CN1947713A - Nano-safflower flavone injection prepn. and its prepn. method - Google Patents
Nano-safflower flavone injection prepn. and its prepn. method Download PDFInfo
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Abstract
A nano-carthamiflavone medicine in the form of liquid injection, powder injection, or perfusion is prepared from carthamiflavone (50-85%) extracted from safflower, medical carrier and medical auxiliary. Its preparing process is also disclosed.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicine pharmacy, be specifically related to a kind of nano-safflower flavone injection preparation and preparation method thereof.
Background technology
Flos Carthami is the dried floral of Compositae annual herb plant Flos Carthami CarthamustinctoriusL., it is one of blood-activating and stasis-removing of using always, effect with anticoagulant, anti-bolt, blood vessel dilating, wherein flavones ingredient is the class main active in the Flos Carthami, main active is a total flavones in the Flos Carthami injection of Chu Shouing in the market, flavones ingredient has the platelet aggregation effect of remarkable inhibition by ADP, thrombin, arachidonic acid-induction, also has the platelet activation effect that suppresses the platelet activating factor mediation; But in clinical practice, Flos Carthami injection poor stability [" time precious traditional Chinese medical science traditional Chinese medicines " the 12nd the 6th phase of volume of calendar year 2001,490, the stability study of Flos Carthami injection], a large amount of serious adverse reactions appears: cause anaphylactic shock 1.; 2. drug eruption; 3. therefore, the medical scientific research research worker should be carried out preparation research with carthamone in heating [Flos Carthami injection causes anaphylaxis, " medical Leader ", 2000,19 (6): 609], develops rapid, the safe carthamone preparation of a kind of onset; Therefore flavone compound, in the process of extracting purification carthamone effective site, should note temperature controlling to thermally labile in the Flos Carthami; Consult document and patent, in the process of extracting carthamone, adopt heated alcohol extraction more, and temperature is extracted in control; In purge process, there is report to adopt organic solvent extractionprocess, in handling the process that reclaims organic solvent, there is not fine control temperature yet, therefore can cause the content of carthamone in the Flos Carthami extract to reduce.
Liposome is the middle made superminiature spheroid carrier preparation of thin film that drug encapsulation is formed in the lipoids bilayer.The material that constitutes lipid bilayer (carrier) mainly contains phospholipid (lecithin, cephalin, fabaceous lecithin) and cholesterol etc., because existing hydrophilic group has hydrophobic group again in their molecular structure, when constituting spherical class Lipid Bilayer Structure, the structure that its hydrophobic group constitutes is relatively got up drug encapsulation.Liposome has the following advantages as the carrier of medicine: (1) this carrier can be protected enveloped; (2) control drug release effectively; (3), can control medicine in in-house distribution and the clearance rate in blood by changing liposome size and electric charge; (4) change certain physical factor, the permeability that temperature that for example changes the partial pH of medication, diseased region etc. can obviously change liposome membrane impels liposome optionally to discharge medicine; (5) after liposome enters in the body mainly by reticuloendothelial system phagocytic, can activate the autoimmune function of body, and drug main will be accumulated in histoorgans such as brain, liver and bone marrow, thus improve the therapeutic index of medicine, reduce the therapeutic dose of medicine and reduce drug toxicity; (6) liposome itself is to human body avirulence and immunosuppressive action.Therefore, liposome especially demonstrates obvious superiority in the brain diseases treatment at numerous disease.
Consult document and patent, do not retrieve the data of nano-safflower flavone injection preparation.
Summary of the invention
For these reasons, we are by a large amount of experimentatioies, Flos Carthami is adopted ultrasonic alcohol extraction earlier, and the control temperature is no more than 40 ℃, in purge process, we adopt D101 type macroporous adsorptive resins to be prepared, all concentration processs of the present invention adopt rotation wiped film vaporization instrument to carry out, and the control temperature is no more than 45 ℃, in whole extraction purge process, better controlled temperature, prevent in the Flos Carthami extract that the active component carthamone decomposes.
The carthamone extract be will obtain and chemical property and analysis of physical carried out, mix with preferred solvent, lipid according to its character, control temperature well, be prepared into nano-safflower flavone, be mixed with into aqueous injection, infusion solution, injectable powder with pharmaceutic adjuvant, pharmacodynamic study, nano-safflower flavone injection preparation of the present invention have characteristics safe, that pharmacological action is good.
