CN1879639A - A nanometer 'Xue Shuan Tong' injection and preparation method thereof - Google Patents
A nanometer 'Xue Shuan Tong' injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a nano Xueshuantong injection and process for preparation, which is the combination of Notoginsen triterpenes, the effective components extracted and purified from principal root of notoginseng with medicinal carrying agents. The preparation can be made into liquid injections, fluid infusions and powder injections. And the preparation also comprises Notoginsen triterpenes 6-8 weight parts, medicinal carrying agents 30-80 weight parts.
Description
Affiliated technical field
The invention belongs to field of traditional Chinese medicine pharmacy, be specifically related to a kind of nanometer ' Xue Shuan Tong ' injection and preparation method thereof.
Technical background
Nanometer Chinese medicine mainly is meant what the utilization nanotechnology was made, and the footpath grain is less than middle pharmaceutically active ingredient, effective site, former medicine and the compound preparation of 100 nanometers.Living organism is the process of a complexity to absorption, the metabolism of medicine, and it is also closely related with the physical state of said preparation that the pharmacodynamics effect that Chinese medicine preparation produces can not only be belonged to the distinctive chemical composition of medicine.Therefore, the physical state of change pharmaceutical preparation is a kind of effective ways of new drug development.Aspect the change physical state, the unit size that changes medicine is highly effective.Owing to quantum size effect and skin effect, nanoparticle presents novel physical chemistry and biological characteristics when particle size enters nanometer scale.Applying nano technology that Here it is may make pharmaceutically active and bioavailability improve and even produces new characteristic according to the place in Chinese medicine research.
The preparation of nanometer Chinese medicine is that research nanometer Chinese medicine is most basic, also is sixty-four dollar question.When the research of Chinese medicine is introduced in nanotechnology, must consider the multiformity of Chinese prescription, the complexity of Chinese medicine ingredients, for example: the Chinese medicine single medicinal material can be divided into mineral drug, plant amedica, animal drugs and fungus medicine etc., and the effective site of Chinese medicine and effective ingredient comprise inorganic compound and organic compound, water soluble ingredient and liposoluble constituent etc. again.Therefore, at different medicines, when carrying out nanorize, must adopt different technology paths.Nanometer Chinese medicine and new product of Chinese medicine relation are very close, how under the guidance of tcm theory, to carry out the research of nanometer new product of Chinese medicine, Chinese medicine is made the modern preparation of efficient, quick-acting, long-acting, little, the low toxicity of metering, taking convenience, also is the problem that must consider when carrying out the Chinese medicine nanorize.
At present, the problem that exists in Chinese medicine research of nanotechnology can not be ignored.One. the preparation difficulty of nanometer Chinese medicine: though China has prepared some nano level Chinese medicines, because herbal species is various, complicated component, different compositions is owing to the difference of its site of action, mechanism of action and effect emergency requires its size, carrier components and dosage all possible different.Nanometer Chinese medicine should have its a cover quality standard simultaneously, makes it produce standardization; Two. the toxic and side effects of nanometer Chinese medicine: medicine is made nanoparticle, and significant variation has all taken place for its physical property and chemical property, and whether these change has all relevant research report of toxicity to human body.But, whether can participate in directly or, there is no about report as the normal chemical reaction of catalyst upset body because the particularity of nano material except penetrable skin, also can enter in the organelle.In addition, nanometer Chinese medicine can also be by the barrier system of body, and whether it can influence the central nervous system, the growth of the generation of sperm and vigor thereof, fetus etc., and these problems all can't be avoided; Three. Chinese medicine is after nanoscale is pulverized, and nano-particle surface is long-pending to become big, because the activity of nano-particle surface makes them be easy to reunite together, this brings very big difficulty for the collection of nanoparticle and the stability of drug effect thereof.
The research of modern Chinese medicine is exactly to inherit on the traditional basis of Chinese medicine, make full use of modern means of science and technology, make Chinese medicine have advanced production technology and modern formulation, accomplish " effective, safe, controlled ", it is one of important directions of modern Chinese medicine development that nanotechnology is applied to the field of Chinese medicines.Nanometer Chinese medicine generally is not simply Chinese crude drug to be crushed to nanometer scale, but carry out the nanotechnology processed at the effective site or even the effective ingredient of certain flavor medicine of forming Chinese medicinal formulae, give Chinese medicine with new function, as: bioavailability improved, the intensifier target tropism; Reduce toxic and side effects; Present new drug effect, widen the indication of former medicine; Enrich the dosage form selection of Chinese medicine; Reduce dosage, save natural resources of Chinese medicinal materials etc.
