CN1994330B - Pulverization method for Chinese animal medicine - Google Patents
Pulverization method for Chinese animal medicine Download PDFInfo
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Abstract
The invention relates to a method for breaking traditional drug, wherein it comprises that: breaking drug normally to be screened at 20-100 deals; dispersing it into micro breaker, to be broken and obtain uniform micro powder. The inventive powder can be used in agent directly.
Description
Technical field
The present invention relates to a kind of breaking method of animal tcm material, especially a kind of disperse medium that adds carries out the method for micronizing to animal medicinal material, belongs to the field of Chinese medicines.
Background technology
One, animal drugs progress
Animal medicinal material, determined curative effect, have high medical value and economic worth, its pharmacological action mainly shows in the following areas: 1. to the influence of blood and hemopoietic system, be widely used diseases such as treatment arteriosclerosis (ASO), hyperlipemia, diabetic peripheral neuropathy, thrombosis; Can treat apoplexy, amenorrhea, paraplegia, angina pectoris, nameless gall, tumor, neck lymph through diseases such as nuclears as Hirudo, hirudin can make transplant operation posterior vein blood vessel keep unimpeded.Still contain multiple medicinal component in the Hirudo body, to eliminating the sequela that causes after the operation, preventing that blood premature solidification etc. from all playing an important role.2. to the influence of function of immune system, the individuality of energy defective makes functional rehabilitation.Therapeutic Method is divided into two kinds of immunostimulant and immunosuppressant.As Carapax et Plastrum Testudinis nourishing YIN for suppressing the hyperactive YANG is arranged, the reinforcing the kidney to strengthen the bone effect.Cornu Cervi has activating blood and removing stasis detumescence, kidney tonifying tonify deficiency, strengthening the tendons and bones, stimulating milk secretion effect.Liu Shouyis etc. cooperate the turtle and deer glue electuary of Radix Ginseng, Fructus Lycii with Carapax et Plastrum Testudinis, Cornu Cervi, significantly the mice WBC sum that causes of antagonism cyclophosphamide reduces, the peritoneal macrophage phagocytic function descends, the reduction of TLC minimizing and serum hemolysin, and make it to return near normal level, show that the turtle and deer glue electuary has the effect that strengthens immune function of mice.3. to the effect of digestive system, be a kind of of Bao class as haliotis discus hannai Ino, its mucin composition forms a kind of barrier at gastric mucosa, and the protection gastric mucosa is avoided the damage of chemical substances such as acetic acid, ethanol.Haliotis discus hannai Ino extract active component burns type gastric ulcer model, pyloric ligation ulcers gastric ulcer model and ethanol to water logging stress gastric ulcer model, acetic acid and causes the gastric mucosa injury model obvious protective effect is arranged, and can reduce ulcer index simultaneously and strengthen ulcer inhibition rate.
But the effective ingredient of animal medicinal material is also not obvious mostly, albumen, peptide class, trace element etc. mostly are its effective ingredient in the bibliographical information animal drugs, its effective ingredient is indeterminate to be the inherent problem of animal medicinal material, adopts traditional extraction, concentration technology based on this, is not suitable for animal medicinal material.The research of animal drugs combines with contemporary science and technology, will break through the bottleneck in the animal drugs research, obtains to use widely in profound field.
Animal drugs is owing to pay attention in the past inadequately, and a lot of precious rare medicinal animals are indiscriminately slaughtered, and medicine resource is destroyed, and the supply of animal drugs is nervous trend, therefore to saving the medicinal animal medical material, becomes the important topic of scientific research from now on.
Adopt superfine communication technique to prepare animal drugs ultra micro mixture,, keep the animal medicinal material effective ingredient, reduce cost, guarantee that curative effect is extremely meaningful for saving valuable animal drug.
Two, micronizing progress
1 micronizing principle and meaning
Superfine communication technique is the machining process that makes the fine and super-refinement of material, provides one of important means of ultrafine powder.Over nearly 20 years, this technology obtains to develop rapidly, has been widely used in industrial circles such as metallurgy, pottery, weaving and Aero-Space abroad, and the nanotechnology of domestic inorganic matter (as the tape magnetic powder) has obtained development faster.The Chinese medicine industry is introduced the micropowder notion and is started from late 1990s, though start late, but since pulverize be Chinese medicine production and use in basic process technology, so micronizing also more and more causes people's attention, superfine communication technique has manifested distinctive advantage and wide application prospect.
