sodica calx 20g, and bottleneck is coated with vaseline), observe each group of mouse diing time.(with respiratory arrest) is the time-to-live. get a remaining each group of mice fortune lumbar injection isoproterenol rope 7.5mg/kg, after 30min, with said method, each group of mice is put into wide mouthed bottle respectively.The results are shown in Table 10.
Table 10 Migaoxinle Drop Pills anti-mouse anoxia functions (
n=10)
| Group | The normobaric hypoxia time-to-live (min) | Another isoproterenol time-to-live (min) |
| Experimental group | 23.1±7.3 | 24.8±5.1 |
| Matched group | 21.8±8.4 | 21.4±5.7 |
| Normal saline group | 15.8±5.4 | 16.3±5.2 |
Result shows, compares with normal saline group, and the dropping pill formulation that preparation method of the present invention obtains and the dropping pill formulation that traditional handicraft obtains all have oxygen lack resistant function, and the drop pill effect that the present invention obtains is better.
Each mouse diet and movable normal in above experimentation, fur is smooth, the no abnormality seen secretions such as mouth, nose, eye, and urine, feces are normal, in 14 days without dead mouse and body weight all increase, show that the sustained-release dropping pill that the present invention obtains is nontoxic.
Detailed description of the invention
Embodiment 1:
Raw material extraction process: prescription: Cinnamomum Migao H.W.Li. 450g, Borneolum Syntheticum 9g, Rhizoma Chuanxiong 360g, Bulbus Allii Macrostemonis 36g;
Method for making: (1) Cinnamomum Migao H.W.Li. is ground into coarse powder, cross 24 mesh sieves, add 8 times amount 75% soak with ethanol, soak time is: 7 hours, ultrasonic extraction 80 minutes, sucking filtration, and collect filtrate, steam steams the solvent in filtrate, and obtain Cinnamoman Migao H.W.Li A, medicinal residues are for subsequent use;
(2) Rhizoma Chuanxiong power is broken into coarse powder, cross 24 mesh sieves, add 10 times amount 70% soak with ethanol 2 hours, reflux 3 times, each extraction time is 3 hours, the ethanol consumption of the 2nd time and later number of times is 8 times of medical material weight, filter, merging filtrate, it is 1.15 ~ 1.25 that filtrate is concentrated into relative density under 50 ~ 70 DEG C of conditions, adding ethanol makes alcohol content be 60%, leave standstill 48 hours, make precipitation, merge, reclaim ethanol, be condensed into thick paste, it is 1-5:5-1 that concentrated solution adds water to volume every milliliter with the ratio of medical material amount every gram, filter, filtrate crosses macroporous adsorptive resins, the reaction first washed with water to sugar is negative, use 35% ethanol elution again, collect eluent, reclaim ethanol, concentrated, filter, obtain extract B for subsequent use, collect medicinal residues, for subsequent use,
(3) medicinal residues getting (1) and (2) add the water of 15 times amount, extract 3 times, each 3 hours, merge extractive liquid, under 50 ~ 60 DEG C of conditions, and filter, merging filtrate, is concentrated into the extractum C that relative density is 1.10 ~ 1.25,
(4) Bulbus Allii Macrostemonis is pulverized, and crosses 24 mesh sieves, adds 70% ethanol and make alcohol content be 50%, place 36 hours, make precipitation, filter, get supernatant, and to be concentrated into relative density under 60 ~ 70 DEG C of conditions be 1.10 ~ 1.20, obtain thick paste, add extract B, extractum C fully mixes, dry, pulverize, obtain fine powder D, for subsequent use.Embodiment 2: prepared by drop pill
(1) Cinnamoman Migao H.W.Li A embodiment 1 obtained and the mixing of 9g Borneolum Syntheticum, add 200ml40% alcoholic solution, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450ml50-60 DEG C is taken in heat-preserving container, take 60g HP-β-CD again: the mixture of Sulfobutyl ether β _ cyclodextrin=1:1 stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40 DEG C, stirs 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, the fine powder D that Example 1 obtains, whitewashing is made in the ethanol and the 30g CMC-Na mixing that add 95%, makes concentration of slurry be 0.12g/ml, adopts fluid bed side spray to spray into, injection flow velocity is 15ml/min, temperature is 70 DEG C, and atomization air pressure is 0.2Mpa, obtained granule mixture;
(4) 60g Macrogol 4000 is taken: the mixture of polyethylene glycol 6000=1:1.5, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill 200g.
The heavy 0.1g of every ball takes twice on 1st, each 4-6 ball.
