CN1951400A - Arenobufagin nanoliposome and preparation method thereof - Google Patents
Arenobufagin nanoliposome and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a secretio bufonis nano liposome which comprises the following constituents (by weight portions): 0.01-1 part of toad venoms extract, 0.1-20 of phospholipids, 0.05-10 parts of cholesterin, and 0.1-10 parts of emulsifying agent. The invention also discloses the process for preparation through film membrane dispersion method. The secretio bufonis nano liposome has a grain size between 10-100nm and the advantages of high medicinal encapsulation efficiency, low medicinal percolation ratio and oxidation index, and better constancy.
Description
Technical field
The present invention relates to a kind of nanometer liposome and preparation method thereof, particularly a kind of arenobufagin nanoliposome and preparation method thereof.
Background technology
The effective ingredient of Chinese medicine Venenum Bufonis (classification name Venenum Bufonis) mainly comprises multiple liposoluble constituents such as Toadpoison Medicine, cinobufagin, bufogenin.Existing Venenum Bufonis Injection is the water formulation of Venenum Bufonis extract, has the effect of antitumor, antiviral, raising immunologic function, in being widely used in clinically, late tumor and chronic hepatitis B patients.But smooth, the blood vessel irritation untoward reaction such as transfusion part is red and swollen, intravenous pain of venoclysis often appear in process of clinical application; And fat-soluble medicine often exists administration artifact availability to cross low and absorbs shortcoming such as instability.
At present, nanotechnology is applied in the pharmaceutics, can significantly improve the deficiency after the fat-soluble medicine administration, and modern biopharmaceutics and pharmacokinetic prove, when the particle of drug delivery system at＜200nm, particularly＜during the 100nm level, be Nano medication drug-supplying system (Nanoparticle DrugDelivery System, NDDS), the change of matter will take place in the absorption of drug delivery system and transporting mechanism, improve curative effect, realize that the aspects such as bioavailability of targeting administration, slow releasing pharmaceutical, raising insoluble drug show good prospects for application.Wherein Recent study heat be nanometer liposome, in lipoids bimolecular (as phospholipid, cholesterol), after engulfing by infiltration or by phagocyte, carrier is decomposed by enzyme and discharges medicine with drug encapsulation for it.But at present the medicinal liposome ubiquity envelop rate made of the whole bag of tricks is low, and particle diameter does not satisfy shortcomings such as the requirement of NDDS or skewness; And liposome commonly used is liquid condition, it is poor stability under liquid condition, exist many problems, as the oxidation under liquid condition of the focusing of the seepage of medicine, particle and phospholipid, hydrolysis etc., these have also influenced the industrialized great production of liposome, have more influenced liposome application clinically.
On the other hand, nanometer Chinese medicine is to adopt nanotechnology that middle pharmaceutically active ingredient, effective site, former medicine or its compound recipe plurality of Chinese are made nanoparticle compound preparation less than 100nm.It is not simply Chinese crude drug to be crushed to nanometer scale, but carries out the nanotechnology processed at the effective site/composition of Chinese medicine, reaches the NDDS requirement.Be different from single western medicine composition, certain Chinese medicine often is not single chemical compound as the effective ingredient or the effective site of Venenum Bufonis, but a kind of mixture.Thereby at preparation Chinese medicine nanometer formulation, when particularly being loaded with the liposome of Chinese medicine, need to consider the loading and the release at different activities composition/position in the Chinese medicine, with and stability etc.Since it should be noted that the performance of Chinese medicine has significantly even the variation of matter behind the nanorize, so this change will not be above-mentioned positive effect, note also its issuable negative effect, as toxic reaction or untoward reaction etc.
Summary of the invention
One of the technical problem to be solved in the present invention provides the arenobufagin nanoliposome of a kind of particle diameter less than 100nm.
Technical scheme of the present invention is: a kind of arenobufagin nanoliposome, it comprises following components in part by weight: 0.01～1 part of Venenum Bufonis extract, 0.1～20 part of phospholipid, 0.05～10 part of cholesterol, 0.1～10 part of emulsifying agent.
