CN1256949C - Notoginsen triterpenes liposome and prepartion thereof - Google Patents
Notoginsen triterpenes liposome and prepartion thereof Download PDFInfo
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- CN1256949C CN1256949C CN 200310108690 CN200310108690A CN1256949C CN 1256949 C CN1256949 C CN 1256949C CN 200310108690 CN200310108690 CN 200310108690 CN 200310108690 A CN200310108690 A CN 200310108690A CN 1256949 C CN1256949 C CN 1256949C
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Abstract
The present invention relates to a notoginsen total saponine liposome and a preparation method thereof, which belongs to the technical field of medicine. A lipophilic additive is added to a notoginsen total saponine and phospholipid to prepare the notoginsen total saponine liposome of the present invention. The liposome can be made into the dosage forms of powder inhalants, aerosols, sprays, etc., is supplied by lung non-injection, improves the deficiency of poor oral absorption of the notoginsen total saponine, and the medication compliance of patients, reduces the stimulation and the toxicity of medicine, increases the bioavailability of the medicine and enhances the therapeutic effect of notoginsen total saponines on cardio-cerebrovascular diseases. The result of quality testing indicates that the notoginsen total saponine liposome of the present invention has the advantages of uniform particle diameter form, high encapsulation efficiency and low leakage rate, and accords with the requirements of pharmacopoeia.
Description
Technical field:
The invention belongs to medical technical field, be specifically related to a kind of total notoginseng saponin liposome and preparation method thereof.
Background technology:
Investigation shows that cardiovascular and cerebrovascular disease is the second largest factor that influences China's population life-span, along with the raising of people's living standard, and the increase of operating pressure, cardiovascular and cerebrovascular disease ill is rejuvenation, and number of patients is the trend of rising.At present, alternative medicine mostly is the Western medicine kind greatly, and herbal species is few, and preparation mostly is conventional dosage forms or general formulation.Radix Notoginseng is the traditional rare Chinese medicine of China, has another name called Radix Notoginseng, is Araliaceae Panax's a kind, and formal name used at school is Panax notoginseng (Buck.) F.H.Chen, abounds with in Yunnan Province of China, Guangxi.The pharmacological action of Radix Notoginseng is coronary artery dilating, improves myocardial ischemia, reduces myocardial oxygen consumption, blood vessel dilating, anti-arrhythmia etc.Its total saponins of clinical practice (Saponins of Panax Notoginseng, PNS) treatment apoplexy, cerebral thrombosis, coronary heart disease, angina pectoris, atherosclerosis, central retinal vein occlusion etc.
Ginsenoside Rb
1, Rg
1Be two the highest activated monomers of content in the Radix Notoginseng total arasaponins, respectively account for about 30% of total saponins.The Radix Notoginseng series products that has gone on the market at present mainly contains injection such as XUESAITONG and oral tablet such as Radix Notoginseng total glucosides tablet.Injection adopts dropleting medicine-feeding, and patient's poor compliance, and side effect also increases has day by day influenced the application of medicine as anaphylaxis etc.Oral tablet clinical practice curative effect is lower, according to relevant: the Radix Notoginseng total arasaponins water solublity is very big, permeability in gastrointestinal tract mucosa is poor, the strong acid environment of stomach has Degradation to medicine, and wherein activated monomer very easily by gastrointestinal enzyme and intestinal bacteria metabolism, therefore caused the bioavailability of PNS oral formulations very low, wherein ginsenoside Rb
1Oral absolute bioavailability only is 4.35%; The ginsenoside Rg
1Oral administration biaavailability be 18.40%, and in blood, eliminate very fast.Therefore seek Radix Notoginseng total arasaponins novel form and new route of administration and seem particularly necessary.
Pulmonary administration is a kind of potential route of administration, clinically has been widely used in treating respiratory tract disease, and its advantage is that surface area is big, blood flow is abundant, and alveolar wall is thin, and the biological metabolism enzyme is active low inside and outside the cell, and there is not liver first-pass effect, the drug bioavailability height.
