CN100457089C - Solid liposome nanoparticles of arenobufagin and preparation method thereof - Google Patents
Solid liposome nanoparticles of arenobufagin and preparation method thereof Download PDFInfo
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Abstract
The invention discloses secretio bufonis solid liposome nano particles which comprise the following constituents (by weight portions): 0.01-1 part of toad venoms extract, grease material 0.2-20 parts, liposoluble emulsifying agent 0.2-15 parts, and water-soluble emulsifying agent 0.2-10 parts. The grease material is selected from stearinic acid, glycol tristearate and mountain-elm glyceride. The invention also discloses the process for preparation through fusion method and high pressure homogeneity. 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 Venenum Bufonis nanometer formulation, particularly a kind of solid liposome nanoparticles of arenobufagin and preparation method thereof.
Background technology
The effective ingredient of 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 solid lipid nanoparticle (SLN) is one of nano-carrier that rises earlier 1990s; being solid-state lipid materials such as fatty acid, aliphatic alcohol and phospholipid etc. under the room temperature that it adopts and physiological compatibility is good is carrier; solid lipid nanoparticle has been concentrated the advantage of Emulsion, liposome, polymer nanoparticle drug-loading system; as the physical stability height, to the protection of labile drugs, make medicine tool slow releasing function, that the research of its route of administration has comprised is oral, the various ways of injection, skin, respiratory tract administration.Simultaneously, can adopt high pressure homogenizer to be prepared, be suitable for suitability for industrialized production.
Yet because the SLN technology still is in the starting stage, to how improving entrapment efficiency and drug loading, preparation stability, problems such as safety need further further investigation to inquire into.And modern biopharmaceutics and pharmacokinetic have proved, when the particle of drug delivery system at＜200nm, particularly＜during the 100nm level, be Nano medication drug-supplying system (Nanoparticle Drug Delivery 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.Therefore, need consider that also the nanoparticle particle diameter of medicine carrying SLN need satisfy the requirement of NDDS.
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 SLN 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 solid liposome nanoparticles of arenobufagin of a kind of wherein nanoparticle particle diameter less than 100nm.
Technical scheme of the present invention is: a kind of solid liposome nanoparticles of arenobufagin, and it contains following components in part by weight: 0.01～1 part of Venenum Bufonis extract, 0.2～20 part of matrix material, 0.2～15 part of fat-soluble emulsifier, 0.2～10 part of water soluble emulsifier; This matrix material is selected from stearic acid, glyceryl tristearate and Rikemal B 200.
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.
Be meant in SLN as carrier material, be solid-state lipid materials with physiological compatibility under the good and room temperature, as for said matrix material as triglyceride, mixed glyceride, fatty acid, steroid, wax, phospholipid etc.For making solid liposome nanoparticles of arenobufagin of the present invention have higher entrapment and drug loading to each effective ingredient of Venenum Bufonis, and consider that it is applied to when clinical, need be suitable for the different administration approach, intravascular particularly, can reduce the side reaction of local excitation and whole body during as intravenous injection, to improve safety, so the present invention is through many experimental studies, preferably be suitable for the stearic acid and the glyceryl tristearate of intravenous formulations, and the SLN that the former Rikemal B 200 that is used for oral formulations is made carried out through muscle, the investigation of intravenous administration safety, find its not only safety, and combination property is preferable.So matrix material of the present invention is Rikemal B 200 more preferably.Wherein, the weight portion of matrix material is relevant with envelop rate, and is too low, particularly is lower than 0.2 part, and then envelop rate is lower than 80%; Otherwise too high meeting causes particle diameter to become big, and as surpassing 20 parts, particle diameter surpasses 100nm.
And the said emulsifying agent of the present invention is the pharmaceutical adjuvant with emulsifying, stable, peptizaiton.Emulsifying agent of the present invention is made up of fat-soluble emulsifier and water soluble emulsifier.Wherein, fat-soluble emulsifier is selected from soybean phospholipid and lecithin, and water soluble emulsifier is selected from poloxamer (Poloxamer) series and tween (Tween) series.For being suitable for intravenous administration better, emulsifying agent of the present invention is the combination of soybean phospholipid and poloxamer 188 more preferably.When the content of emulsifying agent is too low, then medicine can not disperse or be dissolved in the matrix material; Otherwise, too high, then can bring safety problem, produce haemolysis etc. when using as vein.