The purpose that the present invention makes nanometer formulation with carthamone is to solve the reduction untoward reaction, reaches rapid-action and keeps good blood drug level.
The purpose of this invention is to provide a kind of nano-safflower flavone injection preparation;
Another object of the present invention provides the method for preparing nano-safflower flavone injection preparation.
The present invention is achieved through the following technical solutions:
One, process recipes
(1) extraction of carthamone effective site:
Get Flos Carthami, pulverize, put into the supersound extraction jar, the 50%-70% ethanol ultrasonic extraction of 4-8 times of volume of adding Flos Carthami quality 25-40 minute, control is extracted in 30 ℃ of-40 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 40 ℃-45 ℃ of control thickening temperatures, and vacuum is 0.1-0.2 atmospheric pressure, obtain concentrated solution, leave standstill 12-24 hour, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 3-6 times of column volume distillation washing, water lotion discards, and reuse 4-8 times of column volume 60%-80% ethanol elution collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 40 ℃-45 ℃ of control thickening temperatures, vacuum is 0.1-0.2 atmospheric pressure, obtains concentrated solution, cold drying obtains the carthamone extract;
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 8-12 weight portion, lipid 48-142 weight portion, emulsifying agent 32-58 weight portion;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 60-70 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 60-70 ℃ of logical condition of nitrogen gas, spare 5-7 time in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, preparation cost invention nano-safflower flavone hydro-acupuncture preparation;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, preparation cost invention nano-safflower flavone infusion preparation;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, preparation cost invention nano-safflower flavone freeze-dried powder.
Lipid in the preparation method of nano-safflower flavone injection preparation is a monostearate.
Emulsifying agent is an Ovum Gallus domesticus Flavus lecithin in the preparation method of nano-safflower flavone injection preparation.
Two. check and analysis
According to 103 pages of the Pharmacopoeias of the People's Republic of China (version in 2005, an one), Flos Carthami [assay] Rhizoma Kaempferiae prime implicant detection method is carried out check and analysis, and experimental result sees Table 1
Table 1 content relatively
| Group | Carthamone content |
| The commercially available Sofflower injection mg/ of safflower flavone active component % of the present invention bottle nano-safflower flavone liquid drugs injection mg/ bottle nano-safflower flavone infusion solution mg/ bottle | 50-85 2.1 7.8 8.3 |
| Nano-safflower flavone injectable powder mg/ bottle | 8.0 |
Conclusion: show that by above-mentioned experiment technology of the present invention has practical significance.
Three. optimization experiment
Preferred the foundation: " method among Chinese pharmacopoeia version appendix in 2005 the XIX E " microcapsule, microsphere and Liposomal formulation guideline ".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.
Experimental technique: get carthamone effective site of the present invention and different lipids: glyceryl tristearate, tripalmitin, trilaurin, three climb over a wall acid glyceride, monostearate, stearic acid, different emulsifiers soybean lecithin, Ovum Gallus domesticus Flavus lecithin, polysorbate, poloxamer carry out the Nano medication preparation, obtain nano-safflower flavone and experimentize;
Scheme 1: glyceryl tristearate, soybean lecithin;
Scheme 2: tripalmitin, soybean lecithin;
Scheme 3: trilaurin, soybean lecithin;
Scheme climb over a wall at 4: three acid glyceride, soybean lecithin;
Scheme 5: monostearate, soybean lecithin;