Liposome and alveolar have excellent biological compatibility, and preparation technology is simple, and drug encapsulation can reduce drug toxicity in liposome, strengthen pharmacological action, and can reduce the elimination speed of medicine, prolong drug effect, the inside and outside stability of increase medicine.Simultaneously, phospholipid as the film material, itself is nontoxic, cardiovascular and cerebrovascular disease had positive preventive effect, can reduce serum cholesterol, content of triglyceride, also can clean blood vessel makes its softness in the prevention of arterial sclerosis, can significantly alleviate atherosclerosis and Myocardial Ischemia Reperfusion Injury degree, removes the risk factor of the multiple chronic pathological changes such as cardiovascular and cerebrovascular disease of arteriosclerosis initiation.
Summary of the invention
The purpose of this invention is to provide a kind of total notoginseng saponin liposome.Through total notoginseng saponin liposome of the present invention pulmonary non-injection administration, can reduce medicine irritation and toxicity, improve bioavailability of medicament, improve the compliance of patient's medication.
The present invention adds the lipotropy additive preparation by Radix Notoginseng total arasaponins (DFC-SQZD-01, Yunnan mountain of papers) with phospholipid and becomes total notoginseng saponin liposome.
The weight ratio of phospholipid of the present invention and Radix Notoginseng total arasaponins is 0.5: 1-100: 1, and the weight ratio of phospholipid and lipotropy additive is 1: 1-10: 1.
The phospholipid of described liposome, can be lecithin, comprise soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin, two Semen Myristicae phosphatidylcholines, two Semen Myristicae phosphatidyl glycerols, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidic acid, dipalmitoyl phosphatidyl choline, two palmityl phosphatidyl glycerol and distearoyl phosphatidylcholine.Preferably lecithin, two palmityl phosphatidic acid, dipalmitoyl phosphatidyl choline and two palmityl phosphatidyl glycerols.
The present invention adopts lipotropy additive selectivity to improve the characteristic of liposome.Described additive comprises, stearylamine, phosphatidic acid, tocopherol, cholesterol, Cholesteryl hemisuccinate and wool grease extract; Preferred cholesterol.
The medicine pulmonary administration, deposition is that can the reflection medicine effectively bring into play the important indicator of drug effect in the lung, and the size and the shape that enter the drug particles of respiratory tract are the key factors that influence the interior deposition of lung.Liposome particle size range of the present invention is 1-5 μ m, and granule easily arrives respiratory tract deep site of action.
Liposome of the present invention can comprise membrane process, reverse phase evaporation, fusion method, injection method, freeze-drying, surfactant method, multi-emulsion method, calcium fusion method by conventional method, preferred film method, reverse phase evaporation and freeze-drying preparation.
Total notoginseng saponin liposome of the present invention can be made into powder inhalation, and dosage forms such as aerosol and spray are passed through pulmonary administration, it is poor to improve the Radix Notoginseng total arasaponins oral absorption, the deficiency that bioavailability is low strengthens the curative effect of Radix Notoginseng total arasaponins to cardiovascular and cerebrovascular disease, improves the compliance of patient's medication.
The present invention checks the quality of total notoginseng saponin liposome according to two ones of Pharmacopoeia of People's Republic of China versions in 2000.The result shows that total notoginseng saponin liposome size of the present invention meets the requirement of pulmonary administration to the preparation particle diameter, the form homogeneous, and the envelop rate height, percolation ratio is low, meets the every requirement of pharmacopeia to Liposomal formulation.
Description of drawings
Fig. 1 is a PNS liposome photo
A wherein: optical microscope photograph, amplify 300 times, b after 20 times of respective media dilutions: electromicroscopic photograph, amplify 84000 times.
Fig. 2 is the cumulative release curve of PNS liposome in the different temperatures aqueous media, wherein, and n=5, x ± s.
The specific embodiment:
By the following example explanation the specific embodiment of the present invention, but protection scope of the present invention is not limited to this.
