CN101317840A - Nano-composition, preparing method and application thereof - Google Patents
Nano-composition, preparing method and application thereof Download PDFInfo
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- CN101317840A CN101317840A CNA2007101105053A CN200710110505A CN101317840A CN 101317840 A CN101317840 A CN 101317840A CN A2007101105053 A CNA2007101105053 A CN A2007101105053A CN 200710110505 A CN200710110505 A CN 200710110505A CN 101317840 A CN101317840 A CN 101317840A
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Abstract
The present invention relates to a new medicine delivery system carrier material, namely liver target nanometer combination that is made from wheat gliadin and silibinin. The preparation method of the nanometer combination is also provided. Coprecipitation of medicine and material in an identical system is achieved in a desolvation way; the nanometer combination colloidal solution that is made in the method can be produced into freeze-dried power injection after being mixed with the freeze-dried supporting agent acceptable in pharmacy. The nanometer combination can improve blood concentration of the medicine in liver region so that effect of the hepatitis cure medicine can be better exerted.
Description
Technical field
The present invention is the liver-targeted nanometer compositions that a kind of novel drug administration system carrier material wheat gliadin and silibinin are made.Relate to biomaterial, biomedical engineering and new drug research field.
Background technology
(Silybin is by extracting the slightly water-soluble flavone compound that obtains in the feverfew Herba Silybi mariani Silybum Marianum L. fruit SN) to silibinin.Pharmacological evaluation proves that silibinin has significant protective effect to the hepar damnification that multiple hepatotoxic agent causes.Its target organ is a liver, mainly combine after entering in the body with plasma protein, form with the conjunction type silibinin is present in (Shi Xiangguo in blood plasma, bile and the urine, Zhong Dafang, Zhang Yifan, Deng. the concentration of silibinin [J] in the rp-hplc determination rat plasma. Shenyang Pharmaceutical University's journal, 2001,18 (2): 113).To acute, chronic hepatitis, liver cirrhosis and metabolism toxic liver injury have preferably curative effect (Song Liren, Hong Xun, Ding Xuliang, etc. modern Chinese medicine is learned voluminous dictionary. Beijing: the People's Health Publisher, 2001,496-498).
Because silibinin is insoluble in water and common organic solvents, oral absorption is poor, and its bioavailability is lower, thereby has influenced its clinical efficacy.At present, be that the medicine dosage form of effective monomer has oral formulations: silymarin tablet, Yiganling tablet, silibinin lecithin complex hard capsule etc. with the silibinin.Trade name has: sharp liver is grand, Legalon, silybin etc.Injection: mainly be make silybin derivant, as Portugal-N methylamine salt, diethyl amine salt, N, dimethylglycine salt, hyaluronidase uranium salt etc. or make clathrate and make the water solublity injection again.In China, produce the history that the silibinin preparation has decades, common dosage form is mainly tablet, capsule etc., and is therefore wide for the novel form DEVELOPMENT PROSPECT of this effective monomer.
The research of microparticle formulation has become a focus of current pharmaceutics research.And the carrier material of microparticle formulation targeting drug delivery system is with natural macromolecular material, and especially native protein family macromolecule material has more researching value.The protide macromolecule all is easy to metabolism, but in recent years, because the albumen macromolecular material of animal origin may carry virus, therefore the macromolecule protein material of plant origin just demonstrates bigger advantage, for example can embedding various active material, can do not polluted by virus or Protein virus (prion), have pharmacology inertia and characteristics such as nontoxic, and the polysaccharide of plant origin and protein are expected to become the good succedaneum (Xu Hui of synthetic polymer, Ji Yaju, Wang Shaoning, Deng. the preparation of polymer nano granules and application thereof (II) utilize synthetic polymer or natural macromolecular to prepare nano-particle. Chinese journal of Practical Pharmacy, 2004,2 (4): 91-99).
Vegetable protein comprises 4 kinds of phytalbumin, globulin, prolamin and glutelin, compares with animal proteinum, and it is also cheaper that vegetable protein is easier to separation and purification, price.Alcohol soluble protein is with the molecular weight of the debita spissitudo ethanol extraction histone matter at 100kD～30kD from the cereal storage protein.Have more neutrality and lipophilic group, it is extremely low to remove under extreme pH value condition alcohol soluble protein dissolubility in water.It is mainly formed is about 40% glutamic acid and 14% proline, does not almost have charged aminoacid.Research for alcohol soluble protein both at home and abroad only limits to agronomy and Food Science fields such as corn breeding, bread quality.External pharmaceutics aspect is also less as the research of pharmaceutical carrier for alcohol soluble protein.Character according to alcohol soluble protein determines it to be prepared into nanoparticle by the desolvation method, in whole process of preparation, only use ethanol, and do not introduce other organic solvents, reduce production costs greatly, effectively solve the problem of microparticle formulation organic solvent residual, and provide assurance for its industrialization.In addition, the alcohol soluble protein source is abundant, separates easily and purifies, and good biocompatibility is arranged, and does not have cytotoxicity through the in vitro tests proof.Studies show that, owing to its inner H key and S-S key are the rugosity secondary structure, alcohol soluble protein formed peptide blister pharmaceutical carrier and enterocyte, hepatocyte and skin keratin cell have certain affinity, can be used as transfection reagent (carrier), can be in cell with medicament transport, improve drug effect effect (Teglia, A., Secchi, G..Newprotein ingredients for skin detergency:relative wheat proteinsurfactant complexes.Int.J.Cosmet.Sci., 1994,16:235-246).In addition, because its a large amount of active group in surface can coupling specificities antibody, identification antigen reaches the purpose of targeting administration in the born of the same parents.