Scheme 6: monostearate, Ovum Gallus domesticus Flavus lecithin;
Scheme 7: glyceryl tristearate, Ovum Gallus domesticus Flavus lecithin;
Scheme 8: tripalmitin, Ovum Gallus domesticus Flavus lecithin;
Scheme 9: trilaurin, Ovum Gallus domesticus Flavus lecithin;
Scheme climb over a wall at 10: three acid glyceride, Ovum Gallus domesticus Flavus lecithin;
Scheme 11: stearic acid, soybean lecithin;
Scheme 12: stearic acid, Ovum Gallus domesticus Flavus lecithin;
Scheme 13: glyceryl tristearate, polysorbate;
Scheme 14: tripalmitin, polysorbate;
Scheme 15: trilaurin, polysorbate;
Scheme climb over a wall at 16: three acid glyceride, polysorbate;
Scheme 17: monostearate, polysorbate;
Scheme 18: stearic acid, polysorbate;
Scheme 19: glyceryl tristearate, poloxamer;
Scheme 20: tripalmitin, poloxamer;
Scheme 21: trilaurin, poloxamer;
Scheme climb over a wall at 22: three acid glyceride, poloxamer;
Scheme 23: monostearate, poloxamer;
Scheme 24: stearic acid, poloxamer;
1. morphologic observation and particle diameter
Above-mentioned Nano medication is carried out morphologic observation under transmission electron microscope, observation index is: be which kind of state, whether size is even, whether the surface smooth, have or not adhesion, gets 1000-2000 Nano medication respectively and measure size, normal distribution whether, and experimental result sees Table 2:
Different group forms of table 2 and size ratio are
| Group | State | Whether size is even | Whether the surface is smooth | Have or not adhesion | Minimum grain size nm | Maximum particle diameter nm | Mean diameter nm | Normal distribution whether |
| Scheme 1 scheme 2 schemes 3 schemes 4 schemes 5 schemes 6 schemes 7 schemes 8 schemes 9 schemes 10 schemes 11 schemes 12 schemes 13 schemes 14 schemes 15 schemes 16 schemes 17 schemes 18 schemes 19 schemes 20 schemes 21 schemes 22 schemes 23 | The a small amount of spherosome spherosome of the spherosome spherosome spherosome spherosome spherosome spherosome a small amount of spherosome of a small amount of spherosome of a small amount of spherosome of a small amount of spherosome of irregular irregular a small amount of spherosome spherosome spherosome spherosome spherosome | Whether no whether no no no | No no whether no no whether no no no | Have or not do not have not have do not have do not have have no have no | 52 79 57 43 41 10 109 127 85 74 65 73 235 241 148 157 89 96 42 44 79 86 85 | 208 304 186 142 199 120 385 571 204 201 186 285 732 741 547 209 164 301 159 158 214 189 157 | 148±18 201±32 124±17 98±7 133±24 55±8 287±46 421±39 142±42 153±34 128±27 207±32 587±103 652±157 406±99 186±48 128±30 207±46 109±14 132±28 189±40 144±27 122±23 | Whether no no whether no whether no no |
| Scheme 24 | Spherosome | Not | Be | Not | 87 | 302 | 248±101 | Not |
2. envelop rate and drug loading are measured
Adopt above-mentioned check and analysis method that the Nano medication of different schemes is carried out the carthamone 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.
Experimental result: see Table 3.
Table 3 envelop rate and drug loading are relatively
| Group | Envelop rate % | Drug loading % |
| Scheme 1 scheme 2 schemes 3 schemes 4 schemes 5 schemes 6 schemes 7 schemes 8 schemes 9 schemes 10 schemes 11 schemes 12 schemes 13 schemes 14 schemes 15 schemes 16 schemes 17 schemes 18 schemes 19 schemes 20 schemes 21 schemes 22 schemes 23 | 80.1 74.3 79.2 65.3 63.2 92.0 54.3 57.9 58.9 67.3 72.3 74.6 84.3 49.6 57.6 59.1 68.7 78.3 80.2 57.6 65.3 66.9 78.9 | 7.2 6.3 6.8 6.4 10.2 10.1 7.8 7.9 9.8 4.5 5.2 6.3 5.1 4.3 3.8 3.7 5.8 5.2 6.8 8.7 8.2 8.7 4.9 |
| Scheme 24 | 77.2 | 7.3 |
3. study on the stability
The different schemes Nano medication is placed in the bottle sealing respectively.In the environment of refrigerator (3-5 ℃), room temperature (20-25 ℃) and 37 ℃ (RH75%), place, observe outward appearance, size, redispersibility of Nano medication etc. March.The results are shown in Table 4.