Compare with traditional Chinese medicine, nanometer Chinese medicine has following characteristics: 1. improved the availability of medicine, reduced dosage.2. strengthen the targeting of medicine.3. have slow-release function, the Chinese medicine nanoparticle is carried out certain finishing after, may make Chinese medicine have slow releasing function.4. present new drug effect, widen former medicine indication, when Chinese medicine is machined to nano-scale,, thereby can make Chinese medicine present the function that makes new advances because effects such as its quantum size cause the change of its physics, chemical characteristic.5. enrich the dosage form selection of Chinese medicine, promote traditional route of administration.
Xu Huibi etc. have retrieved the patent that related to nanosecond science and technology in 1998～2000 in the United States Patent (USP), find that such patent accounts for more than 80% of sum with biomedical relevant patent, Yang Mengjun has applied for the patent of more than 940 nanometer Chinese medicine in 1 year calendar year 2001, but the major part of its application all is the raw material of Chinese medicine medicine carries out nano-pulverization, and its patent practicality is not strong.
The research of nanometer Chinese medicine at present mainly concentrates on and utilizes nanotechnology that the clearer and more definite monomer effective ingredient of minority composition is carried out nanometer to handle and make nanometer formulation, or crude drug directly is ground into nanoscale, nanometer formulation to most of Chinese medicine is studied also seldom, mainly be because middle pharmaceutically active ingredient and effective site particularly in the Chinese medicine compound effective site itself be exactly one " black box ", real effective ingredient or the effective site research that plays pharmacological action itself is exactly a difficult problem in the Chinese medicine, and because the Chinese medicine ingredients more complicated, so it is prepared into difficult more that nanometer formulation need overcome, therefore, Chinese medicine nanometer formulation and technology are medical scientific research worker's important subject.
The Radix Notoginseng medicinal part is mainly main root and reed head, mainly contain Radix Notoginseng total arasaponins in the Radix Notoginseng main root, has anticoagulant, reduce effects such as blood viscosity, using clinically is to be the XUESHUANTONG ZHUSHEYE of feedstock production with the Radix Notoginseng main root more widely, this product is used for the treatment of the hold concurrently sudden blindness (retinal vein occlusion) of deficiency of both QI and YIN disease of blood stasis, central serous chorioretinopathy and angina pectoris, but the generation of this effect of XUESHUANTONG, need the regular hour, during in vivo test, rabbit vein injects XUESHUANTONG ZHUSHEYE, every day 1 time, need continuous 20 days, obviously effect just appears, point out clinical during in order to treatment thrombosis illness, invalid as the too short possibility of administration time, Radix Notoginseng total arasaponins is to anticoagulant in the Radix Notoginseng main root, though reduce blood viscosity certain effect is arranged, but it is still powerful inadequately to treatment of diseases effects such as the retinal vein occlusions, if can strengthen the anticoagulant function from other mechanism, form and suppress, strengthen its effect, simultaneously, if can microcirculation improvement, activate fibrinolytic, then better efficacy.
Consult document and patent, do not retrieve the data of nanometer ' Xue Shuan Tong ' injection.
Summary of the invention
For these reasons, we are through secular experimentation, Radix Notoginseng total arasaponins and pharmaceutical carrier that the Radix Notoginseng main root is extracted make up, be prepared into nanometer ' Xue Shuan Tong ' injection, use the XUESHUANTONG ZHUSHEYE time clinically than drawbacks such as length, simultaneously by nanometer preparation the effective site Radix Notoginseng total arasaponins thereby solve, can well pass through blood brain barrier, strengthened treatment of diseases effects such as the retinal vein occlusions, when strengthening pharmacological action, do not increased the toxic and side effects of medicine.
The invention reside in the ejection preparation that a kind of nano thrombus dredging is provided;
The present invention also is to provide a kind of preparation method of nanometer ' Xue Shuan Tong ' injection;
The present invention also is to provide the application of nanometer ' Xue Shuan Tong ' injection;
The present invention is achieved through the following technical solutions.
One. process recipes
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 6-8 weight portion, and pharmaceutical carrier 30-80 weight portion, wherein emulsifying agent is 18-42 weight portion, lipid 12-38 weight portion in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 6-8 weight portion, emulsifying agent 18-42 weight portion and lipid 12-38 weight portion, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 6-8 weight portion, lecithin, the husky nurse F-68 of pool network, soil temperature 80 18-42 weight portions, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 12-38 weight portion heating and melting again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 6-8 weight portion, lipid 12-38 weight portion and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent 18-42 weight portion, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 6-8 weight portion, be dissolved in the 30%-70% ethanol; One or more common 12-38 weight portions in the lipid are dissolved in alkane, mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, a controlled pressure 0.1-0.2 atmospheric pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
The lipid that the present invention is used: as fatty acid glycerine esters (comprise glyceryl tristearate, tripalmitin, myristin, trilaurin, three climb over a wall acid glyceride, Witepsol W35, WitepsolH35, Witepsol H42, glyceryl monostearate) and fatty acid (as stearic acid, Palmic acid) etc.;
The emulsifying agent that the present invention is used: as phospholipid (comprising soybean lecithin, Ovum Gallus domesticus Flavus lecithin and phosphatidylcholine etc.), poloxamer, polysorbate, cholate, alevaire etc.;
Method five: oil phase: Radix Notoginseng total arasaponins 6-8 weight portion and oily 30-80 weight portion are mixed into solution (one or more in paracyanogen base alkyl acrylate, polylactic acid, polylactide-co-glycolide, chitosan, the gelatin), mix with dehydrated alcohol, shake up, get clear solution; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant PluronicF68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add pharmaceutic adjuvant, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains infusion solution;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains injectable powder;
The used pharmaceutic adjuvant of infusion solution of the present invention is sodium chloride or glucose; The used adjuvant of injectable powder of the present invention is sucrose, lactose or mannitol;
Nanometer aqueous injection of the present invention, nanometer infusion solution add a small amount of PVP (polyvinylpyrrolidone), can improve stability of formulation.