Embodiment 3: prepared by drop pill
(1) Cinnamoman Migao H.W.Li A embodiment 1 obtained and the mixing of 9g Borneolum Syntheticum, add 230ml40% alcoholic solution, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450ml50-60 DEG C is taken in heat-preserving container, taking 70g hydroxyethyl-β-cyclodextrin again stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, the fine powder D that Example 1 obtains, whitewashing is made in the ethanol and the 40g HPMC mixing that add 95%, makes concentration of slurry be 0.15g/ml, adopts fluid bed side spray to spray into, injection flow velocity is 20ml/min, temperature is 90 DEG C, and atomization air pressure is 0.3Mpa, obtained granule mixture;
(4) 70g Macrogol 4000 is taken: polyethylene glycol 6000=1:1.5 mixture, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
Embodiment 4: prepared by drop pill
(1) Cinnamoman Migao H.W.Li A embodiment 1 obtained and the mixing of 9g Borneolum Syntheticum, add 250ml40% alcoholic solution, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450ml50-60 DEG C is taken in heat-preserving container, take 80g HP-β-CD again: Sulfobutyl ether β _ cyclodextrin=1:1 mixture stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, the fine powder D that Example 1 obtains, adds the ethanol of 95% and the mixture mixing of 45g CMC-Na and EC makes whitewashing, wherein CMC-Na:EC=4:1, concentration of slurry is made to be 0.18g/ml, adopt fluid bed side spray to spray into, injection flow velocity is 25ml/min, and temperature is 80 DEG C, atomization air pressure is 0.1Mpa, obtained granule mixture;
(4) 75g Macrogol 4000 is taken: polyethylene glycol 6000=1:1.5 mixture, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
Embodiment 5: prepared by drop pill
(1) Cinnamoman Migao H.W.Li A embodiment 1 obtained and the mixing of 9g Borneolum Syntheticum, add 280ml40% alcoholic solution, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450ml50-60 DEG C is taken in heat-preserving container, taking 90g methyl-B-cyclodextrin again stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, the fine powder D that Example 1 obtains, whitewashing is made in the ethanol and the mixing of 50g HPMC slow-release auxiliary material that add 95%, makes concentration of slurry be 0.18g/ml, adopts fluid bed side spray to spray into, injection flow velocity is 25ml/min, temperature is 80 DEG C, and atomization air pressure is 0.1Mpa, obtained granule mixture;
(4) 80g Macrogol 4000 is taken: polyethylene glycol 6000=1:1.5 mixture, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
Prepared by embodiment 6 drop pill
(1) by Cinnamoman Migao H.W.Li A and 9 part of Borneolum Syntheticum mixing, add 300ml40% alcoholic solution, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450ml50-60 DEG C is taken in heat-preserving container, take 100 parts again in HP-β-CD: Sulfobutyl ether β _ cyclodextrin=1:1 mixture rustless steel stirs in warm bucket, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, get fine powder D, whitewashing is made in the ethanol and the mixing of 60g CMC-Na slow-release material that add 95%, makes concentration of slurry be 0.15g/ml, adopts fluid bed side spray to spray into, injection flow velocity is 15ml/min, temperature is 80 DEG C, and atomization air pressure is 0.2Mpa, obtained granule mixture;
(4) 90g Macrogol 4000 is taken: polyethylene glycol 6000=1:1.5 mixture, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
Claims (10)
1. a vital energy regualting and blood circulation-promoting sustained-release dropping pill, it is characterized in that, according to listed as parts by weight, be prepared from by following crude drug and ratio of adjuvant: Cinnamomum Migao H.W.Li. 350-600 part, Borneolum Syntheticum 4-15 part, Rhizoma Chuanxiong 250-500 part, Bulbus Allii Macrostemonis 25-50 part, 40% alcoholic solution 200-300 part, cyclodextrin 60-100 part, slow-release material 30-60 part, Polyethylene Glycol substrate 60-90 part.
2. sustained-release dropping pill according to claim 1, is characterized in that, according to listed as parts by weight, described crude drug proportioning is: Cinnamomum Migao H.W.Li. 450 parts, Borneolum Syntheticum 9 parts, Rhizoma Chuanxiong 360 parts, Bulbus Allii Macrostemonis 36 parts.
3. sustained-release dropping pill according to claim 1, is characterized in that: according to listed as parts by weight, and described ratio of adjuvant is: 40% alcoholic solution 230-280 part, cyclodextrin 70-90 part, slow-release material 40-50 part, Polyethylene Glycol substrate 70-80 part.
4. sustained-release dropping pill according to claim 3, is characterized in that, according to listed as parts by weight, described ratio of adjuvant is: 40% alcoholic solution 250 parts, cyclodextrin 80 parts, slow-release material 45 parts, Polyethylene Glycol substrate 75 parts.