The domestic and foreign literature result for retrieval shows does not also find to utilize alcohol soluble protein carrier material parcel silibinin to make the report of nanometer formulation.
Summary of the invention
One of the technical problem to be solved in the present invention has provided a kind of nano-composition with liver targeting, this nano-composition is to be made jointly by wheat gliadin and silibinin, can improve the envelop rate and the drug loading of medicine, solved silibinin slightly water-soluble problem simultaneously, have liver target, improve the clinical efficacy of silibinin.
The present invention further provides the lyophilized injectable powder of the nano-composition of wheat gliadin and silibinin, and corresponding preparation method is provided.
Nano-composition of the present invention is that silibinin wraps up and be adsorbed in wheat gliadin formation with monomeric form, and wherein the quality percentage composition of therapeutic ingredient silibinin is 2%～20%, and the grain of this nano-composition is 50～500nm through size.
Wheat gliadin derives from the Semen Tritici aestivi powder strength flour, the preparation method of carrier material wheat gliadin is a kind of fast and convenient Protein Extraction purification process (I.Ezpeleta etal.Gliadin nanoparicles for the controlled release ofall-trans-retinoic acid.Int J Pharm 131 (1996) 191-200.) in the described nano-composition, with Diluted Alcohol (40%～80%) cereal crops are extracted, obtain the wheat gliadin crude extract through two times centrifugal, and adopt water-sour water-water dialysis purification to obtain wheat gliadin.Its molecular weight ranges is by electrophoretic determination, and wheat gliadin is the compositions of the histone matter between 200KD-30KD as a result.
Nano-composition of the present invention is characterized in that this nano-composition obtains with firming agent (aldehyde, ketone) curing by the preparation of desolvation method and under the ethanol environment, and concrete steps are as follows:
A. silibinin and wheat gliadin are dissolved in 70% ethanol, form phase a;
B. dehydrated alcohol is poured into rapidly under the stirring a mutually in;
C. drip the aldoketones firming agent and solidify, rotary evaporation is removed ethanol, promptly gets silibinin wheat gliadin nano-composition colloid solution.
Also be included in the above-mentioned preparation method and add 2%～10% pharmaceutically acceptable lyophilizing caffolding agent in the silibinin wheat gliadin nano-composition colloid solution, obtained by freeze drying silibinin wheat gliadin nano-composition lyophilized injectable powder.
Lyophilizing caffolding agent described in the above-mentioned preparation method comprises mannitol, sucrose, lactose, glucose, fructose, xylitol, one or more in the trehalose.
Aldehyde described in the above-mentioned preparation method, ketone firming agent comprise formaldehyde, glutaraldehyde or diacetyl, and working concentration is 0.1%～1%.
Nano-composition preparation method of the present invention, also comprise, add surfactant or stabilizing agent in silibinin wheat gliadin nano-composition colloid solution, wherein surfactant or stabilizing agent comprise: one or more of lecithin, poloxamer 188 (Poloxamer188), soybean phospholipid, Tweens, spans, sodium lauryl sulphate, sucrose-fatty esters.
The mixing speed that adopts in the nano-composition preparation process of the present invention is 500～1000rpm, and fully desolvation 10～30min makes the carrier material packaging medicine form nanoparticle.Firming agent solidifies 4h～8h and nanoparticle can be solidified, and along with the prolongation of hardening time, the releasing degree of medicine reduces, and rate of release slows down.
Nano-composition of the present invention is absorbed by the endothelium reticular system during with injection administration and arrives liver, thereby improves liver internal drug concentration, reduces dosage, improves the therapeutic effect of treatment hepatitis.
The beneficial effect of nano-composition of the present invention:
(1) the following observation of nano-composition ultramicroscope is the microencapsulated form structure behind the medicine carrying, release in vitro result shows, the release in vitro behavior of medicament-carried nano compositions in suitable release medium compared with blank medicine and presented tangible slow release effect, and release profiles meets the weibull model.
(2) nano-composition of the present invention has liver target in the mice in-vivo tissue distributes experiment.
