CN105476966A - Silibinin and phospholipid complex nano freeze-dried powder and preparation method thereof - Google Patents
Silibinin and phospholipid complex nano freeze-dried powder and preparation method thereof Download PDFInfo
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Abstract
The invention provides silibinin and phospholipid complex nano freeze-dried powder and a preparation method thereof and belongs to the technical field of medicine. The silibinin phospholipid complex nano freeze-dried powder is prepared from silibinin, phospholipid, a stabilizer and a free-drying protective additive. The product preparation process is simple, and operation is easy. The grain diameter of the redissolved nano freeze-dried powder ranges from 50 nm to 500 nm, dispersion is uniform, the medicine dissolution rate is high, and the good liver protecting effect is achieved.
Description
Technical field
The present invention relates to a kind of silybin-phospholipid complex nano freeze-dried powder and preparation method thereof, belong to medical art.
Background technology
Silibinin is one of main active that extraction and isolation obtains from catananche's Herba Silybi mariani fruit, is widely used in the treatment of the hepar damnification that antiinflammatory, antioxidation and various poisonous substance (if carbon tetrachloride, thioacetamide, malicious deep alkali, ghost are than alkali, mucronatine etc.) cause.
In silibinin water, the shortcoming such as low, liver sausage absorption difference of dissolubility, limits its bioactive performance.In prior art, silibinin can be prepared into soluble-salt, cyclodextrin clathrate, liposome, phosphatide complexes etc.Wherein phosphatide complexes because of preparation technology simple, toxicity is low, easily by liver sausage cell membrane, and advantages such as good stabilities, is favored, and existing procucts listing.The phosphatide complexes comparatively stable compound that to be medicine and phospholipid molecule formed by charge transfer interaction or complex; Although do not change the biological activity of medicine, can significantly improve medicine fat-soluble, promote drug absorption, improve the performance of drug effect.The cosolvent method of the preparation method of phosphatide complexes mainly two kinds of organic solvents, as acetone one normal hexane cosolvent method.Ethanol evaporation method is applied to the preparation of phosphatide complexes gradually in recent years, and the method is simple to operate, and alcohol toxicity is low, and safety is high, is suitable for industrialized great production.
But the preparation of phosphatide complexes, still can not significantly improve dissolubility in the water of medicine, therefore greatly limit the stripping of medicine and the performance of drug effect.According to Ostwald-Freundlich formula, the size of drug microparticles affects drug solubility, and the less dissolubility of particle diameter is larger, when diameter of particle reaches nanoscale, and can significantly increasing medicament dissolubility.Nanocrystallization technology mainly contains liposome technology, nanometer balloons technique, microemulsion technology, inclusion technique, nanometer suspension technology.Nano suspension has increase drug solubility, and gastrointestinal tract adheres to strong, the advantages such as penetration enhancement, and the preparation of preparation can oral, injectable, and its dosage of surfactant is few, and toxicity is little, and preparation technology is simple, is easy to suitability for industrialized production.The preparation method of nano suspension mainly comprises media milling process, crystallization process, emulsion process, high pressure homogenization method, and high pressure homogenize co-crystallization method or emulsion process; Wherein, high pressure homogenization method is simple to operate, and preparation process organic solvent-free involves in, and there is not abrasive media fret wear and cause the problems such as contamination of products, is applicable to industrialized great production.
Disclose a kind of silybin-phospholipid complex nano suspension and preparation method thereof in Chinese patent CN102228430A, because its preparation process is complicated, the defects such as the organic solvent toxicity selected is larger, therefore still need to develop a kind of novel silibinin preparation.On the basis overcoming silibinin water solublity deficiency, simplify preparation technology, reduce toxicity, and improve drug solubility and promote that drug effect plays, and silybin-phospholipid complex nano freeze-dried powder a kind of like this new formulation with using value just.
Summary of the invention
The object of the present invention is to provide a kind of silybin-phospholipid complex nano freeze-dried powder and preparation method thereof, to improve the defect of silibinin poorly water-soluble, and improve its drug effect.