Solid liposome nanoparticles of arenobufagin of the present invention preferably comprises following components in part by weight: 0.05～0.5 part of Venenum Bufonis extract, 0.6～8 part of matrix material, 0.4～7 part of fat-soluble emulsifier, 0.5～5 part of water soluble emulsifier.
Obviously, as required, also can in Venenum Bufonis SLN, 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.
The another technical problem that the present invention will solve provides the preparation method of above-mentioned solid liposome nanoparticles of arenobufagin.
The concrete technical scheme of this preparation method comprises the following steps:
1. Venenum Bufonis extract, matrix material and fat-soluble emulsifying agent are heated to melt temperature, make fused mass in the lipid to be dissolved or dispersed in;
2. water soluble emulsifier is scattered in the water, forms uniform water;
3. with step 1. the fused mass of gained and step 2. the water of gained under this melt temperature, mix, be stirred to and form uniform colostrum;
4. with this colostrum under this melt temperature, high pressure homogenize under 30～120MPa pressure, be cooled to room temperature and following rapidly, can make solid liposome nanoparticles of arenobufagin of the present invention (aqueous dispersion).
Wherein, step 1., 3., 4. described in melt temperature be generally the temperature that is higher than 5～10 ℃ of matrix material fusing points.The selected matrix material according to the present invention, preferred 80～85 ℃ of this melt temperature, temperature is too high, can cause the degraded of Venenum Bufonis active component, most preferably 85 ℃ of the present invention.
As for step 4. described in the high pressure homogenize normally adopt high pressure homogenizer to realize for 3～10 times at described pressure limit internal recycle.This pressure is too little, and then the nanoparticle particle diameter surpasses 100nm; And pressure is too big, then can cause the cohesion of nanoparticle.
Solid liposome nanoparticles of arenobufagin of the present invention is a kind of aqueous dispersion, and the different dosage form specification designs in the time of can be according to pharmacy.The present invention is an example explanation with the 100ml aqueous dispersion, and this aqueous dispersion can be directly used in clinical application, as intravenous injection or instillation.
For ease of storage and transport, the present invention also can make dry powder doses as spray drying or lyophilization with aqueous dispersion by the conventional drying method.
The present invention is a carrier material with the lipid, is stabilizing agent with the emulsifying agent, and the method that adopts fusion method and high pressure homogenize to combine is stated from the lipid nanoparticle pharmaceutical pack.Because preparation method of the present invention not with an organic solvent, can reduce step and the cost of removing it, also avoids near, the at a specified future date untoward reaction of residual solvent to body; Suitability for industrialized production then is convenient in mechanical high pressure homogenize.The more important thing is that the Venenum Bufonis SLN particle diameter that the present invention makes is at 10～100nm, envelop rate and drug loading height are respectively more than 80% with more than 1.6%; Stability is good; And be suitable for the number of ways medication, particularly it can be directly used in intravenous administration as aqueous dispersion, there are not untoward reaction such as allergy, haemolysis, safe, particularly little to local injection site irritation, may be SLN of the present invention, after entering vein by the nanoparticle that is wrapped in Venenum Bufonis, the active component of Venenum Bufonis can directly not contact with blood, has only after it is by hemodilution, just slowly absorbed, so avoided the big untoward reaction of existing Venenum Bufonis Injection blood vessel irritation by body.In addition, the present invention has confirmed the safety of Rikemal B 200 as the intravenous formulations adjuvant first, make and adopt its Venenum Bufonis SLN of the present invention additionally to have the advantage that is suitable for intravenous administration, also increased new lipid carrier material selection for preparing the SLN intravenous formulations later on as the lipid carrier material.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Wherein, its 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.
Used high pressure homogenizer is the high pressure homogenizer of the Italian Niro Soavi company NS1001L PANDA 2K model of producing.
The Nicomp/Pss ZW380 type particle size analyzer dynamic light scattering method that the Venenum Bufonis SLN particle diameter that makes adopts U.S. PSS company to produce records, after envelop rate, drug loading adopt the high speed centrifugation hyperfiltration process, calculate according to formula (two appendix of Chinese Pharmacopoeia version in 2005).
Embodiment 1～11 and comparative examples
With the component of specified volume in each embodiment and the comparative examples shown in the table 1, make Venenum Bufonis SLN of the present invention by following preparation method.