Two. quality standard
Detect foundation: the nanometer quality testing of carrying out according to the Pharmacopoeia of the People's Republic of China (version in 2005, two appendix XIX E microcapsules, microsphere and Liposomal formulation guidelines).
Experimental apparatus: H-7000 type transmission electron microscope instrument (Japanese Hitachi company); Zetamaster photon correlation spectrometer (Britain Malvern company); LC-10A high performance liquid chromatograph (day island proper Tianjin); TGL-18G type table model high speed centrifuge.
1. morphologic observation and particle diameter
This patent Nano medication is carried out morphologic observation under transmission electron microscope, as seen be spherosome, size is more even, smooth surface, no adhesion.Measured 500 according to the light micrograph of Nano medication, mean diameter is 60 ± 20nm, and maximum particle diameter is 120nm, and minimum grain size is 40nm, and particle size distribution meets normal distribution law.
2. envelop rate and drug loading are measured
Adopt high performance liquid chromatography to carry out assay, and with following formula computational envelope rate and drug loading:
Envelop rate (%)=(dosage-free drug amount)/dosage * 100%;
Weight * 100% of drug loading (%)=(dosage-free drug amount)/Nano medication.
The result: envelop rate is 83.2%, and drug loading is 10%-20%.
3. study on the stability
Nano medication is placed in the bottle sealing respectively.In the environment of refrigerator (3-5 ℃), room temperature (20-25 ℃) and 37 ℃ (RH75%), place, in 0,1,2 with observe March such as outward appearance, size, redispersibility of Nano medication etc.The result there is no significant change, and it is good that the Nano medication redispersibility under 3 kinds of conditions keeps, the generation of no polymerism.The results are shown in Table 1.
Table 1 stability experiment result
| The placement condition | Observation index | Time (moon) | |||
| 0 | 1 | 2 | 3 | ||
| 3-5℃ 20-25℃ 37℃(RH75％) | Mean diameter (nm) color mean diameter (nm) color mean diameter (nm) | 63.4 white 63.3 whites 63.4 | 63.4 white 63.4 whites 63.5 | 63.6 white 63.7 whites 63.8 | 63.7 white 63.9 whites 64.0 |
| Color | White | White | White | White | |
Conclusion: show that by above-mentioned experiment this patent Nano medication has good stability, prove absolutely that technology of the present invention has practical significance.
Three. the check and analysis experiment
The check and analysis of 'Xue Shuan Tong ' injection Radix Notoginseng total arasaponins
Measure according to high performance liquid chromatography (appendix VID of Chinese Pharmacopoeia version in 2000).
Chromatographic condition: use octadecylsilane chemically bonded silica as filler; Second is fine-and water (20: 80) is mobile phase.
Reference substance solution preparation: the ginsenoside Rb that learnt from else's experience dry 24 hours
1, the ginsenoside Rg
1Reference substance is an amount of, accurate claims surely, adds mobile phase and is diluted to and contains ginsenoside Rb among the 1ml
1, the ginsenoside Rg
10.8mg solution, promptly get reference substance solution.
The preparation of need testing solution: get the about 100mg of this patent ejection preparation and commercially available XUESHUANTONG ZHUSHEYE (aqueous injection, infusion solution drying), the accurate title, decide, and puts in the 25ml volumetric flask, adds mobile phase and be diluted to scale, shakes up, and obtains need testing solution.
Assay method: precision is measured reference substance solution and need testing solution 10ul, injects high performance liquid chromatograph respectively,, with calculated by peak area content that is, records and the results are shown in Table 2 according to external standard method:.
Table 2 'Xue Shuan Tong ' injection content relatively
| Group | Content of the total saponins in radix notoginseng is (with ginsenoside Rb 1, the ginsenoside Rg 1Calculate) the mg/ bottle |
| Commercially available XUESHUANTONG ZHUSHEYE nano thrombus dredging aqueous injection nano thrombus dredging infusion solution nano thrombus dredging injectable powder | 70.26 70.06 69.87 70.58 |
Conclusion: show that by above-mentioned experiment this patent technology has practical significance.