The technical solution used in the present invention is as follows, a kind of silybin-phospholipid complex nano freeze-dried powder, be made up of following component: silibinin is 1.0 weight portions, phospholipid is 1.5-9.0 weight portion, stabilizing agent is 0.3-6.0 weight portion, and freeze drying protectant is 35.0-140.0 weight portion;
As preferably, the mean diameter of described silybin-phospholipid complex nano freeze-dried powder is 50-500nm;
As preferably, described phospholipid is selected from the one or more combination in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and two myristoyl Phosphorylcholines;
As preferably, described stabilizing agent is selected from the one or more combination in PLURONICS F87, polyvinyl alcohol, Tween 80, PVP K30 and hypromellose;
As preferably, described freeze drying protectant is selected from the one or more combination in mannitol, sucrose, lactose, glucose, sorbitol, hydroxylated cellulose, hydroxypropyl cellulose and hypromellose;
Preparation process of the present invention is as follows:
1) get appropriate silibinin and phospholipid joins in ethanol, heating for dissolving is to clarification, and rotary evaporation removing ethanol obtains silybin-phospholipid complex to drying;
2) 1 is got) silybin-phospholipid complex prepared is pre-dispersed in deionized water;
3) stabilizing agent and freeze drying protectant deionized water dissolving, with 2) mix, high pressure homogenization technique homogenizing;
4) lyophilization obtains silybin-phospholipid complex nano freeze-dried powder;
As preferably, described step 1) heating for dissolving temperature is 40-80 DEG C, rotating evaporation temperature is 40-80 DEG C, and vacuum is 0.05-0.1mbar;
As preferably, described step 2) instrument of pre-dispersed employing is high speed disperser, rotating speed is 8000-12000rpm/min, and the pre-dispersed time is 1-5min;
As preferably, described step 3) homogenization pressure is 50-1500bar, homogenization cycles is 2-10 time;
As preferably, described step 4) freeze-drying process is: pre-freeze 24h at-60 DEG C, then at-60 DEG C, under vacuum 0.1mbar condition, lyophilizing 48h;
The present invention finds through screening, silybin-phospholipid complex is prepared into nano freeze-dried powder, has good particle size distribution and dissolution rate, can be used for the treatment of hepar damnification that antiinflammatory, antioxidation and poisonous substance cause for oral, injection and Transdermal delivery systems.
The present invention has the following advantages:
1. silybin-phospholipid complex nano freeze-dried powder of the present invention, preparation technology is simple, and preparation process organic solvent toxicity used is little, and gained preparation safety is effective, and phospholipid oxidation is few, and cost is lower, is easy to industrialization.
2. silybin-phospholipid complex nano freeze-dried powder of the present invention, after redissolving, particle diameter is little, narrowly distributing, and good stability, can effectively improve drug solubility and dissolution rate, and the hepatic injury that maintenance carbon tetrachloride causes.
Accompanying drawing explanation
Grain size distribution after Fig. 1 silybin-phospholipid complex nano freeze-dried powder redissolves.
The stripping curve of Fig. 2 silybin-phospholipid complex nano freeze-dried powder, silybin-phospholipid complex and adjuvant (stabilizing agent and freeze drying protectant) physical mixture, silibinin and adjuvant physical mixture.
Mouse liver injury models liver lobus dexter same position slice map after the treatment of Fig. 3 normal mouse, mouse liver injury models, silybin-phospholipid complex nano freeze-dried powder.
Specific embodiments
Below by specific embodiments and the drawings, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Dimyristoyl phosphatidyl choline 260mg
Polyvinyl alcohol 50mg
Mannitol 5g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows:
Take 140mg silibinin, 260mg dimyristoyl phosphatidyl choline in 20ml dehydrated alcohol, 40 DEG C fully dissolve, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 12000rpm/min condition, the pre-dispersed 1min of high speed, obtains silybin-phospholipid complex solution.
Take 50mg polyvinyl alcohol, 5g mannitol is fully dissolved in 50ml deionized water, and fully mix with silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, homogenizing 10 times under 1500bar, obtains silybin-phospholipid complex nanometer solution again; Then by pre-freeze 24h at its-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtain silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, and in round pie, without atrophy and cavitation, after being redissolved by normal saline, phosphoric acid saline solution or 5% glucose solution, mean diameter is 225.4nm, and polydispersity index PI is 0.279.