The said Venenum Bufonis extract of the present invention is meant the ethanol extraction of Venenum Bufonis, its extraction process is carried out according to existing Venenum Bufonis Injection technology (" the Sanitation Ministry medicine standard Chinese traditional patent formulation preparation " the 17 Venenum Bufonis Injection quality standard), and extracting solution is reclaimed the ethanol evaporate to dryness promptly.
And described phospholipid can be natural phospholipid, as a kind of in soybean phospholipid, the lecithin or two kinds.The preferred natural phospholipid of the present invention:, little because of its liposome particle diameter that makes, envelop rate is high, safety good as soybean phospholipid, lecithin.
Wherein, the content of phospholipid is relevant with envelop rate, and too low, then envelop rate is low; Otherwise, too high, then envelop rate is not had obvious improvement, and influence product stability because of its easy oxidation, hydrolysis.
And described cholesterol level and film is permeability-related, too low, and then permeability is bad; Otherwise, too high, then produce seepage.
The said emulsifying agent of the present invention is the pharmaceutical adjuvant with solubilising, emulsifying, Stabilization.The preferred poloxamer of the present invention (Poloxamer) 188 or Tween 80.When the content of emulsifying agent is too low, then medicine dissolution is incomplete, the liposome instability; Otherwise, too high, can bring the haemolysis safety issue during then as intravenous formulations.
Arenobufagin nanoliposome of the present invention preferably comprises following components in part by weight: 0.05～0.2 part of Venenum Bufonis extract, 1～2 part of phospholipid, 0.1～0.5 part of cholesterol, 0.4～2 part of emulsifying agent.
Obviously, as required, also can in arenobufagin nanoliposome, add various additives, the isotonic agent that need add as used for intravenous injection preparation or ophthalmic preparation time the: glycerol, glucose etc.; As antioxidant: vitamin E, vitamin C, sodium sulfite etc.; The antibacterial that need add as unsterilised oral or external preparation time the: sorbic acid and salt thereof, benzoic acid and salt thereof etc.
For ease of storage and transport, the present invention also can be by the conventional drying method, above-mentioned liposome is made the pro-liposome of dry powder doses as spray drying or lyophilization.
Another technical problem that the present invention will solve provides the preparation method of above-mentioned arenobufagin nanoliposome.
Its technical scheme that adopts is: film dispersion method specifically comprises the steps:
1) phospholipid and cholesterol are dissolved in the organic solvent and 30-50 ℃ down rotation flash to film;
2) emulsifying agent is dissolved in the buffer that pH is 6.0-7.3, again Venenum Bufonis extract is dissolved in this buffer;
3) with step 2) solution of gained adds in the film that step 1) makes, mixes homogenize and get arenobufagin nanoliposome (suspension form).
The step 1) of said method of the present invention is a conventional method, and organic solvent wherein can be methanol, chloroform, ethanol, ether or both mixture wherein.
Step 2) buffer in adopts conventional phosphate buffer (PBS), and the concentration that this emulsifying agent is dissolved in the buffer is generally 0.1～10g/100ml.
And can adopt vortex vibration to mix in the step 3), the thin film of bottle wall is come off fully in buffer, form suspension; Also can be stirred, as magnetic agitation, its time decides on the form of the suspension of formation, generally is no more than 2 hours.
Positive progressive effect of the present invention is: the particle diameter of product of the present invention between 10-100nm, the entrapment efficiency height, at least more than 80%, the drug leakage rate is low, does not use the oxidation index under the antioxidant situation low, good stability; When being used for intravenous injection, can reducing existing Venenum Bufonis preparation to the venous zest, and have higher blood drug level and certain long-acting.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Wherein, the extraction process of Venenum Bufonis extract of the present invention is carried out according to existing Venenum Bufonis Injection technology (" the Sanitation Ministry medicine standard Chinese traditional patent formulation preparation " the 17 Venenum Bufonis Injection quality standard), get a certain amount of Venenum Bufonis, soak, grind with 10 times of amount waters for injection, adding ethanol makes and contains alcohol amount and reach 75%, stir evenly, leave standstill, cold preservation, filter, filtrate recycling ethanol and evaporate to dryness are promptly.