Four. irritant experiment
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
Laboratory animal: healthy big ear rabbit, male and female dual-purpose.
Experimental technique: get 3 of healthy big ear rabbit, animal is fixed in the rabbit hutch, with ethanol with skin degerming after, in right side auricular vein place injection this patent nanometer ' Xue Shuan Tong ' injection, the grade of injecting same volume in the opposite side corresponding position is oozed G/W in contrast.Inject every day 1 time, continuous 3 times, observe the reaction of rabbit ear edge vein.Behind last administration 24h,, take off two ears, soak,, dissect and take out vein, do the tissue slice inspection, observe the reaction of injection site apart from injection site 1-4cm place with 10% formalin with the rabbit sacrificed by exsanguination.
Experimental result: in the process of the test, place, perusal two ear vein injection site, swollen, the heat of show etc. does not stimulate performance.Show: administration group section position tissue morphology no significant difference, do not see that the pathomorphology due to this product toxicity changes (blood vessel structure is normal, no endothelial cell damage, no thrombosis formation and the variation of other pathologic).
Five. toxicological experiment
Experiment 1
Hemolytic toxicity is investigated
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
Experimental technique:
The preparation of 2% red blood cell suspension: get rabbit ear edge vein and get blood 10-20ml, put into the conical flask that fills bead, Fibrinogen is removed in jolting 10 minutes, makes to become to take off fine blood.Add the normal saline solution of 10 times of amounts, shake up, centrifugal, remove supernatant, sedimentary erythrocyte reuse normal saline solution washing 2-3 time, when supernatant does not take on a red color till.It is 2% suspension that the erythrocyte of gained is made into concentration with normal saline, promptly.
Test method: get 6 in test tube, add 2% red blood cell suspension and normal saline solution successively by the proportional quantity in the table 3, mixing was placed 30 minutes in 37 ℃ of calorstats, added not commensurability nanometer ' Xue Shuan Tong ' injection of the present invention (is blank with the 6th pipe) respectively, after shaking up, put in 37 ℃ of calorstats, beginning was observed 1 time every 15 minutes, after 1 hour, observed 1 time every 1 hour, observed altogether 2 hours.
Each group proportional quantity of table 3
| The test tube numbering | 2% red blood cell suspension (ml) | Normal saline solution (ml) | Medicinal liquid (ml) |
| 1 2 3 4 5 6 | 2.5 2.5 2.5 2.5 2.5 2.5 | 2.0 2.1 2.2 2.3 2.4 2.5 | 0.5 0.4 0.3 0.2 0.1 0 |
Experimental result: be as the criterion with the 3rd test tube, each Guan Junwei dyes redness, and microscopically is observed and do not seen that erythrocyte fragmentation is arranged, and not haemolysis of this patent nanometer ' Xue Shuan Tong ' injection is described, safety is good.
Experiment 2
Acute toxicity testing
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
XUESHUANTONG ZHUSHEYE (LiZhu Medicine Group Co., Ltd)
Laboratory animal: healthy mice 18-22g,, male and female half and half.
Experimental technique: get mice, be divided into commercially available XUESHUANTONG ZHUSHEYE group, this patent nano thrombus dredging aqueous injection group, infusion solution group, injectable powder group, the tail intravenously administrable, dosage is converted into the mice dosage according to 50 times of people's dosage according to body surface area, this patent nano thrombus dredging injection is identical with commercially available XUESHUANTONG ZHUSHEYE dosage, administration every day 1 time continuous 7 days, is observed the dead mouse situation, record data, experimental result sees Table 4:
The medication of table 4 mice, survival condition are relatively
| Group | Number of animals only | Death toll only | Mortality rate % |
| Commercially available XUESHUANTONG ZHUSHEYE group this patent nano thrombus dredging aqueous injection this patent nano thrombus dredging transfusion group this patent nano thrombus dredging injectable powder group | 20 20 20 20 | 2 2 3 2 | 10 10 15 10 |
Conclusion: show that by above-mentioned experiment this patent nanometer ' Xue Shuan Tong ' injection has identical safety with commercially available XUESHUANTONG ZHUSHEYE
Six. pharmacological evaluation
Experiment 1
See through the blood brain barrier experiment
The mensuration of cerebrospinal fluid Chinese medicine concentration
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
XUESHUANTONG ZHUSHEYE (LiZhu Medicine Group Co., Ltd)
Laboratory animal: new zealand rabbit, the about 2.5kg of body weight, male and female are not limit.