1) with Venenum Bufonis extract, matrix material and fat-soluble emulsifier, under temperature conditions shown in the table 2, heat, make it become fused mass;
2) water intaking dissolubility emulsifying agent is scattered in the 100ml water for injection, forms uniform water;
3) step 1) being prepared the fused mass and the step 2 of gained) water of gained mixes under temperature conditions shown in the table 2, stirred (more than the 10000rpm) 1 minute, forms uniform colostrum;
4) colostrum of step 3) gained is transferred in the high pressure homogenizer, under condition shown in the table 2, carried out homogenizing, be chilled to room temperature rapidly, can make solid lipid nanoparticle (aqueous dispersion) 100ml of 10-100nm.
Table 1
A is a poloxamer 188, and b is a poloxamer 407, and c is a tween 80, and d is a Tween-60.
Wherein comparative examples is the blank solid lipid nanoparticle of making by the prescription (not throwing Venenum Bufonis extract) of embodiment 4.
Table 2
| Embodiment | Temperature (℃) | Pressure (MPa) | Cycle-index |
| 1 | 85 | 50 | 3 |
| 2 | 85 | 60 | 5 |
| 3 | 85 | 60 | 5 |
| 4 | 85 | 70 | 7 |
| 5 | 85 | 110 | 10 |
| 6 | 80 | 30 | 3 |
| 7 | 80 | 80 | 3 |
| 8 | 80 | 120 | 8 |
| 9 | 80 | 40 | 4 |
| 10 | 80 | 60 | 5 |
| 11 | 80 | 100 | 9 |
| Contrast | 85 | 70 | 7 |
Nanoparticle particle diameter, envelop rate and the drug loading of each the embodiment Venenum Bufonis SLN that makes are as shown in the table:
Table 3
| Embodiment | Particle diameter (nm) | Envelop rate (%) | Drug loading (%) |
| 1 | 20 | 82 | 2.1 |
| 2 | 32 | 86 | 4.3 |
| 3 | 45 | 87 | 3.1 |
| 4 | 50 | 95 | 4.3 |
| 5 | 86 | 96 | 3.3 |
| 6 | 33 | 81 | 1.6 |
| 7 | 78 | 88 | 3.4 |
| 8 | 92 | 92 | 2.6 |
| 9 | 55 | 83 | 1.7 |
| 10 | 62 | 86 | 3.1 |
| 11 | 88 | 87 | 2.7 |
The foregoing description is that example illustrates the present invention with the 100ml aqueous dispersion, also can make other specification as required, as with step 2) in water for injection increase to 120/150/200/250/500ml, then can make the Venenum Bufonis SLN aqueous dispersion of the present invention of 120/150/200/250/500ml.
Rikemal B 200 in the foregoing description is French Jia Fasai (Gattefosse) product, trade name Compritol 888 ATO; Stearic acid is a Rui'an City Master oils and fats factory product; Glyceryl tristearate (Tristearin) is a U.S. fluka company product; Soybean phospholipid, lecithin are Shanghai Taiwei Pharmaceutical Co., Ltd.'s product; Poloxamer 188, poloxamer 407 are U.S. Basf company product; Tween-60, tween 80 are Shen, Shanghai space chemical industry company limited product.
Experimental example 1 stability test
With embodiment 4 is that example is carried out influence factor and study on the stability to used for intravenous injection Venenum Bufonis SLN, the result shows this product each influence factor test of 10 days, accelerated test (30 ℃, RH 75%) 6 months and room temperature under illumination (4500Lux), high temperature (40 ℃), cold preservation (4～8 ℃) condition (25 ℃, RH 60%) 6 months the study on the stability that keeps sample, its outward appearance, mean diameter and initial data relatively have no significant change, and the results are shown in Table 4.