Table 4 stability experiment relatively
| Group | 3-5℃ | 3-5℃ | 20-25℃ | 20-25℃ | 37℃(RH75％) | 37℃(RH75％) |
| Scheme 1 scheme 2 schemes 3 schemes 4 schemes 5 schemes 6 schemes 7 schemes 8 schemes 9 schemes 10 schemes 11 schemes 12 schemes 13 schemes 14 schemes 15 schemes 16 schemes 17 schemes 18 schemes 19 schemes 20 schemes 21 schemes 22 schemes 23 | Particle diameter (nm) 157 ± 24 211 ± 27 128 ± 18 102 ± 9 135 ± 27 56 ± 7 294 ± 48 428 ± 41 144 ± 40 155 ± 33 139 ± 29 214 ± 30 595 ± 104 667 ± 159 418 ± 102 197 ± 49 131 ± 33 211 ± 45 111 ± 17 137 ± 29 197 ± 48 158 ± 30 131 ± 29 | The white colourless variable color of the white white variable color variable color of the variable color variable color colourless white of colourless white variable color variable color of colours white | Particle diameter (nm) 178 ± 63 237 ± 39 138 ± 29 119 ± 15 139 ± 29 57 ± 8 308 ± 52 429 ± 40 148 ± 49 159 ± 39 147 ± 34 219 ± 42 599 ± 102 672 ± 168 427 ± 93 203 ± 53 139 ± 36 219 ± 49 125 ± 24 148 ± 34 203 ± 43 167 ± 37 139 ± 33 | The variable color of the colourless white canescence canescence white of the white variable color variable color white of color variable color variable color variable color variable color white variable color variable color variable color | Particle diameter (nm) 187 ± 57 258 ± 58 144 ± 39 128 ± 48 143 ± 34 58 ± 7 324 ± 67 437 ± 49 157 ± 51 173 ± 48 152 ± 28 228 ± 58 607 ± 109 684 ± 157 434 ± 107 212 ± 58 147 ± 47 237 ± 49 139 ± 31 152 ± 39 214 ± 54 178 ± 41 148 ± 47 | The white variable color variable color of color variable color variable color white variable color electrochromic variable look variable color variable color electrochromic variable look variable color variable color variable color white variable color variable color canescence variable color variable color |
| Scheme 24 | 257±106 | Canescence | 266±114 | Variable color | 278±115 | Variable color |
4. blood brain barrier research
Get new zealand rabbit, the about 2.5kg of body weight, male and female are not limit.Intravenous administration, 20 minutes extraction 0.5ml cerebrospinal fluid experimentize after administration.After getting cerebrospinal fluid 0.25ml solubilizer suspendible 15min, leaving standstill 15min, with the centrifugal 1min of 10000r/min, get supernatant 20 μ l sample introductions, is index determining with the carthamone, and it is standard index with scheme 6 that experimental result sees Table 5:(, promptly 100%)
The different group cerebrospinal fluid of table 5 Chinese medicine concentration
| Group | Cerebrospinal fluid Chinese medicine concentration (%) |
| Scheme 1 scheme 2 schemes 3 schemes 4 schemes 5 | 84.1 87.9 70.0 82.9 81.9 |
| Scheme 6 schemes 7 schemes 8 schemes 9 schemes 10 schemes 11 schemes 12 schemes 13 schemes 14 schemes 15 schemes 16 schemes 17 schemes 18 schemes 19 schemes 20 schemes 21 schemes 22 schemes 23 | 100 78.9 74.1 76.8 83.9 85.7 87.3 89.1 81.2 81.9 75.6 78.5 84.1 85.9 84.3 72.9 76.8 77.3 |
| Scheme 24 | 80.1 |
Experiment conclusion: by above-mentioned optimization experiment, we determine that lipid is a monostearate, and emulsifying agent is an Ovum Gallus domesticus Flavus lecithin; Show that by above-mentioned experiment as seen Nano medication of the present invention is spherosome, size is more even, smooth surface, no adhesion has been measured 1500 according to the light micrograph of Nano medication, mean diameter is 55 ± 8nm, maximum particle diameter is 120nm, and minimum grain size is 10nm, and particle size distribution meets normal distribution law, envelop rate is 92.0%, drug loading is 10.1%, and good stability is made good use of by blood brain barrier.