Experimental technique: get new zealand rabbit, be divided into commercially available XUESHUANTONG ZHUSHEYE group, this patent nano thrombus dredging aqueous injection group, infusion solution group, injectable powder group, the auricular vein administration, extracting 0.5ml left and right sides cerebrospinal fluid at different time experimentizes, be respectively 5,10,20,30 behind the injectable drug, 60min sample time, 120min.After getting cerebrospinal fluid 0.25ml and adding an amount of solvent suspendible 15min, leave standstill 15min,, get supernatant 20 μ l sample introductions with the centrifugal 1min of 10000r/min.The results are shown in Table 5.
The mensuration (ug/ml) of table 5 cerebrospinal fluid Chinese medicine concentration
| Group | 5min | 10min | 20min | 30min | 60min | 90min | 120min |
| Commercially available XUESHUANTONG ZHUSHEYE group nano thrombus dredging aqueous injection of the present invention group nano thrombus dredging transfusion of the present invention group nano thrombus dredging injectable powder of the present invention group | 7.3 30.2 29.8 30.7 | 12.9 42.3 43.0 43.1 | 8.4 37.2 37.8 37.7 | - 31.2 31.4 31.1 | - 23.1 23.7 23.4 | - 14.7 15.1 14.8 | - 8.9 8.7 8.6 |
Conclusion: show that by above-mentioned experiment nanometer ' Xue Shuan Tong ' injection of the present invention can well pass through blood brain barrier.
Experiment 2
Influence to the rabbit retinal vein
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
XUESHUANTONG ZHUSHEYE (LiZhu Medicine Group Co., Ltd)
High molecular dextran (70) (No.3 Pharmaceutical Factory, Guilin City production)
Laboratory animal: rabbit, male and female dual-purpose.
Experimental technique: rabbit is got in rabbit ball retinal capillary fork net number influence test, and the male and female dual-purpose is divided into XUESHUANTONG ZHUSHEYE group, nano thrombus dredging aqueous injection group of the present invention, infusion solution group, injectable powder group at random.Behind 3% pentobarbital sodium intraperitoneal injection of anesthesia, inject 10% high molecular dextran normal saline solution 15ml/kg from auricular vein, cause acute model of microcirculation obstacle.Blood capillary on 20min usefulness microscopic examination rabbit left eye ball retina after the injection, select to observe on the ball retina blood capillary crossing net in the fixed-area scope count (value before the medicine) by the eyepiece that has measured area device (1m * 1mm grid), and then every group of difference quiet notes 2ml/kg (infusion solution and injectable powder are mixed with the solution with the aqueous injection equal densities), observing the blood capillary crossing net of measuring fixed position with method behind the administration 40min counts (being worth behind the medicine), with difference (being worth before the value-medicine behind the medicine) is index, between organizing, administration group and matched group compare (t or t ' check), result such as table 6.
Table 6 XUESHUANTONG is to the influence of rabbit ball retinal capillary fork net number
| Group | Number of animals only | Difference | The P value |
| The commercially available XUESHUANTONG ZHUSHEYE of normal saline nano thrombus dredging aqueous injection of the present invention nano thrombus dredging infusion solution of the present invention nano thrombus dredging injectable powder of the present invention | 5 5 5 5 5 | 0.56±0.72 1.52±0.38 2.97±0.92 2.89±0.93 2.94±0.87 | - ＜0.05 ＜0.01 ＜0.01 ＜0.01 |
Conclusion: show that by above-mentioned experiment nanometer ' Xue Shuan Tong ' injection of the present invention has better pharmacological action to the retinal vein occlusion.
Experiment 3
Protective effect to rat myocardial ischemia and reperfusion damage different time
The experiment medicine: the present invention respectively organizes nano thrombus dredging preparation (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
XUESHUANTONG ZHUSHEYE (LiZhu Medicine Group Co., Ltd)
Laboratory animal: the wistar rat, male and female are not limit, body weight 250 ± 45g.