Embodiment 2
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Ovum Gallus domesticus Flavus lecithin 800mg
PLURONICS F87 200mg
Mannitol 10g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows:
Take 140mg silibinin, 800mg Ovum Gallus domesticus Flavus lecithin in 20ml dehydrated alcohol, 40 DEG C fully dissolve, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 12000rpm/min condition, the pre-dispersed 5min of high speed, obtains silybin-phospholipid complex solution.
Take 200mg PLURONICS F87,10g mannitol is fully dissolved in 50ml deionized water, and fully mix with silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, each homogenizing 3 times under 500bar and 1000bar again, last under 1500bar homogenizing 5 times, obtain silybin-phospholipid complex nanometer solution; Then by its pre-freeze 24h at-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtain silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, in round pie, without atrophy and cavitation, the mean diameter after being redissolved by normal saline, phosphoric acid saline solution or 5% glucose solution is 168.2nm (Fig. 1), polydispersity index PI is 0.263.
Embodiment 3
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Soybean phospholipid 1.2g
Tween 80 800mg
Mannitol 20g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows:
Take 140mg silibinin, 1.2g soybean phospholipid adds 20ml dehydrated alcohol, 40 DEG C fully dissolve, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 8000rpm/min condition, the pre-dispersed 5min of high speed, obtains silybin-phospholipid complex solution.
Take 800mg Tween 80,20g mannitol is fully dissolved in 50ml deionized water, and fully mix with silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, each homogenizing 3 times under 500bar and 1000bar again, last under 1500bar homogenizing 10 times, obtain silybin-phospholipid complex nanometer solution; Then by pre-freeze 24h at its-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtain silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, and in round pie, without atrophy and cavitation, after normal saline, phosphoric acid saline solution or 5% glucose solution redissolve, mean diameter is 76.8nm, and polydispersity index PI is 0.178.
Embodiment 4
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Dipalmitoyl phosphatidyl choline 260mg
Hypromellose 100mg
Lactose 5g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows:
Take 140mg silibinin, 260mg dipalmitoyl phosphatidyl choline in 20ml dehydrated alcohol, 50 DEG C fully dissolve, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 8000rpm/min condition, the pre-dispersed 1min of high speed, obtains silybin-phospholipid complex solution.
Take 100mg hypromellose, 5g lactose is fully dissolved in 50ml deionized water, and fully mix with silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, each homogenizing 5 times under 500bar and 1000bar again, last under 1500bar homogenizing 5 times, obtain silybin-phospholipid complex nanometer solution; Then by pre-freeze 24h at its-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtain silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, and in round pie, without atrophy and cavitation, after normal saline, phosphoric acid saline solution or 5% glucose solution redissolve, mean diameter is 292.6nm, and polydispersity index PI is 0.297.
Embodiment 5
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Distearoyl phosphatidylcholine 260mg
PVP K30 400mg
Glucose 10g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows.
Take 140mg silibinin, 260mg distearoyl phosphatidylcholine in 50ml dehydrated alcohol, fully dissolve at 50 DEG C, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 12000rpm/min condition, the pre-dispersed 3min of high speed, obtains silybin-phospholipid complex solution.
Take 400mg PVP K30,10g glucose is fully dissolved in 50ml deionized water, and fully mix in silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, each homogenizing 5 times under 500bar and 1000bar again, last under 1500bar homogenizing 10 times, obtain silybin-phospholipid complex nanometer solution; Then by pre-freeze 24h at its-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtain silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, and in round pie, without atrophy and cavitation, after normal saline, phosphoric acid saline solution or 5% glucose solution redissolve, mean diameter is 478.8nm, and polydispersity index PI is 0.285.
Embodiment 6
Silybin-phospholipid complex nano freeze-dried powder prescription is as follows:
Silibinin 140mg
Dipalmitoyl phosphatidyl choline 260g
PLURONICS F87 100mg
Sucrose 20g
The silybin-phospholipid complex nano freeze-dried powder preparation method of the present embodiment is as follows.