In the crushing process of Chinese crude drug, medical material is subjected to the effect of intensive forward extrusion power and tangential shearing force, utilization at a high speed, high-energy is pulverized, cell is extruded, shear, cell wall is torn, disconnect, cell is fractured into fragment or is crushed, resulting powder diameter generally reaches more than 300 orders, medium particle diameter reaches 15～35 μ m, the cell wall breaking rate reaches more than 95%, its contained chemical constituent of the medicated powder of " breaking cellular wall " directly comes out, compare with traditional Chinese medicine medicated powder (chemical constituent is present in the complete cell wall), produced the variation of " matter ", preliminary pharmacological evaluation confirms: the cell grade super fine can obviously improve drug effect, is widely used aspect the modernization of Chinese medicine.Its principle is tentatively thought at present: the ultra-micro powder after the cell wall breaking can keep wherein each kind of composition by whole part, form oil/water type or the solid state emulsified thing of water/oil type between these compositions, the cell grade super fine is easily long by small intestinal sorption, the time of staying, be beneficial to absorption, the whole part of chemical constituent that directly exposes and emulsifying attitude is easy to the permeable membrane absorption simultaneously, has improved its bioavailability greatly.
Chinese medicine ultra-fine powder is broken to have brought a revolution to the form of Chinese drug reform and the modernization of Chinese medicine; cell wall breaking rate, specific surface area, effective ingredient dissolution, bioavailability have been improved; pharmacological action be can strengthen, reduce dosage, medical material and protection herb resource saved; also can improve abnormal smells from the patient, mouthfeel simultaneously; improve drug quality, conventionally relatively at present pulverize, decocting boils or method such as organic solvent extraction has incomparable advantage.Especially for the resinae medical material; animal drugs and valuable medicinal such as Sanguis Draxonis; Hirudo; Moschus; Calculus Bovis etc.; because composition is indeterminate in these medical materials; should not extract; after pulverizing, routine goes into the diffusing application of ball mostly; and behind the introducing superfine communication technique; to bring the influence of generation to traditional preparation process; make original material be in a kind of " new state " of ultramicro powder; give full play to the micropowders unique physical and chemical properties; Effective Components of Chinese Herb not only can not lose or reduce; but also can fully be absorbed by human body, the characteristic of Chinese medicine will obtain bigger performance.
The problem of the broken existence of 2 Chinese medicine ultra-fine powders
Although the broken research of Chinese medicine ultra-fine powder has become upsurge, but some problem with practical application meaning or difficult problems are arranged, so far do not have to such an extent that effectively solve, these problems or a difficult problem comprise: in the pulverizing medicinal materials process, along with reducing of grain diameter, the energy of required further pulverizing constantly increases (1), after grain diameter acquires a certain degree, crush efficiency obviously reduces (2) both just after pulverizing is finished and since particle diameter reduce still cause easily: surface energy increases, and granule is played pendulum; Mobile poor, easily assemble forming false bulky grain; Wettability increases, easily the moisture absorption; Adsorptivity increases, easily the impurity in the absorbed air.(3) because the existence of above problem, cause that the Chinese medicine micropowder occurs in the preparation process that powder fluidity is poor, divided dose is inaccurate, the easy moisture absorption, tablet technical problem such as easy-formation not, have a strong impact on the practical application of Chinese medicine micropowder, become the bottleneck that broken technology of Chinese medicine ultra-fine powder or Chinese medicine ultra-fine powder and Chinese medicine preparation are connected mutually.
At other industrial circles, also there is above similar problem, as the production of magnetic powder or ink powder, solution is broken with pigment exactly, and the fine powder of generation is distributed to rapidly in the water, weakens its aggregation, after treating that pulverizing is finished, again water is got rid of, dried, promptly obtain careful uniform magnetic powder or ink powder.But this method can not directly transplanting to the field of Chinese medicines because the former is a mineral, character is relatively stable, both water fasts is heated and can not destroys, and does not also have the process of preparation; Chinese medicine is then different, and ingredient complexity, character have nothing in common with each other, if also liquid feeding is pulverized, the solid-liquid separation process after pulverizing so (no matter being to filter or heat to concentrate) will damage the composition in the liquid.Therefore, at the field of Chinese medicines, the method for liquid feeding (referring generally to water) micronizing is considered to infeasible always.