Experimental technique: get rat, random packet, the open suction of ether anaesthetized, the blood heparinization, cut off the thoracic cavity, add a little trash ice bits immediately and supply epicardial cooling in the thoracic cavity, cut off pericardium, ascending aorta is cut off at nearly innominate artery place, nearly pulmonary artery crotch is cut off main pulmonary artery, mention heart then, in the ligation, postcava and pulmonary artery, and in its distal severed, rapidly heart is placed cold cardioplegic solution (4 ℃), stop to heart beating from the ascending aorta broken ends of fractured bone constant voltage lavation (pressure 3.99-5.32kpa) of cutting off with same cardioplegic solution, till myocardium color bleached, the isolated heart that stops jumping behind the perfusion cardioplegic solution still was kept in the former cardioplegic solution.Cut off the abdominal cavity from median line, ventral aorta and postcava dissociate, below bilateral renal arteries, more than the iliac artery bifurcated, the blocking-up lead to dorsal part in, little communicating branch, to be inserted in the dual-purpose bag of cold circulation traction for the heart simultaneously, cut off ventral aorta in the stringer of same plane, the about 3cm of postcava antetheca, to do holostrome for the ventral aorta otch of heart ascending aorta and receptor Mus sews up continuously, to do continuous stitching for the postcava otch of heart main pulmonary artery and receptor Mus, take out the confession body-centered, and 40min behind the perfused hearts cardioplegic solution recovers the heart transplant blood supply, graft cardiac rebeating in the 30min, send intestinal tube back to abdominal cavity by original position, close abdomen, the normal raising, by the stomach wall palpation heart transplant situation of beating, judge whether heart transplant survives.24h experimental group and the blank group 1ml that takes a blood sample respectively centrifugally goes out serum, measures 1 day, 3 days, 7 days, 15 days, 20 days, 25 days CK vigor with the automatic clinical chemistry analyzer 7150 that Hitachi, Ltd produces.Experimental result sees Table 7:
The protective effect of the different time of table 7 pair rat myocardial ischemia and reperfusion damage
| Group | Laboratory animal number | 1 day CK vigor U/L | 3 days CK vigor U/L | 7 days CK vigor U/L | 15 days CK vigor U/L | 20 days CK vigor U/L | 25 days CK vigor U/L |
| The commercially available XUESHUANTONG ZHUSHEYE of blank group nano thrombus dredging liquid drugs injection of the present invention nano thrombus dredging infusion solution of the present invention nano thrombus dredging powder-injection of the present invention | 10 10 10 10 10 | 192.90±21.36 194.54±23.15 258.94±27.31 # 257.35±28.01 # 259.12±28.57 # | 193.07±20.78 217.89±18.74 296.32±28.94 ** 【*】 295.87±27.42 ** 【*】 296.38±27.52 ** 【*】 | 193.90±19.78 235.41±21.26 304.23±27.51 ** 【*】 305.89±28.03 ** 【*】 304.18±28.02 ** 【*】 | 192.88±19.57 241.24±24.21 304.94±28.12 ** 【*】 304.75±28.07 ** 【*】 305.28±27.87 ** 【*】 | 193.85±21.36 269.34±25.36 ** 305.12±27.36 ** 【*】 305.88±29.57 ** 【*】 306.07±28.18 ** 【*】 | 193.70±19.36 269.97±26.22 ** 305.38±28.04 ** 【*】 305.79±27.82 ** 【*】 305.71±25.76 ** 【*】 |
Annotate: compare with the blank group
*P＜0.01, #P＜0.05; Compare [*] P＜0.05 with positive controls
Conclusion: show by above-mentioned experiment, commercially available XUESHUANTONG ZHUSHEYE just has certain therapeutical effect about 20 days, and this patent nanometer ' Xue Shuan Tong ' injection just had therapeutical effect in the time of 3 days, prove absolutely Radix Notoginseng total arasaponins carried out nanometer preparation after, when the treatment thrombotic disease, have onset characteristics rapidly; This patent nanometer ' Xue Shuan Tong ' injection and commercially available XUESHUANTONG ZHUSHEYE relatively have better pharmacological action.
Seven. preparation embodiment
Embodiment 1
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 60 grams, and pharmaceutical carrier 300 grams, wherein emulsifying agent is 180 grams, lipid 120 grams in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 60 grams, emulsifying agent soybean lecithin 180 grams and lipid glyceryl tristearate 120 grams, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 60 grams, lecithin, the husky nurse F-68 of pool network, soil temperature 80 totally 180 grams, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 120 gram heating and meltings again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 60 grams, lipid tripalmitin 120 grams and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent Ovum Gallus domesticus Flavus lecithin 180 grams, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 60 grams, be dissolved in 30% ethanol; Trilaurin in the lipid is dissolved in the normal hexane mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, 0.1 atmospheric pressure of controlled pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 60 grams and paracyanogen base alkyl acrylate 300 grams are mixed into oil solution, mix, shake up, get clear solution with dehydrated alcohol; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant PluronicF68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add pharmaceutic adjuvant sodium chloride, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of infusion solutions;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant sucrose, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains 1000 bottles of injectable powder;
[above-mentioned nanometer formulation is detected, and its nanometer particle size is the 40-120 nanometer]
Embodiment 2
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 80 grams, and pharmaceutical carrier 800 grams, wherein emulsifying agent is 420 grams, lipid 380 grams in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 80 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 420 grams and lipid myristin 380 grams, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 80 grams, lecithin, the husky nurse F-68 of pool network, soil temperature 80 totally 420 grams, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 380 gram heating and meltings again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 80 grams, lipid trilaurin 380 grams and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent phosphatidylcholine 420 grams, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the 10ml water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 80 grams, be dissolved in 70% ethanol; Lipid Witepsol W35 380 grams are dissolved in the liquid alkane mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, 0.2 atmospheric pressure of controlled pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 80 grams and polylactic acid 800 grams are formed oil solution, mix, shake up, get clear solution with dehydrated alcohol; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant Pluronic F68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add the pharmaceutic adjuvant glucose, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of infusion solutions;