Table 4
| Outward appearance | Average nanoparticle particle diameter (nm) | |
| Original | Milky, translucent | 50 |
| Illumination | Milky, translucent | 52 |
| High temperature | Milky, translucent | 51 |
| Cold preservation | Milky, translucent | 50 |
| Accelerated test | Milky, translucent | 49 |
| Room temperature keeps sample | Milky, translucent | 50 |
Experimental example 2 irritation tests
1. muscle irritation test
Get 4 of the above healthy rabbit of body weight 2kg, be divided into 2 groups, one group respectively about it in two lower limb quadriceps femoris aseptic manipulation respectively inject the solid liposome nanoparticles of arenobufagin aqueous dispersion 1ml of the present invention of embodiment 4, another group respectively about it in two lower limb quadriceps femoris aseptic manipulation respectively inject the blank solid lipid nanoparticle 1ml of comparative examples, inject and put to death animal in back 48 hours, dissect and take out quadriceps femoris, vertically cut, observe the injection site irritation reaction and the corresponding order of reaction that converts.Calculate the summation of 4 quadriceps femoris order of reactions then.The muscle irritation experimental observation is the result show, the summation of two groups of 4 quadriceps femoris order of reactions all＜10, blank solid lipid nanoparticle and the solid liposome nanoparticles of arenobufagin of the present invention made with Rikemal B 200 are little to local muscle irritation.
2. blood vessel irritation test
Get 4 of rabbit, be divided into two groups, inject (iv) of the present invention solid liposome nanoparticles of arenobufagin of 1ml embodiment 4 or the blank solid lipid nanoparticle of comparative examples 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.
Experimental example 3 whole body initiative anaphylaxiss
Get healthy do not have hinder 6 of Cavia porcelluss, body weight 200-250g, by the sterile working, the next day every solid liposome nanoparticles of arenobufagin aqueous dispersion 0.5ml of the present invention that intramuscular injection embodiment 4 makes, totally 3 times, it is divided into two groups.One group of after injection first the 14th day, 2ml attacks by the intravenous injection sample, observes injection back animal and has or not symptoms of allergic such as grabbing nose, perpendicular hair, dyspnea, spasm, shock even death.Second group of attacking with method in 21st after injection first observed.Two groups of Cavia porcelluss all do not have significant reaction.
Conclusion: used for intravenous injection Venenum Bufonis SLN of the present invention does not produce anaphylaxis to Cavia porcellus.
Experimental example 4 hemolytic tests
The medicinal liquid preparation:
Get the solid liposome nanoparticles of arenobufagin of the present invention of the embodiment of the invention 4 and the blank solid lipid nanoparticle of comparative examples and be divided into two groups, observe hemolytic reaction.
Experimental technique:
Extract tame rabbit whole blood 5ml, it is former to defibrinate with the bead jolting, washes 3 times with 0.9% normal saline, no longer present redness to supernatant till, overstock volume with erythrocyte and be made into 2% red cell suspension with normal saline.
Get 7 in test tube for every group and add various solution by table 5, the 6th pipe does not add test sample and adds normal saline as blank (feminine gender) contrast, and the 7th pipe does not add test sample, replaces normal saline to contrast as complete hemolysis (positive) with distilled water, shake up gently to put in 37 ℃ of water-baths and be incubated observed result after 1 hour.
Every group of various solution that add of table 5
The result shows that two groups are not all had hemolytic reaction.
Conclusion: blank solid lipid nanoparticle and the solid liposome nanoparticles of arenobufagin of the present invention made with Rikemal B 200 all do not have haemolysis.
Experimental example 5 toxicity tests
1. the blank SLN that makes of Rikemal B 200
1.1 maximum tolerance determination
Get 20 of Kunming mouses, 18～22g, male and female half and half can't be measured the LD of the blank solid lipid nanoparticle that Rikemal B 200 makes through prerun
50, use the blank solid lipid nanoparticle that the Rikemal B 200 of iv various dose makes instead and measure maximum tolerated dose, use the Rikemal B 200 contrast of ip (lumbar injection) various dose simultaneously, observed altogether 21 days.
The result shows, limits because of the concentration and the administration volume that are subjected to sample, and the maximum tolerated dose of mice can reach 3.96g/kg.
1.2 long term toxicity test
Get 60 of SD rat, every 200g, male and female half and half, be divided into high, normal, basic 3 dosage groups, 20 every group, every day high dose group iv 1ml, middle dosage group iv 0.5ml, the blank solid lipid nanoparticle that low dose group iv 0.2ml Rikemal B 200 is made shows that through 6 months long term toxicity tests Rikemal B 200 can be used as the used for intravenous injection adjuvant.