5., according to the arbitrary described sustained-release dropping pill of claim 1,3,4, it is characterized in that: described cyclodextrin inclusion compound material is: one or more mixing of beta-schardinger dextrin-, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin, Sulfobutyl ether β _ cyclodextrin, carboxymethyl-beta-cyclodextrin.
6. sustained-release dropping pill according to claim 5, is characterized in that: described cyclodextrin inclusion compound material is HP-β-CD: the mixture of Sulfobutyl ether β _ cyclodextrin=1:1.
7., according to the arbitrary described sustained-release dropping pill of right 1,3,4, it is characterized in that: described slow-release material is: one or more mixing of hypromellose, Carboxymethyl cellulose sodium, ethyl cellulose.
8. sustained-release dropping pill according to claim 7, is characterized in that: described slow-release material is hypromellose: the mixture of ethyl cellulose=4:1.
9., according to the arbitrary described sustained-release dropping pill of claim 1,3,4, it is characterized in that, described Polyethylene Glycol substrate is Macrogol 4000: the mixed-matrix of polyethylene glycol 6000=1:1.5.
10. preparation as arbitrary in claim 1-4 as described in the method for vital energy regualting and blood circulation-promoting sustained-release dropping pill, it is characterized in that, the method comprises the following steps:
Raw material extraction process:
(1) get Cinnamomum Migao H.W.Li. by formula proportion to pulverize, add 8 times amount 75% soak with ethanol 7 hours, ultrasonic echography extracts 80 minutes, sucking filtration, and filtrate water vapor method steams solvent, and obtain Cinnamoman Migao H.W.Li A, medicinal residues are for subsequent use;
(2) get Rhizoma Chuanxiong power by formula proportion and be broken into coarse powder, extract 3 times with 10 times amount 75% alcohol heating reflux, reclaim ethanol, concentrated, after thick paste adds suitable quantity of water heating for dissolving, sucking filtration, filtrate crosses macroporous adsorptive resins, and the reaction first washed with water to sugar is negative, then uses ethanol elution, reclaim ethanol, concentrated, filter, obtain total extract B for subsequent use, collect medicinal residues, for subsequent use;
(3) medicinal residues getting (1) and (2) decoct with water, and extracting solution filters, and is condensed into extractum C;
(4) get Bulbus Allii Macrostemonis by formula proportion to pulverize, add the alcohol dipping 36 hours of 75%, heating and refluxing extraction, merge, reclaim ethanol, be condensed into extractum, add extract B, extractum C fully mixes, dry, pulverize, obtain fine powder D, for subsequent use;
Preparation process thereof:
(1) Borneolum Syntheticum of Cinnamoman Migao H.W.Li A and formula proportion amount is mixed, add 40% alcoholic solution of formula proportion, stir and make it dissolve completely, obtain mixed ethanol solution;
(2) warm water of 450 parts 50-60 DEG C is taken in heat-preserving container, the cyclodextrin taking formula proportion again stirs in warm bucket in rustless steel, stirring makes cyclodextrin melting, poured in heat-preserving container by heat-preserving container funnel by mixed ethanol solution obtained for step (1) and carry out mix and blend, enclose temperature remains on 40-50 DEG C, carries out stirring 45 minutes, cooling leaves standstill 8 hours, sucking filtration, 40 DEG C of vacuum dryings 5 hours, obtain pastille clathrate;
(3) pastille clathrate is crossed 100 mesh sieves, it can be used as master batch to put into and drop into spray pot at the bottom of fluid bed, get fine powder D, add the ethanol of 95% and whitewashing is made in the slow-release material mixing of formula proportion, make concentration of slurry be 0.12-0.18g/ml, adopt fluid bed side spray to spray into, injection flow velocity is 15-25ml/min, temperature is 70-90 DEG C, and atomization air pressure is 0.1-0.3Mpa, obtained granule;
(4) take the substrate of formula proportion, drop in 80-90 DEG C of heating in water bath container and heat while stirring, after substrate incorporates completely, add obtained granule mixture, fully mix, the obtained melt and dissolved liquid of solid dispersion;
(5) the melt and dissolved liquid of solid dispersion that step (4) is obtained puts into the water dropper tank of pill dripping machine, and system temperature of controlling well is 82 DEG C, is instilled in condensed fluid, removes surface condensate, dry, obtains vital energy regualting and blood circulation-promoting sustained-release dropping pill.
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| CN1833677A (en) * | 2006-01-05 | 2006-09-20 | 贵州益佰制药股份有限公司 | Chinese medicinal injection and its prepn. method |
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