The injectable powder preparation: get above-mentioned suspension and add the pharmaceutic adjuvant lactose, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains 1000 bottles of injectable powder;
[above-mentioned nanometer formulation is detected, and its nanometer particle size is the 40-120 nanometer]
Embodiment 3
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 65 grams, and pharmaceutical carrier 443 grams, wherein emulsifying agent is 301 grams, lipid 142 grams in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 65 grams, emulsifying agent poloxamer 301 grams and lipid glyceryl monostearate 142 grams, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 65 grams, lecithin, the husky nurse F-68 of pool network, soil temperature 80 totally 301 grams, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 142 gram heating and meltings again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 65 grams, lipid stearic acid, Palmic acid 142 grams and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent polysorbate 301 grams, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 65 grams, be dissolved in 35% ethanol; Lipid glyceryl tristearate, tripalmitin are dissolved in the normal hexane mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, 0.12 atmospheric pressure of controlled pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 65 grams and polylactide-co-glycolide, chitosan totally 443 are restrained the formation oil solutions, mix, shake up, get clear solution with dehydrated alcohol; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant Pluronic F68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add the pharmaceutic adjuvant glucose, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of infusion solutions;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant sucrose, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains injectable powder;
[above-mentioned nanometer formulation is detected, and its nanometer particle size is the 40-120 nanometer]
Embodiment 4
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 70 grams, and pharmaceutical carrier 503 grams, wherein emulsifying agent is 287 grams, lipid 216 grams in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 70 grams, emulsifying agent cholate, alevaire 287 grams and lipid WitepsolH35, Witepsol H42, glyceryl monostearate 216 grams, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 70 grams, lecithin, the husky nurse F-68 of pool network, soil temperature 80 totally 287 grams, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 216 gram heating and meltings again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 70 grams, the lipid glyceryl monostearate, Palmic acid 216 grams and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent cholate 287 grams, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 70 grams, be dissolved in 50% ethanol; Lipid trilaurin, three is climbed over a wall in acid glyceride, the Witepsol W35 liquid alkane mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, 0.16 atmospheric pressure of controlled pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 70 grams and polylactide-co-glycolide, chitosan, gelatin oil 503 grams are formed solution, mix, shake up, get clear solution with dehydrated alcohol; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant Pluronic F68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add the pharmaceutic adjuvant glucose, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of infusion solutions;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant sucrose, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains 1000 bottles of injectable powder;
[above-mentioned nanometer formulation is detected, and its nanometer particle size is the 40-120 nanometer]
Embodiment 5
The XUESHUANTONG nanotechnology:
Prescription is: Radix Notoginseng total arasaponins 75 grams, and pharmaceutical carrier 682 grams, wherein emulsifying agent is 412 grams, lipid 270 grams in the liposome preparation.
Method one: get Radix Notoginseng total arasaponins 75 grams, emulsifier sorbitol 412 grams and lipid stearic acid, Palmic acid 270 grams, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 75 grams, lecithin, the husky nurse F-68 of pool network, soil temperature 80 totally 412 grams, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 270 gram heating and meltings again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 75 grams, lipid Witepsol W35, Witepsol H35, glyceryl tristearate is in totally 270 grams and the acetone adding container, ultrasonicly make abundant dissolving, add emulsifying agent soybean lecithin 412 grams, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 75 grams, be dissolved in 65% ethanol; Climb over a wall acid glyceride, Witepsol W35 of lipid trilaurin, three is dissolved in liquid alkane, mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, 0.18 atmospheric pressure of controlled pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 75 grams and polylactide-co-glycolide 682 grams are formed oil solution, mix, shake up, get clear solution with dehydrated alcohol; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant PluronicF68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add pharmaceutic adjuvant sodium chloride, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains 1000 bottles of infusion solutions;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant mannitol, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains 1000 bottles of injectable powder;
[above-mentioned nanometer formulation is detected, and its nanometer particle size is the 40-120 nanometer].
Claims (3)
1. a nanometer ' Xue Shuan Tong ' injection is characterized in that its composition comprises Radix Notoginseng total arasaponins 6-8 weight portion, pharmaceutical carrier 30-80 weight portion; Its feature is that also nanometer particle size is the 40-120 nanometer in the nanometer ' Xue Shuan Tong ' injection.
2. the preparation method of a kind of nanometer ' Xue Shuan Tong ' injection according to claim 1, its feature may further comprise the steps:
The XUESHUANTONG nanotechnology:
Method one: get Radix Notoginseng total arasaponins 6-8 weight portion, emulsifying agent 18-42 weight portion and lipid 12-38 weight portion, under logical condition of nitrogen gas, be heated to 80 ± 5 ℃, the saturated aqueous solution that under stirring condition, adds uniform temp glycerol and the pool husky nurse 188 of network (the two mass ratio 1: 1), make thick breast, under 80 ± 5 ℃ of logical condition of nitrogen gas, carry 41.4MPa pressure stimulating milk secretion even 5 times with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly.