Summary of the invention
The object of the present invention is to provide a kind of new superfine grinding method, especially be applied to the superfine grinding method of animal medicinal material, can solve the broken insurmountable problem of present Chinese medicine ultra-fine powder.
The present invention seeks to realize like this:
With the clean animal drug of drying, routine was pulverized 20～100 mesh sieves, added suitable disperse medium, placed micronizing equipment in the lump, carried out micronizing, promptly.
The animal drug that this breaking method comprised can be selected from but be not limited to the combination of following one or more: Hirudo, Eupolyphaga Seu Steleophaga, Formica fusca, Tabanus.
Above-mentioned preparation method specifically can be in the following method any one:
A. get dry clean animal drug, routine was pulverized 20～100 mesh sieves, added 0.01～5 times of solid dispersion medium that amount is suitable, used vibromill micronizing 10～60 minutes, promptly.
B. get dry clean animal drug, routine was pulverized 20～100 mesh sieves, added 0.2～5 times of amount appropriate liquid disperse medium, used vibromill micronizing 10～60 minutes, promptly.
In such scheme, involved disperse medium can be divided into solid dispersion medium, liquid dispersion medium two big classes by its state, is specially:
Solid dispersion medium can be selected from but be not limited to the combination of following one or more: solid polyethylene glycol, micropowder silica gel, microcrystalline Cellulose, cyclodextrin, magnesium stearate, Pulvis Talci, starch, carboxymethylstach sodium, acrylic resin, hydroxypropyl first, card pool nurse.
Liquid dispersion medium can be selected from but be not limited to the combination of following one or more: soybean oil, Oleum Arachidis hypogaeae semen, rapeseed oil, Semen Maydis oil, Oleum sesami, safflower oil, ethyl oleate, Oleum Cocois esters, Oleum helianthi monoglyceride, Cera Flava, Polyethylene Glycol, glycerol, propylene glycol, sorbitol, phospholipid, cholesterol, tween, span, Pa Luoshamu.
In such scheme, the operating temperature of vibromill can be the operation down of low temperature such as room temperature or logical cooling water, liquid nitrogen; And solid dispersion medium is best with one or more compositions dispersion effect of micropowder silica gel, solid polyethylene glycol, cyclodextrin in the above-mentioned used disperse medium, liquid dispersion medium is best with any one or a few compositions dispersion effect in Polyethylene Glycol, propylene glycol, glycerol, the tween, improvement to bioavailability is the most obvious, use the most general, therefore the inventor has carried out further design, formulate the technical scheme of following optimization, be not limited only in the following technical scheme any one but technical scheme that this patent comprises can be selected from:
A. get animal drug to be pulverized, routine was pulverized 20～100 mesh sieves, added in the micropowder silica gel, solid polyethylene glycol, cyclodextrin of 0.02～2 times of amount one or more compositions, with vibromill micronizing 20～60 minutes, promptly.
B. get animal drug to be pulverized, routine was pulverized 20～100 mesh sieves, added in the Polyethylene Glycol, propylene glycol, glycerol, tween of 0.2～2 times of amount any one or a few compositions, with vibromill micronizing 20～60 minutes, promptly.
The ratio that the further preferred ratio of wherein above-mentioned polyethylene glycol composition is Polyethylene Glycol-propylene glycol-glycerol-tween is 6～9: 1～3: 0～3: 0～3.
At last, according to the state difference of gained ultra micro compositions, it is as follows that the inventor designs dosage form selection:
Add solid disperse medium gained ultra micro mixture and can be used for directly preparing solid preparations such as pill, powder, tablet, granule, capsule.
Add liquid disperse medium gained ultra micro mixture and can be used for directly preparing solid or semi-solid preparations such as soft capsule, hard capsule, oral gel, solid/semisolid preparation capable of permeating skin and Orally taken emulsion, especially be directly used in fill Chinese medicinal soft capsule, hard capsule.