The arenobufagin nanoliposome particle diameter that makes adopts Nicomp/Pss ZW380 type particle size analyzer (U.S. PSS company) to record, envelop rate ultrafiltration centrifuging, burst size, percolation ratio are calculated according to conventional formula after with the film dialysis, and oxidation index adopts two appendix of Chinese Pharmacopoeia version in 2005 to record.
Embodiment 1
With the 0.1g soybean phospholipid, the 0.05g cholesterol is dissolved in the ethanol, passes through the rotary evaporation film forming in 50 ℃ water-bath; 0.3g poloxamer 188 is dissolved in the PBS buffer of 100ml pH6.0, again Venenum Bufonis extract 0.01g is dissolved in this solution; The solution that makes is added in the above-mentioned film, vortex vibrate liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 10-20nm, and envelop rate is that burst size is that 35%, 36 hour percolation ratio is 2% in 80%, 0.5 hour, and oxidation index is 0.01.
Embodiment 2
With the 1g soybean phospholipid, the 0.1g cholesterol is dissolved in the ether, passes through the rotary evaporation film forming in 30 ℃ water-bath; 0.4g poloxamer 188 is dissolved in the phosphate buffer 98ml of pH7.3, Venenum Bufonis extract 0.05g is dissolved in this buffer solution; The solution that makes is added in the above-mentioned film, the magnetic agitation homogenize is 0.5 hour after the vortex mixed again, gets liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 20-30nm, and envelop rate is that burst size is that 27%, 36 hour percolation ratio is 0.3% in 95%, 0.5 hour, and oxidation index is 0.03.
Embodiment 3
With the 1.5g soybean phospholipid, the 0.3g cholesterol is dissolved in the chloroform, passes through the rotary evaporation film forming in 40 ℃ water-bath; 1.5g poloxamer 188 is dissolved in the phosphate buffer 90ml of pH6.5, again Venenum Bufonis extract 0.1g is dissolved in the above-mentioned solution; The solution that makes is added in the above-mentioned film, stir homogenize 1 hour after the vibrating dispersion, get liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 20-40nm, and envelop rate is that burst size is that 28%, 36 hour percolation ratio is 0.3% in 94%, 0.5 hour, and oxidation index is 0.08.
Embodiment 4
With the 2g soybean phospholipid, the 0.5g cholesterol is dissolved in the ether, passes through the rotary evaporation film forming in 30 ℃ water-bath; 2g poloxamer 188 is dissolved in the phosphate buffer 85ml of pH7.2, Venenum Bufonis extract 0.2g is dissolved in the above-mentioned buffer solution; The solution that makes is added in the above-mentioned film, stir homogenize 1.5 hours after the vibrating dispersion, get liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 50-80nm, and envelop rate is that burst size is that 24%, 36 hour percolation ratio is 0.2% in 96%, 0.5 hour, and oxidation index is 0.1.
Embodiment 5
With the 20g soybean phospholipid, the 10g cholesterol is dissolved in the ethanol, passes through the rotary evaporation film forming in 50 ℃ water-bath; 10g poloxamer 188 is dissolved in the PBS buffer 98ml of pH6.0, again Venenum Bufonis extract 1g is dissolved in this solution; The solution that makes is added in the above-mentioned film, and the vortex vibrating dispersion gets liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 60-70nm, and envelop rate is that burst size is that 34%, 36 hour percolation ratio is 2% in 89%, 0.5 hour, and oxidation index is 0.06.
Embodiment 6
With 0.3g lecithin, the 0.06g cholesterol is dissolved in the chloroform, passes through the rotary evaporation film forming in 40 ℃ water-bath; The 0.1g tween 80 is dissolved in the phosphate buffer 95ml of pH6.5, again Venenum Bufonis extract 0.01g is dissolved in the above-mentioned solution; The solution that makes is added in the above-mentioned film, stir homogenize 1 hour after the vibrating dispersion, get liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 20-40nm, and envelop rate is that burst size is that 26%, 36 hour percolation ratio is 0.5% in 97%, 0.5 hour, and oxidation index is 0.05.