Get soybean lecithin (Shanghai Taiwei Pharmaceutical Co., Ltd.) 1.25 grams; cholesterol (Shanghai chemical reagents corporation of Chinese Medicine group) 0.3 restrains with 60 milliliters of ether dissolutions in 250ml pyriform bottle; reduction vaporization is gone out ether on Rotary Evaporators; lipid becomes a thin film on the bottle wall, add 15ml Radix Notoginseng total arasaponins phosphate buffer rotation aquation and obtain total notoginseng saponin liposome.Envelop rate is 81%.
Get soybean lecithin 2 grams, cholesterol 1 gram uses the 100ml ether dissolution in 250ml pyriform bottle, add 20ml Radix Notoginseng total arasaponins phosphate buffer again, the ultrasonic single_phase system that becomes homogeneous that makes of water-bath, reduction vaporization is removed ether to gel formation, continue reduction vaporization 15 minutes, and obtained total notoginseng saponin liposome.Envelop rate is 60%.
Get soybean lecithin 1.25 grams, cholesterol 0.3 restrains with 60 milliliters of ether dissolutions in 250ml pyriform bottle, reduction vaporization is gone out ether on Rotary Evaporators, lipid becomes a thin film on the bottle wall, add 15ml phosphate buffer rotation aquation and obtain blank liposome, adds an amount of trehalose, mixing, lyophilization in a vacuum disperses with the jolting of Radix Notoginseng total arasaponins phosphate buffer immediately, obtains total notoginseng saponin liposome.Envelop rate is 55%.
Get soybean lecithin 2 grams, cholesterol 2 grams, use the 80ml ether dissolution, the insulation of Radix Notoginseng total arasaponins phosphate buffer is in 60 ℃ of constant temperature shaking baths, with microsyringe the ether lipid soln is slowly injected buffer solution, and logical nitrogen removes remaining ether fume, obtain total notoginseng saponin liposome.Envelop rate is 50%.
Get soybean lecithin 2 gram, cholesterol 1 gram fusion mixing slowly adds the Radix Notoginseng total arasaponins phosphate buffer in the fused solution, is organizing the blender high speed to stir, and forms to liposome.Envelop rate is 48%.
Through lyophilization, the powder inhalation device of packing into obtains the total notoginseng saponin liposome powder inhalation with total notoginseng saponin liposome.The liposome powder is contained in the proportioning device, initiatively sucks through the patient.
Embodiment 7:
Total notoginseng saponin liposome is inserted in the aerosol device with propellant, obtained the total notoginseng saponin liposome aerosol.Liposome turbid liquor is the mist ejection under the propellant effect.
Embodiment 8:
Total notoginseng saponin liposome is packed in the spray device, obtain the total notoginseng saponin liposome spray.Liposome turbid liquor directly sprays under pressure and is vaporific.
Embodiment 9 total notoginseng saponin liposome quality examinations
1.PNS the particle diameter of liposome and form thereof
Particle size determination PNS liposome after the phosphate buffer dilution, is measured its size with Zeta potential and particle size analyzer in right amount.
Morphologic observation PNS liposome is put on the copper mesh in right amount, after the phosphotungstic acid negative staining, observes liposome structure down in transmission electron microscope.And get in right amount after dilution, place its form of observation and distribution optical microscope under.
Total notoginseng saponin liposome is large unilamellar vesicle (LUV), and is circular or oval, and the profile rounding is smooth, form distribution homogeneous.Mean diameter is 1546.5nm ± 321.4nm.
2. entrapment efficiency determination
It is an amount of to get the total notoginseng saponin liposome suspension, puts in the low-temperature and high-speed centrifuge, and 4 ℃, 20000g * 30min is centrifugal, gets supernatant 20 μ l, is diluted to 5ml with phosphate buffer, shakes up.The RP-HPLC method is measured free Rb1 and is calculated as follows envelop rate.