Beneficial effect
Technical scheme of the present invention is considered from practical angle, in conjunction with the needs of preparation, adds suitable disperse medium micronizing and prepares semi-finished product, directly makes required preparation.Thereby selected disperse medium is not a water, but multiple pharmaceutic adjuvant, this method has solved micronizing to a certain extent and has been applied to adaptability problem in the Chinese medicine preparation, broken through tired the scratching of technology that conventional micronizing efficient constantly reduces, broken the first powder process thinking model of preparation again, also abandoned the traditional view that Chinese medicine can not add the medium micronizing, this method has been crossed the broken bottleneck that is connected mutually with Chinese medicine preparation of Chinese medicine ultra-fine powder, be with the optimised process of pulverizing with the preparation perfect adaptation, will greatly promote superfine communication technique at the Chinese medicine single medicinal material, compound recipe is the application in the compound recipe especially, be the new trend that superfine communication technique is used in Chinese drugs agentia, reach the saving medical material, simplify the doulbe-sides' victory effect of preparation process.Specifically, this patent method is removed has the raising grinding particle size, improves bioavailability, outside the advantages such as saving medical material, also has following advantage:
1. take into full account medical material character medical material: animal medicinal material, mostly be protein, polypeptide constituents, easy deliquescing, albuminous degeneration are heated, mainly be its easily glutinous company, conventional pulverizing is not easy to operate, and destroys bigger to composition, normal adopt low temperature or freezing under pulverize, energy consumption is big, to the equipment requirements height; Adopt this patent invention preparation method, it has following clear superiority:
1. avoiding glutinous connects: if add suitable disperse medium, as add an amount of micropowder silica gel or Polyethylene Glycol, disperseed rapidly in the medicine crushing process, avoid glutinous and connect; 2. the time is short: pulverize time ratio and shortened originally, crush efficiency is than improving greatly originally; 3. fine size: the granularity that has improved medical material greatly, especially thinner with the waterproof pulverization granularity, gained mixture 90% particle diameter is in 10 μ m, and its medium particle diameter is in 4 μ m, more conventional micronizing granularity improves greatly, and it is convenient that animal medicinal material is pulverized.4. room temperature or low-temperature operation: by external cooling water or liquid nitrogen, can guarantee to pulverize and under room temperature or low temperature, carry out, can significantly protect effective ingredient to be subjected to heat damage.5. good stability: adopt this method operation, can avoid mince polymerization in put procedure of superfine powder, solve the problem of poor stability in this constituents storage.
2. take into full account need combining of preparation with pulverizing with preparation, angle from preparation, consider the factors such as raising of stability of formulation, bioavailability, select suitable disperse medium, for example if be prepared into capsule, the micropowder silica gel of normal selection adding 5～10% is pulverized, and the gained stabilized with mixture is good, mobile strong, can be directly used in capsule charge; Be equipped with soft capsule if draw up, can select to add vegetable oil or PEG400, other adds pharmaceuticss such as suitable suspending agent, stabilizing agent adjuvant commonly used, pulverizes in the lump, and gained fluid or semifluid are directly used in the filling soft capsule.
3. do not have subsequent technique, have problems in the solution explained hereafter:, therefore do not exist liquid, solid to be difficult to problems such as separation because this technology is directly made preparation after pulverizing; Added disperse medium again in pulverizing, the flowability of ultrafine powder is improved greatly, hygroscopicity reduces, and makes the easier molding of preparation, stable, has avoided the inherent defective of ultrafine powder.
4. the advantage of adjuvant itself is to improving the effect of micronizing
1. the application of micropowder silica gel
Have another name called white carbon, its odorless, tasteless, water insoluble; Do not react with most medicines, good flowability and adhesive force are arranged; Lubricant is made in short disintegrate, can increase stripping, solid dispersion, because of its light weight, volume are big, good fluidity as disperse medium, can significantly improve the flowability of superfine powder, avoid intermolecular reunion, guarantee the weight differential of preparation, its application value in the micronizing process is great.
2. the application of PEG400
Recommend to use the soft capsule adjuvant as American Pharmacopeia, be incorporated in the micronizing, further high degree of dispersion can improve bioavailability greatly, and effect is more outstanding, and this point has report in pharmacological testing; In the medicine crushing process, directly add PEG400, can make it in time, combine with ingredient fully, its in conjunction with effect be tradition " pulverize afterwards earlier and mix " method can not compare.