Four. toxicological experiment
Experiment 1
Acute toxicity testing
Experiment medicine: nano-safflower flavone injection preparation of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); Commercially available injection Flos Carthami injection (Shengtai Pharmaceutical Co., ltd., Harbin)
Laboratory animal: healthy mice 18-22g,, male and female half and half;
Experimental technique: get mice, be divided into commercially available Flos Carthami injection group, this patent nano-safflower flavone injection group, intraperitoneal administration, be converted into the mice dosage according to body surface area, administration every day 3 times, continuous 7 days, observe the dead mouse situation, record data calculate LD by the improvement karber's method
50The value experimental result sees Table 6:
Table 6 mice medication LD
50Value relatively
| Group | Number of animals only | LD 50 mg/kg |
| Commercially available Flos Carthami injection nano-safflower flavone aqueous injection of the present invention nano-safflower flavone infusion solution of the present invention | 20 20 20 | 542.6±23.1 672.3±28.9 670.9±30.0 |
| Nano-safflower flavone injectable powder of the present invention | 20 | 673.1±28.4 |
Experiment 2
Hemolytic is investigated
Experiment medicine: nano-safflower flavone injection preparation of the present invention (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, mixing was placed 30 minutes in 37 ℃ of calorstats, added not commensurability medicinal liquid (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.The results are shown in Table 7.
Each group proportional quantity of table 7
| The test tube numbering | 2% red blood cell suspension (ml) | Normal saline solution (ml) | Medicinal liquid (ml) |
| 1 2 3 4 5 | 2.5 2.5 2.5 2.5 2.5 | 2.0 2.1 2.2 2.3 2.4 | 0.5 0.4 0.3 0.2 0.1 |
| 6 | 2.5 | 2.5 | 0 |
The 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 product is described, safety is good.
Experiment 3
Blood vessel irritation is investigated
Experimental technique: get 9 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 nano-safflower flavone injection preparation 5mg/kg, 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.
The 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).
Conclusion: show that by above-mentioned experiment nano-safflower flavone injection preparation of the present invention is better than commercially available Flos Carthami injection safety.
Four. pharmacological evaluation
Experiment 1
Influence to the rat local cerebral ischemia
Experiment medicine: nano-safflower flavone injection preparation of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); Commercially available injection Flos Carthami injection (Shengtai Pharmaceutical Co., ltd., Harbin)
Laboratory animal: regular grade Wistar rat, male, 280～350g.
Experimental technique: get rat, be divided into sham operated rats, model control group, commercially available Flos Carthami injection group, nano-safflower flavone injection agent group of the present invention at random, 10 every group.Behind the fasting 12h, each treated animal is the ig relative medicine respectively, and dosage is 3.5mg/kg.Undergo surgery behind the administration 2h, cause rats with left middle cerebral artery ischemia, sham operated rats is only carried out the separation (above experiment is all carried out at 23 ℃～25 ℃) of left carotid, internal carotid artery, external carotid artery, observes and write down the behavior disorder of rat behind the 24h.Rat is put to death in behavior disorder scoring back, gets brain, removes olfactory bulb, cerebellum and low brain stem, crownly is cut into 5, and TTC dyeing is taken a picture, and asks the infarct size ratio with the pathological image analysis software.Data are represented with x ± s, t check between group.The results are shown in Table 8.
The different preparations of table 8 are to the influence of rat local cerebral ischemia
| Group | Behavior scoring | Ischemic areas % |
| The commercially available Flos Carthami injection group of sham operated rats model control group nano-safflower flavone aqueous injection of the present invention group nano-safflower flavone infusion solution of the present invention group | 0 10.10±1.37 7.50±3.03 ** 6.90±2.33 **# 6.81±2.27 **# | 0 24.26±4.13 18.41±2.84 ** 13.09±7.17 **# 12.94±6.90 **# |
| Nano-safflower flavone injectable powder group of the present invention | 6.85±2.20 **# | 13.14±7.20 **# |
Annotate: compare with model control group
*P＜0.01; Compare #P＜0.05. with positive controls
Experiment 2
To the thrombotic influence of rat vein
Experiment medicine: nano-safflower flavone injection preparation of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); Commercially available injection Flos Carthami injection (Shengtai Pharmaceutical Co., ltd., Harbin)
Laboratory animal: regular grade Wistar rat, male, 280～350g.