3. the external leakage of liposome
Investigate PNS liposome release in vitro situation of 5 days of persistent oscillation in (25 ± 0.5) ℃ and (37 ± 0.5) ℃ water bath with thermostatic control respectively.Liposome is placed in the bag filter in right amount, and release medium is a phosphate buffer, and frequency of oscillation is 80r/min, persistent oscillation 5 days, respectively at 1d, 2d, 3d, 4d, 5d gets dialysis solution 1ml, and replenishes equality of temperature fresh phosphoric salt buffer 1ml simultaneously, and RP-HPLC measures free Rb1 in the dialysis solution.After dialysis is finished, break bag filter, the liposome in the collecting bag also destroys with 10%Triton X-100, the drug leakage amount as the time when infinitely great.Calculate its cumulative release amount, estimate the vitro stability of PNS liposome.
The extracorporeal releasing experiment result shows that the PNS liposome discharges slowly at 25 ℃ and 37 ℃ of medium Chinese medicines, 2.04%, 25 ℃ of cumulative in vitro burst size of 5 days that 37 ℃ of cumulative in vitro burst sizes of 5 days account for time liposome burst size when infinitely great account for the time when infinitely great the liposome burst size 0.43%.
Claims (4)
1, a kind of total notoginseng saponin liposome, it is characterized in that, described liposome is made up of Radix Notoginseng total arasaponins, soybean lecithin and lipotropy additive, described lipotropy additive is selected from stearylamine, phosphatidic acid, tocopherol, cholesterol, Cholesteryl hemisuccinate, the particle size range of described liposome are 1-5 μ m.
2, total notoginseng saponin liposome according to claim 1 is characterized in that wherein the weight ratio of soybean lecithin and Radix Notoginseng total arasaponins is 0.5: 1-100: 1, and the weight ratio of soybean lecithin and lipotropy additive is 1: 1-10: 1.
3, total notoginseng saponin liposome according to claim 1 is characterized in that described lipotropy additive is a cholesterol.
4, according to any described total notoginseng saponin liposome of claim 1-3, can be made into powder inhalation, aerosol and spray.
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| CN 200310108690 CN1256949C (en) | 2003-11-19 | 2003-11-19 | Notoginsen triterpenes liposome and prepartion thereof |
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| CN1256949C true CN1256949C (en) | 2006-05-24 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813682A (en) * | 2012-07-19 | 2012-12-12 | 李振刚 | Stir-frying technology for Chinese yew powder rich in paclitaxel liposome by using membrane-ultrasonic wave dissolving technique |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100460017C (en) * | 2006-08-14 | 2009-02-11 | 云南植物药业有限公司 | Total arasaponin precursor liposome and its prepn process |
| CN101530389B (en) * | 2008-03-11 | 2012-02-15 | 沈阳市万嘉生物技术研究所 | Ginsenoside Rg 3 and phospholipid complex and preparing method thereof |
| CN102178714B (en) * | 2011-04-26 | 2012-07-25 | 中国药科大学 | Preparation for improving oral adsorption of panax notoginsenosides and preparation method thereof |
| CN103653179B (en) * | 2013-12-25 | 2014-12-10 | 福州大学 | Cinnamon essential oil nano lipidosome and preparation method thereof |
| CN104906042B (en) * | 2015-05-28 | 2017-08-11 | 浙江中医药大学 | It is a kind of to treat novel skin drug-delivery preparation of acute and closed soft tissue injury and preparation method thereof |
| CN107375921B (en) * | 2017-06-12 | 2019-10-29 | 商丘美兰生物工程有限公司 | A kind of glycyrrhizin liposome immunization adjuvant and preparation method thereof |
| CN114404464A (en) * | 2022-01-05 | 2022-04-29 | 广西医科大学 | Panax notoginseng saponins myocardial targeted liposome and preparation method thereof |
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2003
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813682A (en) * | 2012-07-19 | 2012-12-12 | 李振刚 | Stir-frying technology for Chinese yew powder rich in paclitaxel liposome by using membrane-ultrasonic wave dissolving technique |
| CN102813682B (en) * | 2012-07-19 | 2014-03-19 | 李振刚 | Stir-frying technology for Chinese yew powder rich in paclitaxel liposome by using membrane-ultrasonic wave method |
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Granted publication date: 20060524 Termination date: 20111119 |