3. the application of cyclodextrin
Add an amount of hydroxypropyl cyclodextrin or beta-schardinger dextrin-in the disperse medium; can treat and pulverize that the volatile oil composition has direct bag and effect in medical material such as Moschus, Borneolum Syntheticum or the medical material; and envelop rate and bag and efficient height; can effectively protect volatility or the strong composition of sublimability, improve the stability of specific examples of such components in preparation.
5, make things convenient for preparation, improve preparation stability
Adopt the method that adds suitable disperse medium micronizing, gained ultra micro mixture can directly be made preparation according to clinical needs, and gained mixture height uniformly emulsify, granularity is little, good stability, no lamination, available this method solves stays the powder medical material to prepare the difficult problem of long-term puzzlement such as the easy layering of soft capsule, precipitation, equally also can improve stability as other preparation ultrafine powders such as capsule, powders, and preparation technology is simple and easy to do, be with the optimised process of pulverizing, will in ultra micro preparation production from now on, be promoted with the preparation perfect adaptation.
6, single medical material, Chinese medicine compound all can
This patent institute proposition method, be not only applicable to the processing of Chinese crude drug, can also be used to contain animal drugs, resin medicine, valuable medicine and stay the further development and use of the Chinese medicine compound of powder, be traumatology medicine commonly used as Anisodus carniolicoides C.Y.Wu et C.Chen, its annual sales volume be used to buy Chinese crude drug more than 30%, add the disperse medium micronizing if adopt, on the basis that guarantees curative effect, decrement is used, and can save about 50% medical material, its direct economy income is considerable, so this technology has boundless market prospect.
For further specifying the obtained beneficial effect of the present invention, the inventor describes from crushing effect, ultra micro stabilized with mixture and pharmacological testing three aspects:
One, crushing effect
(prescription is formed and is comprised Hirudo, Eupolyphaga Seu Steleophaga to select Hirudo (single, animal drug) and its open capsule of compound recipe horse, be animal drug) be representative, carry out conventional micronizing respectively and add 1 times of amount PEG-propylene glycol (9: 1) micronizing, pulverize separately 30 minutes, adopt the WJ9200 laser particle analyzer to measure granularity respectively, the results are shown in Table 1.
As seen from Table 1, the Sanguis Draxonis maximum particle diameter of conventional micronizing is greater than 200 μ m (fragment for multiple poly-accounts for 6～8%, but screening examination), and medium particle diameter is about 20 μ m; After adding the liquid disperse medium, maximum particle diameter is less than the particle of 20 μ m, and medium particle diameter is about 4 μ m; The compound recipe Ma Qitong maximum particle diameter of conventional micronizing is about 200 μ m (for multiple poly-fragment, account for 4～6%, but screening examination), and medium particle diameter is about 24 μ m; After adding the liquid disperse medium, maximum particle diameter is about 21 μ m, and medium particle diameter is about 4 μ m; Therefore, add disperse medium after, improved the granularity of medical material greatly, effect is remarkable.
Two, preparation stability
The more conventional micronizing of test objective and add the half-finished stability of medium micronizing gained
Trial drug
1. the conventional superfine powder of animal compound medicines prepares soft capsule content: get water purification trematodiasis, Eupolyphaga Seu Steleophaga medical material, and after the precomminution, micronizing, the gained micropowder adds 1.5 times of amount PEG400-propylene glycol (9: 1) and makes substrate, makes soft capsule content, uses for stability test;
2. the animal compound medicines adds disperse medium and directly pulverizes the preparation soft capsule content: get water purification trematodiasis, Eupolyphaga Seu Steleophaga medical material, after the precomminution, add 1.5 times of amount PEG400-propylene glycol (9: 1) and make substrate, micronizing, the gained mixture is made soft capsule content, makes stability test and uses.
Test method
Centrefuge experiment is got the 5g sample respectively and is put in the centrifuge tube, and with the centrifugal 20min of 3000rpm, observation has or not lamination, and result of study sees Table 2.
Cold-resistant heat-resistant experiment is got an amount of sample respectively and is put low temperature 2-5 ℃, 30d; And high temperature 50-53 ℃, 24h, the color and luster of observation sample, denseness, uniformity have no change, and result of study sees Table 21.