Embodiment 7
With 4g lecithin, the 0.1g cholesterol is dissolved in the ether, passes through the rotary evaporation film forming in 30 ℃ water-bath; The 2g tween 80 is dissolved in the phosphate buffer 80ml of pH7.2, Venenum Bufonis extract 0.1g is dissolved in the above-mentioned buffer solution; The solution that makes is added in the above-mentioned film, stir homogenize one hour after the vibrating dispersion, get liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 60-90nm, and envelop rate is that burst size is that 22%, 36 hour percolation ratio is 1% in 96%, 0.5 hour, and oxidation index is 0.12.
Embodiment 8
With 18g lecithin, the 8g cholesterol is dissolved in the ether, passes through the rotary evaporation film forming in 30 ℃ water-bath; The 5g tween 80 is dissolved in the phosphate buffer 80ml of pH7.2, Venenum Bufonis extract 1g is dissolved in the above-mentioned buffer solution; The solution that makes is added in the above-mentioned film, stir homogenize one hour after the vibrating dispersion, get liposome turbid liquor 100ml.
Resulting arenobufagin nanoliposome is measured with said method, records mean diameter between 70-90nm, and envelop rate is that burst size is that 21%, 36 hour percolation ratio is 1.2% in 94%, 0.5 hour, and oxidation index is 0.14.
Phospholipid in the foregoing description is that Shanghai Taiwei Pharmaceutical Co., Ltd. produces, cholesterol is that source, Shanghai consor thing Science and Technology Ltd. product, poloxamer 188 and tween 80 are that Nanjing WeiEr chemical engineering Co., Ltd produces; Phosphate buffer is pressed the Chinese Pharmacopoeia autogamy; All the other reagent are conventional commercially available prod.
Application Example 1 stability test
With embodiment 3 is that example is carried out influence factor and study on the stability to arenobufagin nanoliposome, the result shows this product each influence factor test of 10 days, accelerated test (30 ℃, RH75%) 6 months and room temperature under illumination (4500Lux), high temperature (40 ℃), cold preservation (4～8 ℃) condition (25 ℃, RH60%) 6 months the study on the stability that keeps sample, its outward appearance and mean diameter and initial data relatively have no significant change, and the results are shown in Table 1.
Table 1
| Outward appearance | Mean diameter (nm) | |
| Original | The translucent colloid of milky | 25 |
| Illumination | The translucent colloid of milky | 26 |
| High temperature | The translucent colloid of milky | 24 |
| Cold preservation | The translucent colloid of milky | 25 |
| Accelerated test | The translucent colloid of milky | 28 |
| Room temperature keeps sample | The translucent colloid of milky | 25 |
The test of Application Example 2 blood vessel irritations
Get 4 of rabbit, be divided into two groups, inject the (iv) of the present invention arenobufagin nanoliposome of 1ml embodiment 3 to rabbit vein every day, after continuous three days, dissects animal blood vessels and make the pathology sections observation.The result shows that the blood vessel of two treated animals has slight hypertrophy, hyperemia, hemorrhage, but the reaction of significant stimulation such as equal inorganization degeneration of blood vessel or necrosis.
The above results shows that Venenum Bufonis extract by after liposomal encapsulated, can reduce the zest of medicine to blood vessel effectively.
Application Example 3 rat body giving drugs into nose are for dynamic test
Get 12 of SD rats, be divided into two groups at random, one group in the arenobufagin nanoliposome test group of the present invention of tail vein injection 0.5ml embodiment 3, other one group (dissolves with 1% tween 80 solution in tail vein injection 0.5ml Venenum Bufonis extract aqueous solution, every ml contains the Venenum Bufonis extract with the liposome same dose) organize in contrast, test group and matched group respectively at administration after 0.17h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 5h eye socket venous plexus get blood, whole blood is put in the heparinization plastic centrifuge tube, in the centrifugal 5min of 6000rpm, separated plasma.
Get plasma sample, the accurate rat plasma 0.2ml that draws puts in the 5ml plastic centrifuge tube, add the 3.0ml ethyl acetate, vortex extraction 5min, centrifugal (10000rpm) 10min draws upper organic phase and puts in the 5ml glass point end test tube, 40 ℃ of water-bath nitrogen current volatilize, residue adds 100 μ l dissolve with methanol, leaves standstill, and gets supernatant 20 μ l and carries out HPLC (chromatographic column: Kromasil C
18(250 * 4.6mm, 5 μ m); Mobile phase: 0.5% potassium dihydrogen phosphate-acetonitrile (50: 50); The detection wavelength is 296nm; Flow velocity: 1.0ml/min) analyze.