Method two: get Radix Notoginseng total arasaponins 6-8 weight portion, lecithin, the husky nurse F-68 of pool network, soil temperature 80 18-42 weight portions, in the distilled water of 70 ± 5 ℃ of high-speed stirred condition addings, treat that complete fusion is as water, take by weighing glyceryl monostearate 12-38 weight portion heating and melting again as oil phase, oil phase is slowly added aqueous phase, ultra-sonic dispersion behind the lasting stirring 1h: room temperature, frequency 45-50Hz, ultrasonic time 5-8 minute, promptly get clear and bright suspension.
Method three: get Radix Notoginseng total arasaponins 6-8 weight portion, lipid 12-38 weight portion and acetone add in the container, ultrasonicly make abundant dissolving, add emulsifying agent 18-42 weight portion, slight fever makes the melt into organic facies, it is soluble in water that other gets the husky nurse F-68 of co-emulsifier pool network, constitute water, organic facies under stirring, (1000r/min) is injected 75 ± 2 ℃ of aqueous phases, continue heated and stirred 4h, organic matchmaker of melting is evaporated fully and system is concentrated, the translucent system of gained is stirred the water that (1000r/min) down is dissolved in 0-2 ℃ fast, continue to stir 2h, promptly get suspension.
Method four: get Radix Notoginseng total arasaponins 6-8 weight portion, be dissolved in the 30%-70% ethanol; One or more common 12-38 weight portions in the lipid are dissolved in alkane, mixing and stirring; Dissolve with ethanol thing and alkane solute are mixed, put into rotation wiped film vaporization instrument, a controlled pressure 0.1-0.2 atmospheric pressure is removed organic solvent to the greatest extent, distillation is put into hermetic container carry out supersound process, obtains suspension.
Method five: oil phase: Radix Notoginseng total arasaponins 6-8 weight portion and oily 30-80 weight portion are mixed into solution (one or more in paracyanogen base alkyl acrylate, polylactic acid, polylactide-co-glycolide, chitosan, the gelatin), mix with dehydrated alcohol, shake up, get clear solution; Water: the aqueous solution (pH value about 6) that is 0.5% nonionic surfactant Pluronic F68, biphasely be 20 ℃, oil phase is injected the aqueous phase of electromagnetic agitation by silica gel tube or fine needle head, form nanocapsule immediately, solution for vacuum is evaporated to about 1/5 of original volume, filter with glass sand hourglass (9-15 μ m), promptly get suspension.
Formulation preparation:
The aqueous injection preparation: get above-mentioned suspension, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains aqueous injection;
The infusion solution preparation: get above-mentioned suspension and add pharmaceutic adjuvant, add the dissolving of injection water fully, add stabilizing agent PVP, regulate pH value, filter, sterilization, fill obtains infusion solution;
The injectable powder preparation: get above-mentioned suspension and add pharmaceutic adjuvant, add the dissolving of injection water fully, regulate pH value, filter, sterilization, lyophilization obtains injectable powder.
3. have blood circulation promoting and blood stasis dispelling, blood vessel dilating, the sanguimotor function of improvement according to claim 1 and 2 described nanometer ' Xue Shuan Tong ' injections, in the application of diseases such as treatment central retinal vein occlusion, cardiovascular and cerebrovascular disease and sequela, internal ophthalmopathy, hyphema.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510077501 CN1879639A (en) | 2005-06-17 | 2005-06-17 | A nanometer 'Xue Shuan Tong' injection and preparation method thereof |
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| CN 200510077501 CN1879639A (en) | 2005-06-17 | 2005-06-17 | A nanometer 'Xue Shuan Tong' injection and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512467A (en) * | 2011-12-29 | 2012-06-27 | 广州花海药业股份有限公司 | Ophthalmic preparation of panax notoginseng saponins and preparation method thereof |
| CN103848986A (en) * | 2012-11-28 | 2014-06-11 | 杨子剑 | New compound containing cephalosporin structure as well as preparation method and application thereof |
-
2005
- 2005-06-17 CN CN 200510077501 patent/CN1879639A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512467A (en) * | 2011-12-29 | 2012-06-27 | 广州花海药业股份有限公司 | Ophthalmic preparation of panax notoginseng saponins and preparation method thereof |
| CN103848986A (en) * | 2012-11-28 | 2014-06-11 | 杨子剑 | New compound containing cephalosporin structure as well as preparation method and application thereof |
| CN103848986B (en) * | 2012-11-28 | 2019-10-11 | 杨子剑 | Compound and preparation method and purposes containing cephalosporin structure |
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