Sample thief is an amount of respectively for room temperature reserved sample observing method, respectively adorns three tool plug test tubes, adopts room temperature reserved sample observing method working sample after 3 months, and whether appearance character is stable, and result of study sees Table 2.
As seen from the experiment, with new approaches micronizing gained mixture, good stability, no lamination can tentatively be determined to stay the powder medical material to prepare the difficult problem of long-term puzzlement such as the easy layering of soft capsule, precipitation with this method solution.
Three, pharmacological testing checking
For further checking the present invention in order to prove that pharmaceutical preparation of the present invention is improving dissolution in vitro and bioavailability, the contribution that save medical material, improves the drug effect aspect, it is representative that the inventor selects Hirudo, cures mainly according to its function, has carried out animal contrast pharmacodynamic experiment.
One, basic document
1, is subjected to the reagent thing: Hirudo: available from building connection pharmacy, through accreditation; Hirudo coarse powder: get dry water purification trematodiasis and pulverize, collect 100 order powder; Hirudo ultra micro mixture: select PEG400-propylene glycol (9: 1) to make substrate, mix obtaining through micronizing, mean diameter (3.89 ± 0.43) μ m, content of dispersion 50%, 1/2 of the quite primary dose of superfine powder group administration is tested.Blank: do blank with normal saline.
2, experimental animal: the NIH mice, 20 ± 2g, male and female half and half are provided by Beijing Medical University's Experimental Animal Center.
Two, content of the test:
1. test sample is to the influence of clotting time of mice
The NIH mice is divided into 3 groups at random, 12 every group.Press medicine listed in the table 3 and dosage gastric infusion, compare with normal saline.Every day 3 times, successive administration 3d behind the 4th day administration 1h, adjoins the ball rear vein beard from the mice ophthalmic and gets blood, presses capillary tube method, measures the clotting time of respectively organizing mice, analyzes through the t inspection statistics, the results are shown in Table 3.
Experiment shows that Hirudo coarse powder and Hirudo superfine powder all have definite anticoagulating active, and the anticoagulating active of superfine powder obviously is better than common loosing.
2. test sample is to the influence in mice bleeding time
The NIH mice is divided into 3 groups at random, 12 every group.Press medicine listed in the table 4 and dosage gastric infusion, compare with normal saline.Every day 2 times, continuous irrigation stomach 3d behind the 4th day administration 1h, respectively organizes the bleeding time that mice is cut tail 5mm with cutting tail method mensuration.The results are shown in Table 4.
Experiment shows that Hirudo coarse powder and Hirudo superfine powder all have definite anticoagulating active, and the anticoagulating active of superfine powder obviously is better than common loosing.
3. test sample is to the influence of thromboembolism preventing effect in the mice body
Because of the mouse tail bleeding time, have good collimation with Mus carotid artery bypass thrombosis method, sieve method is used for experiment so can be used as in a kind of body of simple and easy to do anti-thrombosis drug just.The NIH mice is divided into 3 groups at random, 12 every group.Irritate stomach 3d with given dose, behind the 4th day administration 1h, mice is fixed, cut off, vertically put into (37 ± 1) ℃ normal saline, make tail end 3cm under liquid level, in the record bleeding time, the results are shown in Table 5 apart from tail point 3mm place.
Experiment shows that thromboembolism preventing effect in the body is also loose for excellent with ultra micro.
4. acute toxicity test in mice
Give mouse stomach common flour, each 85g/kg of superfine powder in one day, be equivalent to more than 100 times of clinical 70kg people's per kilogram of body weight consumption per day, observed continuously seven days, mice generally in order, none death illustrates this product low toxicity, safety.
5. rat long term toxicity test
Get the Wistar rat, successive administration 30 days, general situation such as the activity of rat, behavior, feed, drinking-water, hair color, fecaluria is not seen appreciable impact, and none death, the hematology of rat, blood biochemical learn and important organ pathological tissue index does not all have remarkable change, recovered to observe through 10 days after administration finishes, do not observe other the back something lost and the toxic action of secondary.Prompting ultra micro preparation clinical practice safety, low toxicity.