Measure and respectively to organize each time point bufogenin concentration after the rat administration, the results are shown in Table 2:
Table 2
| Time (h) | Venenum Bufonis aqueous solution (mg/L) | Arenobufagin nanoliposome (mg/L) |
| 0.17 | 7.0782 | 6.1894 |
| 0.5 | 1.4379 | 4.0621 |
| 1 | 0.2161 | 1.2737 |
| 1.5 | 0.0757 | 0.2492 |
| 2 | 0.032 | 0.326 |
| 3 | 0.0148 | 0.1293 |
| 4 | 0.0191 | 0.0648 |
| 5 | 0.009 | 0.0195 |
Analyze by statistics, arenobufagin nanoliposome of the present invention is compared with the Venenum Bufonis aqueous solution, has significantly reduced the medicine maximum concentration, can reduce the ill effect of Venenum Bufonis extract to vascular stimulation; Significantly delayed simultaneously the release of medicine, made the certain long-acting of arenobufagin nanoliposome tool of the present invention.
Claims (8)
1, a kind of arenobufagin nanoliposome, it comprises following components in part by weight: 0.01～1 part of Venenum Bufonis extract, 0.1～20 part of phospholipid, 0.05～10 part of cholesterol, 0.1～10 part of emulsifying agent.
2, arenobufagin nanoliposome as claimed in claim 1 is characterized in that it comprises following components in part by weight: 0.05～0.2 part of Venenum Bufonis extract, 1～2 part of phospholipid, 0.1～0.5 part of cholesterol, 0.4～2 part of emulsifying agent.
3, arenobufagin nanoliposome as claimed in claim 1 is characterized in that described phospholipid is soybean phospholipid or lecithin, and described emulsifying agent is poloxamer 188 or Tween 80.
4, as the preparation method of each described arenobufagin nanoliposome of claim 1～3, it adopts film dispersion method, comprises the steps:
1) phospholipid and cholesterol are dissolved in the organic solvent and 30-50 ℃ down rotation flash to film;
2) emulsifying agent is dissolved in the buffer that pH is 6.0-7.3, again Venenum Bufonis extract is dissolved in this buffer;
3) with step 2) solution of gained adds in the film that step 1) makes, mixes homogenize and get arenobufagin nanoliposome.
5, preparation method as claimed in claim 4 is characterized in that this buffer is a phosphate buffer.
6, preparation method as claimed in claim 4 is characterized in that step 2) in the concentration that is dissolved in the buffer of emulsifying agent be 0.1～10g/100ml.
7, preparation method as claimed in claim 4 is characterized in that mixing described in the step 3) homogenize and adopts the vortex vibration.
8, preparation method as claimed in claim 7 is characterized in that mixing described in the step 3) homogenize and also adopts magnetic agitation.
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| CN101732349B (en) * | 2008-11-14 | 2012-05-23 | 上海医药工业研究院 | Venenum bufonis nanometer long-circulating liposome and preparation method thereof |
| CN101574373B (en) * | 2008-05-09 | 2013-06-12 | 北京因科瑞斯医药科技有限公司 | Toad venom alcohol plastid and preparation method thereof |
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| CN104922072A (en) * | 2015-07-14 | 2015-09-23 | 合肥华方医药科技有限公司 | Total toad-poison lactone liposome injection and preparing method thereof |
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| CN107929324B (en) * | 2017-12-08 | 2020-11-13 | 大连工业大学 | Liposome loaded with sea cucumber decoction extract and preparation method thereof |
| CN110720590A (en) * | 2019-11-26 | 2020-01-24 | 云南省农业科学院农产品加工研究所 | Preparation method of panax notoginseng aerial part nano functional rice |
| CN114432247A (en) * | 2022-01-18 | 2022-05-06 | 南京中医药大学 | Toad tryptamine liposome and preparation method and application thereof |
| CN116196279A (en) * | 2023-04-27 | 2023-06-02 | 上海中医药大学 | Cholesterol-free liposome of venenum bufonis extract, and preparation method and application thereof |
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