Take 140mg silibinin, 260mg dipalmitoyl phosphatidyl choline in 50ml dehydrated alcohol, fully dissolve at 50 DEG C, and also dry in synthermal lower rotation evaporating ethanol, obtain silybin-phospholipid complex; Add 50ml deionized water again, under 12000rpm/min condition, the pre-dispersed 3min of high speed, obtains silybin-phospholipid complex solution.
Take 100mg PLURONICS F87,20g sucrose is fully dissolved in 50ml deionized water, and fully mix with silybin-phospholipid complex solution, magnetic agitation 5min, respectively at homogenizing each under 50bar and 100bar 2 times, each homogenizing 5 times under 500bar and 1000bar again, last under 1500bar homogenizing 10 times, obtain silybin-phospholipid complex nanometer solution; Then by pre-freeze 24h at its-60 DEG C, and in-60 DEG C, lyophilizing 48h under vacuum 0.1mbar condition, obtains silybin-phospholipid complex nano freeze-dried powder.Gained silybin-phospholipid complex nano freeze-dried powder profile is good, and in round pie, without atrophy and cavitation, after normal saline, phosphoric acid saline solution or 5% glucose solution redissolve, mean diameter is 376.5nm, and polydispersity index PI is 0.135.
Embodiment 7
Silybin-phospholipid complex nano freeze-dried powder study in vitro dissolution
The silybin-phospholipid complex nano freeze-dried powder of the embodiment of the present invention 2, silybin-phospholipid complex and adjuvant (containing equal proportion stabilizing agent and freeze drying protectant) physical mixture, silibinin and adjuvant physical mixture are carried out In Vitro Dissolution experimentation, and the sample of different time points is through assay and calculate accumulation stripping percent.Result shows silybin-phospholipid complex nano freeze-dried powder dissolution rate of the present invention apparently higher than other two groups (Fig. 2).
1. Dissolution experiments method
Get silybin-phospholipid complex nano freeze-dried powder, silybin-phospholipid complex and adjuvant physical mixture, silibinin and each 6 parts of adjuvant physical mixture, every part is equivalent to silibinin 35mg, by 2015 editions " Chinese Pharmacopoeias " four dissolution determination second methods (slurry processes), 0.5% Tween 80 aqueous solution is contained for dissolution medium with 1000ml, temperature (37 ± 0.5) DEG C, rotating speed is 100rpm/min, respectively at 5, 10, 20, 30, 45, 60, 80, 120min samples 20ml, and supplement equivalent isothermal dissolution medium, the centrifugal 5min of sample 12000rpm/min, get supernatant HPLC to detect.
2.HPLC chromatographic condition
Chromatographic column: Chinese nation HederaODS-2 post (250nm × 4.6nm, 5 μm); Mobile phase: methanol: water: glacial acetic acid (48: 52: 1); Determined wavelength: 288nm; Flow velocity: 1ml/min; Column temperature: 40 DEG C; Sampling volume: 20 μ l;
3. linear relationship is investigated
It is appropriate that precision takes silibinin standard substance, and in 50ml volumetric flask, dissolve with methanol is also settled to scale, obtains 200 μ g/ml silibinin reference substance storing solutions.Precision measures storing solution in right amount in 10ml volumetric flask respectively, methanol dilution is to scale, obtain concentration and be respectively 1,5,10,20,30,40,50 μ g/ml series standard liquid, measure as stated above, with peak area (A), linear regression is carried out to concentration (C), obtain regression equation A=53397C-15556 (R
2=0.9991), show that silibinin peak area and drug level in 1-50 μ g/ml are good linear relationship.
Embodiment 8
Silybin-phospholipid complex nano freeze-dried powder is to the research of carbon tetrachloride-injured mouse liver cell repair
Purchase male and female half and half mice (20-30g) 9, be divided at random 3 groups (n=3), fasting 12h before experiment, freely drinks water, weighs, according to Weight computation gavage volume (0.1ml/10g).Blank group continuous 6 days gavage normal saline; Toxicity control group continuous 6 days gavage normal saline, and before the 5th day gavage lumbar injection 0.1% carbon tetrachloride solution (0.1ml/10g); Treatment group continuous 6 days gavage silybin-phospholipid complex nano freeze-dried powders solution (200mg/kg), and before the 5th day gavage lumbar injection 0.1% carbon tetrachloride solution (0.1ml/10g).And put to death after last administration 24h, get the same position 0.3g of liver lobus dexter and solidify in 10% formalin, after specimens paraffin embedding slices and HE dyeing, observe (Fig. 3) under an optical microscope.