By above results of pharmacodynamic test, except that its therapeutical effect of proof, also further specify its need 1/2 recipe quantity, can meet or exceed the effect of former prescription, illustrate that the variation of matter has taken place this medical substance, be a kind of new medical substance
The specific embodiment
Enumerate embodiment below, further specify the present invention, each embodiment only is used to illustrate the present invention, does not limit the present invention:
Embodiment 1 micronizing prepares Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 20 mesh sieves, add 1.5 times of amount PEG400-propylene glycol (9: 1) mixture and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 2 micronizing prepare Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 40 mesh sieves, add 0.5 times of amount decanoyl/octanoyl glycerides and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 3 micronizing prepare Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 60 mesh sieves, add 3 times of amount Tween 80-ethyl oleate-propylene glycol (60: 20: 20) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 4 micronizing prepare Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 80 mesh sieves, add 2 times of amount soybean oil-sorbester p17-Cera Flavas (9: 0.7: 0.3) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 5 dry process Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 20 mesh sieves, add the micropowder silica gel of 0.2 times of amount and make dispersant, use vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 6 directly pulverizes preparation Hirudo ultra micro mixture
Get dry water purification trematodiasis, pulverize the back with common pulverizer and cross 20 mesh sieves, directly used the vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 7 micronizing prepare Hirudo, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 20 mesh sieves, add 1.5 times of amount PEG400-propylene glycol (9: 1) mixture and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 8 micronizing prepare Hirudo, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 40 mesh sieves, add 0.5 times of amount decanoyl/octanoyl glycerides and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 9 micronizing prepare Hirudo, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 60 mesh sieves, add 3 times of amount Tween 80-ethyl oleate-propylene glycol (60: 20: 20) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 10 micronizing prepare Hirudo, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 80 mesh sieves, add 2 times of amount soybean oil-sorbester p17-Cera Flavas (9: 0.7: 0.3) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 11 dry process Hirudos, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 20 mesh sieves, add the micropowder silica gel of 0.2 times of amount and make dispersant, use vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 12 directly pulverizes preparation Hirudo, Eupolyphaga Seu Steleophaga ultra micro mixture
Get dry water purification trematodiasis, Eupolyphaga Seu Steleophaga, pulverize the back with common pulverizer and cross 20 mesh sieves, directly used the vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 13 micronizing prepare Formica fusca ultra micro mixture
Get the clean Formica fusca of drying, pulverize the back with common pulverizer and cross 20 mesh sieves, add 1.5 times of amount PEG400-propylene glycol (9: 1) mixture and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 14 micronizing prepare Formica fusca ultra micro mixture
Get the clean Formica fusca of drying, pulverize the back with common pulverizer and cross 40 mesh sieves, add 0.5 times of amount decanoyl/octanoyl glycerides and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 15 micronizing prepare Formica fusca ultra micro mixture
Get the clean Formica fusca of drying, pulverize the back with common pulverizer and cross 60 mesh sieves, add 3 times of amount Tween 80-ethyl oleate-propylene glycol (60: 20: 20) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 16 micronizing prepare Formica fusca ultra micro mixture
Get the clean Formica fusca of drying, pulverize the back with common pulverizer and cross 80 mesh sieves, add 2 times of amount soybean oil-sorbester p17-Cera Flavas (9: 0.7: 0.3) and make substrate, use vibrating mill micronizing 30 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 17 dry process Formica fusca ultra micro mixture
Get the clean Formica fusca of drying, pulverize the back with common pulverizer and cross 20 mesh sieves, add the micropowder silica gel of 0.2 times of amount and make dispersant, use vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Embodiment 18 directly pulverizes preparation Formica fusca ultra micro mixture
Get dry clean Formica fusca, pulverize the back with common pulverizer and cross 20 mesh sieves, directly used the vibrating mill micronizing 45 minutes, make the ultra micro mixture of medium particle diameter, promptly less than 10 μ m.