Experimental technique: get rat, be divided into model control group, commercially available Flos Carthami injection group, nano-safflower flavone injection agent group of the present invention at random, 10 every group, behind the fasting 12h, each treated animal is the ig relative medicine respectively, and dosage is 3.5mg/kg, behind the 2h, chloral hydrate (350mg/kg, ip) anesthesia is opened abdomen and is separated postcava, with cordonnet ligation postcava, sew up abdominal part in the left renal vein below.Again open abdomen behind the 6h, 2cm place folder closes blood vessel below ligation place, cuts tube chamber open, and removal of thromboses is weighed.Data represent that with x ± s the t check the results are shown in Table 9 between group.
The different preparations of table 9 are to the thrombotic influence of rat vein
| Group | Wet weight of thrombus mg | Suppression ratio % |
| The commercially available Flos Carthami injection group of model control group nano-safflower flavone aqueous injection of the present invention group nano-safflower flavone infusion solution of the present invention group | 29.91±17.16 14.01±5.76 ** 9.17±6.65 **# 9.20±5.81 **# | - 53.16 71.48 69.24 |
| Nano-safflower flavone injectable powder group of the present invention | 9.14±6.32 **# | 69.44 |
Annotate: compare with model control group
*P＜0.01; Compare #P＜0.05. with positive controls
Experiment 3
Influence to rat platelet aggregation
Experiment medicine: nano-safflower flavone injection preparation of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); Commercially available injection Flos Carthami injection (Shengtai Pharmaceutical Co., ltd., Harbin)
Laboratory animal: regular grade Wistar rat, male, 280～350g.
Experimental technique: get rat, be divided into model control group, commercially available Flos Carthami injection group, nano-safflower flavone injection agent group of the present invention at random, every group 10, behind the fasting 12h, each treated animal is the ig relative medicine respectively, and dosage is 3.5mg/kg, behind the 2h, behind the fasting 12h, rat aorta is got blood 5mL, with 3.8% sodium citrate anticoagulant.Separate platelet rich plasma (PRP), platelet poor plasma (PPP), and adjust platelet count＜2 * 10 of PRP
6/ ml pipettes 0.3mlPRP to opacity tube, and opacity tube is put into the platelet aggregation instrument after the PPP zeroing, add the corresponding medicine of 10 μ l, add 10 μ l ADP behind 37 ℃ of incubation 3min, open platelet aggregation instrument simultaneously and carry out record, be 6min writing time.Data represent that with x ± s the t check the results are shown in Table 10 between group.
The different preparations of table 10 are to the influence to rat platelet aggregation
| Group | Aggregation rate % | Suppression ratio % |
| The commercially available Flos Carthami injection group of model control group nano-safflower flavone aqueous injection of the present invention group nano-safflower flavone infusion solution of the present invention group | 41.10±6.85 25.55±3.3 ** 22.53±3.0 **# 21.93±3.2 **# | - 37.83 45.18 46.76 |
| Nano-safflower flavone injectable powder group of the present invention | 22.10±3.4 **# | 46.23 |
Annotate: compare with model control group
*P＜0.01; Compare #P＜0.05. with positive controls
Experiment conclusion: the result shows that under same dose, test group and negative control group comparing difference have the significance meaning, and experimental result explanation nano-safflower flavone injection preparation has better effect than commercially available Flos Carthami injection group.