Result display blank group murine liver tissue is normal; Focal steatosis is seen in the liver of toxicity control group mice; And treatment group mouse liver cell major part recovers normal.Show that the hepar damnification of silybin-phospholipid complex nano freeze-dried powder to tetrachloro-methane induction has good therapeutical effect.
Claims (10)
1. a silybin-phospholipid complex nano freeze-dried powder, is characterized in that, is made up of following component, and silibinin is 1.0 weight portions, and phospholipid is 1.5-9.0 weight portion, and stabilizing agent is 0.3-6.0 weight portion, and freeze drying protectant is 35.0-140.0 weight portion.
2. silybin-phospholipid complex nano freeze-dried powder according to claim 1, is characterized in that, the particle diameter after described nano freeze-dried powder redissolves is 50-500nm.
3. silybin-phospholipid complex nano freeze-dried powder according to claim 1, it is characterized in that, described phospholipid is selected from the one or more combination in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline and two myristoyl Phosphorylcholines.
4. silybin-phospholipid complex nano freeze-dried powder according to claim 1, is characterized in that, described stabilizing agent is selected from the one or more combination in PLURONICS F87, polyvinyl alcohol, Tween 80, PVP K30 and hypromellose.
5. silybin-phospholipid complex nano freeze-dried powder according to claim 1; it is characterized in that, described freeze drying protectant is selected from the one or more combination in mannitol, sucrose, lactose, glucose, sorbitol, hydroxylated cellulose, hydroxypropyl cellulose and hypromellose.
6. a preparation method for silybin-phospholipid complex nano freeze-dried powder, is characterized in that, concrete steps are as follows:
1) get appropriate silibinin and phospholipid adds in ethanol, heating for dissolving is to clarification, and rotary evaporation removing ethanol obtains silybin-phospholipid complex to drying;
2) 1 is got) silybin-phospholipid complex prepared is pre-dispersed in deionized water;
3) agent of ionized water steady dissolution and freeze drying protectant is removed, with 2) mix, and by high pressure homogenization technique homogenizing;
4) lyophilization obtains silybin-phospholipid complex nano freeze-dried powder.
7. the preparation method of silybin-phospholipid complex nano freeze-dried powder according to claim 6, is characterized in that, described step 1) heating for dissolving temperature be 40-80 DEG C, rotating evaporation temperature is 40-80 DEG C, and vacuum is 0.05-0.1mbar.
8. the preparation method of silybin-phospholipid complex nano freeze-dried powder according to claim 6, it is characterized in that, described step 2) the instrument of pre-dispersed employing be high speed disperser, rotating speed is 8000-12000rpm/min, and the pre-dispersed time is 1-5min; Described step 3) homogenization pressure be 50-1500bar, homogenization cycles is 2-10 time.
9. the preparation method of silybin-phospholipid complex nano freeze-dried powder according to claim 6, is characterized in that, described step 4) freeze-drying process be: pre-freeze 24h at-60 DEG C, and in-60 DEG C, under vacuum 0.1mbar condition, lyophilizing 48h.
10. the silybin-phospholipid complex nano freeze-dried powder prepared according to claim 1-9, add normal saline or phosphate buffer or 5% glucose solution to dissolve, with intravenous injection or intramuscular injection or oral injection or percutaneous dosing mode, for the treatment of the hepar damnification that antiinflammatory, antioxidation and poisonous substance cause.
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| CN107875121A (en) * | 2017-11-06 | 2018-04-06 | 大连理工大学 | A kind of preparation method of 2,3 dehydro-silibinin phosphatide complexes nano suspension |
| CN110123751A (en) * | 2018-06-14 | 2019-08-16 | 中国药科大学 | A kind of milk thistle class medicament nano cream dust composition and preparation method thereof |
| CN109453123A (en) * | 2018-11-19 | 2019-03-12 | 中国药科大学 | A kind of Combretastatin analog derivative freeze-dried powder and preparation method thereof |
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