Subordinate list:
The different superfine grinding method grinding particle size of table 1 check table
Table 2 results of stability table
| The investigation project | Conventional micronizing | Adding disperse medium pulverizes | The allantoin homogeneity is checked |
| Centrefuge experiment | Slight lamination is arranged | No lamination | Qualified |
| Cold-resistant heat-resistant experiment | The upper strata color is shallow, rarer, and lower floor's color depth is thick | Sample is stable | Qualified |
| Reserved sample observing | As seen appearance character has obvious lamination upper strata rare, and lower floor is thick | Appearance character is stable, no lamination | Qualified |
Table 3 test sample to the influence of clotting time of mice (X ± S, n=12)
| Group | Dosage (g/kg) | Clotting time (min) | Rate elongation % (blank) | Rate elongation % (than coarse powder) |
| Blank | - | 2.87±1.47 | ||
| The Hirudo coarse powder | 0.5 | 5.79±2.13 | 101.7 | |
| Hirudo ultra micro mixture | 0.5 | 7.42±2.34 | 158.5 | 28.2 |
Table 4 test sample to the influence in mice bleeding time (X ± S, n=12)
| Group | Dosage (g/kg) | Bleeding time (min) | Rate elongation % (blank) | Rate elongation % (than coarse powder) |
| Blank | - | 8.42±2.63 |
| The Hirudo coarse powder | 0.5 | 12.33±5.39 | 46.4 | |
| Hirudo ultra micro mixture | 0.5 | 14.45±6.14 | 71.6 | 17.2 |
Table 5 test sample to thromboembolism preventing effect in the mice body relatively (X ± S, n=12)
| Group | Dosage g/kg | Clotting time min | Rate elongation % (blank) | Rate elongation % (than coarse powder) |
| Blank | - | 1.32±0.28 | ||
| The Hirudo coarse powder | 0.5 | 1.58±0.57 | 19.7 | |
| Hirudo ultra micro mixture | 0.5 | 1.73±0.62 | 31.1 | 9.5 |
Claims (6)
1. one kind adds the preparation method that disperse medium prepares the animal drugs superfine powder, it is characterized in that:
1) described animal drug is the combination of following one or more: Hirudo, Eupolyphaga Seu Steleophaga, Formica fusca, Tabanus;
2) described preparation method is any one in the following method:
A. get animal drugs, routine was pulverized 20～100 mesh sieves, added 0.01～5 times of solid dispersion medium that amount is suitable, used vibromill micronizing 10～60 minutes, promptly;
B. get animal drugs, routine was pulverized 20～100 mesh sieves, added 0.2～5 times of amount appropriate liquid disperse medium, used vibromill micronizing 10～60 minutes, promptly;
3) used solid dispersion medium is the combination of following one or more among the said method a.: solid polyethylene glycol, micropowder silica gel, microcrystalline Cellulose, cyclodextrin, magnesium stearate, Pulvis Talci, starch, carboxymethylstach sodium, acrylic resin, hydroxypropyl first, card pool nurse; Used liquid dispersion medium is the combination of following one or more among the said method b.: soybean oil, Oleum Sesami, Oleum Arachidis hypogaeae semen, rapeseed oil, Semen Maydis oil, Oleum sesami, safflower oil, ethyl oleate, Oleum Cocois esters, Oleum helianthi monoglyceride, Cera Flava, liquid macrogol, glycerol, propylene glycol, sorbitol, phospholipid, cholesterol, tween, span, Pa Luoshamu.
2. preparation method as claimed in claim 1, it is characterized in that steps of the method are: get animal drugs to be pulverized, routine was pulverized 20～100 mesh sieves, the compositions that adds in the micropowder silica gel, solid polyethylene glycol, cyclodextrin of 0.02～2 times of amount one or more, with vibromill micronizing 20～60 minutes, promptly.
3. preparation method as claimed in claim 1, it is characterized in that steps of the method are: get animal drugs to be pulverized, routine was pulverized 20～100 mesh sieves, the compositions that adds in the Polyethylene Glycol, propylene glycol, glycerol, tween of 0.2～2 times of amount any one or a few, with vibromill micronizing 20～60 minutes, promptly.
4. preparation method as claimed in claim 3, the ratio that it is characterized in that Polyethylene Glycol-propylene glycol-glycerol-tween is 6～9:1～3:0～3:0～3.
5. the application of preparation method as claimed in claim 1 or 2 in preparation pill, powder, tablet, granule, capsule.
6. as claim 1, the application of 3 or 4 described preparation methoies in preparation soft capsule, hard capsule, oral gel, solid/semisolid preparation capable of permeating skin and Orally taken emulsion.
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