Five, preparation embodiment
Embodiment 1
(1) extraction of carthamone effective site:
Get Flos Carthami 226.4 grams, pulverize, put into the supersound extraction jar, 50% ethanol ultrasonic extraction of 4 times of volumes of adding Flos Carthami quality 25 minutes, control is extracted in 30 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 40 ℃ of control thickening temperatures, and vacuum is 0.1 atmospheric pressure, obtain concentrated solution, leave standstill 12 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 3 times of column volume distillation washings, water lotion discards, and 4 times of column volume 60% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 40 ℃ of control thickening temperatures, vacuum is 0.1 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 12 grams; [carthamone content is 50%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 12 grams, lipid monostearate 142 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 58 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 60 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 60 ℃ of logical condition of nitrogen gas, spare 5 times in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 1000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Embodiment 2
(1) extraction of carthamone effective site:
Get Flos Carthami 135.6 grams, pulverize, put into the supersound extraction jar, 70% ethanol ultrasonic extraction of 8 times of volumes of adding Flos Carthami quality 40 minutes, control is extracted in 40 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 45 ℃ of control thickening temperatures, and vacuum is 0.2 atmospheric pressure, obtain concentrated solution, leave standstill 24 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 6 times of column volume distillation washings, water lotion discards, and 8 times of column volume 80% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 45 ℃ of control thickening temperatures, vacuum is 0.2 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 8 grams; [carthamone content is 85%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 8 grams, lipid monostearate 48 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 32 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 70 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 70 ℃ of logical condition of nitrogen gas, spare 7 times in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 1000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Embodiment 3
(1) extraction of carthamone effective site:
Get Flos Carthami 181.8 grams, pulverize, put into the supersound extraction jar, 60% ethanol ultrasonic extraction of 6 times of volumes of adding Flos Carthami quality 35 minutes, control is extracted in 35 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 42 ℃ of control thickening temperatures, and vacuum is 0.15 atmospheric pressure, obtain concentrated solution, leave standstill 16 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 4 times of column volume distillation washings, water lotion discards, and 6 times of column volume 70% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 42 ℃ of control thickening temperatures, vacuum is 0.15 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 10 grams; [carthamone content is 75%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 10 grams, lipid monostearate 95 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 45 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 65 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 65 ℃ of logical condition of nitrogen gas, spare 5-7 time in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 1000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Embodiment 4
(1) extraction of carthamone effective site:
Get Flos Carthami 160.7 grams, pulverize, put into the supersound extraction jar, 55% ethanol ultrasonic extraction of 5 times of volumes of adding Flos Carthami quality 30 minutes, control is extracted in 32 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 41 ℃ of control thickening temperatures, and vacuum is 0.13 atmospheric pressure, obtain concentrated solution, leave standstill 13 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 4 times of column volume distillation washings, water lotion discards, and 5 times of column volume 65% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 41 ℃ of control thickening temperatures, vacuum is 0.12 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 9 grams; [carthamone content is 55%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 9 grams, lipid monostearate 52 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 36 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 62 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 63 ℃ of logical condition of nitrogen gas, spare 5-7 time in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 1000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Embodiment 5
(1) extraction of carthamone effective site:
Get Flos Carthami 203.7 grams, pulverize, put into the supersound extraction jar, 65% ethanol ultrasonic extraction of 7 times of volumes of adding Flos Carthami quality 38 minutes, control is extracted in 38 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 44 ℃ of control thickening temperatures, and vacuum is 0.19 atmospheric pressure, obtain concentrated solution, leave standstill 22 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 5 times of column volume distillation washings, water lotion discards, and 7 times of column volume 75% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 44 ℃ of control thickening temperatures, vacuum is 0.19 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 11 grams; [carthamone content is 80%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 11 grams, lipid monostearate 130 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 51 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 68 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 68 ℃ of logical condition of nitrogen gas, spare 6 times in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 1000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 1000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Embodiment 6
(1) extraction of carthamone effective site:
Get Flos Carthami 1872.7 grams, pulverize, put into the supersound extraction jar, 60% ethanol ultrasonic extraction of 6 times of volumes of adding Flos Carthami quality 30 minutes, control is extracted in 35 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 43 ℃ of control thickening temperatures, and vacuum is 0.14 atmospheric pressure, obtain concentrated solution, leave standstill 15 hours, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 5 times of column volume distillation washings, water lotion discards, and 6 times of column volume 70% ethanol elutions of reuse are collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 43 ℃ of control thickening temperatures, vacuum is 0.16 atmospheric pressure, obtains concentrated solution, cold drying obtains carthamone extract 103 grams; [carthamone content is 70%]
(2) preparation of nano-safflower flavone:
Prescription is: carthamone extract 103 grams, lipid monostearate 953 grams, emulsifying agent Ovum Gallus domesticus Flavus lecithin 457 grams;
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get recipe quantity carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 66 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 64 ℃ of logical condition of nitrogen gas, spare 5-7 time in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(3) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 10000 bottles of preparation cost invention nano-safflower flavone hydro-acupuncture preparations;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, 10000 bottles of preparation cost invention nano-safflower flavone infusion preparations;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, 10000 bottles of preparation cost invention nano-safflower flavone freeze-dried powders.
[nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation]
Claims (2)
1. nano-safflower flavone injection preparation, it is characterized in that it be by ultrasonic alcohol extraction, rotation wiped film vaporization instrument concentrate, concentrated solution D101 type macroporous adsorptive resins eluting, eluent rotation wiped film vaporization instrument concentrate, cold drying obtains carthamone extract 8-12 weight portion, lipid monostearate 48-142 weight portion, emulsifying agent Ovum Gallus domesticus Flavus lecithin 32-58 weight portion are prepared into, wherein carthamone content is 50%-85% in the carthamone extract, and nanometer particle size is the 10-120 nanometer in the nano-safflower flavone injection preparation.
2. the preparation method of a nano-safflower flavone injection preparation is characterized by:
(1) extraction of carthamone effective site:
Get Flos Carthami, pulverize, put into the supersound extraction jar, the 50%-70% ethanol ultrasonic extraction of 4-8 times of volume of adding Flos Carthami quality 25-40 minute, control is extracted in 30 ℃ of-40 ℃ of extracting solution rotations of temperature knifing instrument and is concentrated ethanol extremely to the greatest extent, 40 ℃-45 ℃ of control thickening temperatures, and vacuum is 0.1-0.2 atmospheric pressure, obtain concentrated solution, leave standstill 12-24 hour, centrifugal, D101 type macroporous adsorptive resins on the supernatant, earlier with 3-6 times of column volume distillation washing, water lotion discards, and reuse 4-8 times of column volume 60%-80% ethanol elution collected eluent, concentrate ethanol to most in the eluent rotation knifing instrument, 40 ℃-45 ℃ of control thickening temperatures, vacuum is 0.1-0.2 atmospheric pressure, obtains concentrated solution, cold drying obtains the carthamone extract;
(2) preparation of nano-safflower flavone:
The glycerol and the poloxamer-188 that get equal in quality are prepared into saturated aqueous solution; Get carthamone extract, emulsifying agent and lipid, under logical condition of nitrogen gas, be heated to 60-70 ℃, at following saturated aqueous solution that adds uniform temp glycerol and poloxamer-188 of stirring condition, make thick breast, under 60-70 ℃ of logical condition of nitrogen gas, spare 5-7 time in 41.4MPa pressure stimulating milk secretion with the high pressure dispersing emulsification machine, after the inflated with nitrogen packing, cooling forms the principal agent suspension rapidly;
(4) formulation preparation:
The preparation of hydro-acupuncture preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, preparation cost invention nano-safflower flavone hydro-acupuncture preparation;
The preparation of infusion preparation: get above-mentioned suspension, add PVP, add to the full amount of water for injection, stir evenly, adding glucose accent etc. oozes, and adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, and sterilization, preparation cost invention nano-safflower flavone infusion preparation;
The preparation of freeze-dried powder: get above-mentioned suspension, add excipient, add the injection water and adjust concentration, adjust pH is 6.5-7.5, with 0.22 μ m filtering with microporous membrane, lyophilization, preparation cost invention nano-safflower flavone freeze-dried powder.
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| CN 200510112700 CN1947713A (en) | 2005-10-14 | 2005-10-14 | Nano-safflower flavone injection prepn. and its prepn. method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106070863A (en) * | 2016-06-08 | 2016-11-09 | 宁洱众鑫生物科技有限公司 | A kind of Pseudobulbus Bletillae (Rhizoma Bletillae) scented tea and preparation method thereof |
| CN108379320A (en) * | 2018-05-31 | 2018-08-10 | 临沂大学 | A kind of ultrasonic extraction safflower total flavone technique |
-
2005
- 2005-10-14 CN CN 200510112700 patent/CN1947713A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106070863A (en) * | 2016-06-08 | 2016-11-09 | 宁洱众鑫生物科技有限公司 | A kind of Pseudobulbus Bletillae (Rhizoma Bletillae) scented tea and preparation method thereof |
| CN108379320A (en) * | 2018-05-31 | 2018-08-10 | 临沂大学 | A kind of ultrasonic extraction safflower total flavone technique |
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