2. solid liposome nanoparticles of arenobufagin of the present invention
Experimental technique: get embodiment 4 Venenum Bufonis SLN, be diluted to debita spissitudo.Animal is evenly divided into groups by body weight, each 10 animal of administration group male and female, fasting is 4 hours before the zoopery, freely drinks water.The administration group is pressed the heavy every 0.4ml/20g volume intravenous injection of animal body.Observe reaction of animals after the administration continuously and write down animal dead number in 7 day time.Each dosage treated animal death toll is calculated other LD of two individual characteies with bliss method in the Ministry of Public Health new drug statistical procedure
50(95% fiducial limit) value.
Result: the LD that calculates respectively with the Bliss method
50(95% fiducial limit) female mice is 8.2mg/kg, and male mice is 8.1mg/kg.
Conclusion: an intravenous injection acute toxicity of used for intravenous injection solid liposome nanoparticles of arenobufagin mice of the present invention LD
50For female: 8.2mg/kg, hero: 8.1mg/kg.
By above-mentioned experimental example as seen, solid liposome nanoparticles of arenobufagin of the present invention has stability preferably.And its safety is good, during especially for intravenous injection, does not have untoward reaction such as tangible vascular stimulation reaction, systemic anaphylaxis and hemolytic reaction.
Claims (6)
1, a kind of solid liposome nanoparticles of arenobufagin is characterized in that it contains following components in part by weight: 0.05～0.5 part of Venenum Bufonis extract, 0.6～8 part of matrix material, 0.4～7 part of fat-soluble emulsifier, 0.5～5 part of water soluble emulsifier; This matrix material is selected from stearic acid, glyceryl tristearate and Rikemal B 200, and this fat-soluble emulsifying agent is soybean phospholipid or lecithin, and this water soluble emulsifier is poloxamer or tween.
2, solid lipid nanoparticle as claimed in claim 1 is characterized in that it is an intravenous formulation.
3, a kind of preparation method of solid liposome nanoparticles of arenobufagin as claimed in claim 1 or 2, it comprises the following steps:
1. Venenum Bufonis extract, matrix material and fat-soluble emulsifying agent are heated to melt temperature, make fused mass in the lipid to be dissolved or dispersed in;
2. water soluble emulsifier is scattered in the water, forms uniform water;
3. with step 1. the fused mass of gained and step 2. the water of gained under this melt temperature, mix, be stirred to and form uniform colostrum;
4. with this colostrum under this melt temperature, high pressure homogenize under 30～120MPa pressure, be cooled to room temperature and following rapidly, promptly make solid liposome nanoparticles of arenobufagin of the present invention.
4, preparation method as claimed in claim 3, it is characterized in that step 1., 3., 4. described in melt temperature be the temperature that is higher than 5～10 ℃ of matrix material fusing points.
5, preparation method as claimed in claim 4 is characterized in that this melt temperature is 80～85 ℃.
6, preparation method as claimed in claim 3 is characterized in that high pressure homogenize described in step 4. is to adopt high pressure homogenizer described pressure limit internal recycle 3～10 times.
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| CN104706622B (en) * | 2015-03-24 | 2017-10-20 | 合肥华方医药科技有限公司 | Total toadpoison lactone lyophilization of solid lipid nanoparticles and preparation method thereof |
| CN104739807B (en) * | 2015-04-22 | 2017-10-20 | 合肥华方医药科技有限公司 | A kind of total toadpoison lactone nano-micelle preparations and preparation method thereof |
| CN108186732A (en) * | 2018-03-15 | 2018-06-22 | 亳州市乾元动物药业有限责任公司 | A kind of production method of ox toad particle |
| CN113575942A (en) * | 2021-08-16 | 2021-11-02 | 于永涛 | Ginseng and pilose antler fruit nutrient lipid particle and preparation method thereof |
| CN114432247A (en) * | 2022-01-18 | 2022-05-06 | 南京中医药大学 | Toad tryptamine liposome and preparation method and application thereof |
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| CN1660141A (en) * | 2005-01-31 | 2005-08-31 | 北京正大绿洲医药科技有限公司 | Drop pills of arenobufagin and preparation method |
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Non-Patent Citations (2)
| Title |
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| 聚乙烯醇包覆的果酸脂质体的制备及性质研究. 穆筱梅，钟振声，陈焕钦.日用化学工业，第33卷第04期. 2003 |
| 聚乙烯醇包覆的果酸脂质体的制备及性质研究. 穆筱梅，钟振声，陈焕钦.日用化学工业，第33卷第04期. 2003 * |
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