Get 50 of Kunming mouses, body weight (20 ± 2) g, male and female half and half are divided into 10 groups at random, 5 every group.Wherein 5 groups of tail vein injections give the nano-composition lyophilized injectable powder and (face with preceding water and redissolve, make every ml and contain silibinin (SN) 0.56mg, carry out administration by 5.6mg/kg) as experimental group, other 5 groups of tail vein injections contrast medicine silibinin (SN) solution (use 70% dissolve with ethanol, drip the 0.2M sodium hydroxide and be mixed with the solution that every ml contains SN 0.56mg) group in contrast; 2min, 5min, 15min, 30min, 60min eye socket are got blood execution after administration, and whole blood is put in the heparinization plastic centrifuge tube.Dissect organs such as putting to death the mice taking-up heart, liver, spleen, lung, kidney, brain rapidly, filter paper blots, and after weighing, cold preservation is standby immediately.Whole blood is in 10, the centrifugal 10min of 000rpm, and separated plasma, standby.All samples is all put-20 ℃ of refrigerator and cooled and is frozen preservation.Press the weight of internal organs, add the normal saline of 2 times of (or 4 times) volumes, homogenized.Homogenate is put into refrigerator-20 ℃ freezing preservation, uses when preparing for sample.With acetonitrile and 0.4% acetic acid (32.5: 67.5) solution is mobile phase, and biological sample utilizes C after the heavy albumen of methanol is handled
18Post separates, and adopts internal mark method determination.
Measurement result demonstration silibinin wheat gliadin nano-composition is compared with control drug, prolonged the holdup time of silibinin in liver, and the liver that has increased medicine distributes, and mean residence time (MRT) is respectively and is 4.90min and 12.97min (P＜0.05) in the body of control drug (silibinin) and silibinin wheat gliadin nano-composition.Wherein the liver of control drug is distributed as 10%, and the liver distribution that is prepared into behind the nano-composition rises to 28.6%, has certain hepatic targeting.
(3) nano-composition of the present invention influences result of the test explanation to what carbon tetrachloride caused the chmice acute hepatic injury, and silibinin wheat gliadin nano-composition lyophilized injectable powder causes the chmice acute hepatic injury to carbon tetrachloride tangible preventive and therapeutic effect.
Test sample: according to the silibinin wheat gliadin nano-composition lyophilized injectable powder (SN-GNP) of embodiment 1 method preparation
Method: get 72 of Kunming mouses, male and female half and half, be divided at random blank group, model control group, positive controls (diammonium glycyrrhizinate 50mg/kg), SN-GNP little (5mg/kg), in (10mg/kg), big (20mg/kg) dosage group, totally 6 groups, 12 every group.Each group of positive controls and SN-GNP is all by the administration of 0.1ml/10g tail vein injection, blank group and model control group give isopyknic normal saline, every day 1 time, totally 8 days, and in administration on the 7th after 1.5 hours except that the blank group, all the other each group is all carried out modeling by 0.1ml/10g volume lumbar injection 0.12% carbon tetrachloride peanut oil solution.Water 16h is can't help in fasting after the modeling, plucks eyeball and gets blood survey Serum ALT, AST, gets liver simultaneously and weighs, and calculates the liver coefficient.
Result: SN-GNP is little, in, heavy dose of group and model control group relatively, ALT value is reduction obviously, difference has significance (P＜0.05～P＜0.001); Among the SN-GNP, heavy dose of group and model control group relatively, AST value is reduction obviously, difference has significance (P＜0.05, P＜0.01); Each dosage group liver coefficient of SN-GNP has reduction trend.
Table 1SN-GNP causes the influence (x ± s) of chmice acute hepatic injury Serum ALT, AST to carbon tetrachloride
Annotate: compare with the blank group,
▲ ▲ ▲P＜0.001; Compare * P＜0.05, * * P＜0.01, * * * P＜0.001. with model control group
Table 2SN-GNP causes the influence (x ± s) of chmice acute hepatic injury liver coefficient to carbon tetrachloride
Annotate: compare with the blank group,
▲ ▲P＜0.05.
Conclusion: silibinin wheat gliadin nano-composition lyophilized injectable powder causes the chmice acute hepatic injury to carbon tetrachloride tangible preventive and therapeutic effect.
Discuss: it is one of classical model of present the liver protecting and ALT lowering drug screening that carbon tetrachloride causes the chmice acute hepatic injury.After carbon tetrachloride enters in the body, activate through liver cytochrome P 450, generate the trichloromethyl free radical, adsorb the phospholipid molecule of attacking on the endoplasmic reticulum by oxygen, cause the lipid peroxidation of film, the trichloromethyl free radical carries out covalent bond with membrane lipid and protein macromolecule then, causes the destruction of membrane structure and functional completeness, the trichloromethyl free radical also suppresses calcium pump activity on cell membrane and the microsomal membrane, makes Ca
2+Stream increases in the ion, thereby causes cytotoxic death.Intracytoplasmic ALT, AST transaminase are discharged in the blood in a large number, cause that serum alt, AST transaminase activity significantly raise, and make the liver enlargement.This experiment is the modeling agent with the carbon tetrachloride, with the positive contrast of bifendate, is observation index with Serum ALT, AST content and liver coefficient, studies silibinin wheat gliadin nano-composition lyophilized injectable powder and whether has liver-protecting activity.The result shows, the modeling success, positive drug is effective, illustration method is feasible, silibinin wheat gliadin nano-composition lyophilized injectable powder is little, in, heavy dose of group and model control group relatively, ALT value is reduction obviously, difference has significance; In the silibinin wheat gliadin nano-composition lyophilized injectable powder, heavy dose of group and model control group relatively, serum AST value is reduction obviously, difference has significance; Each dosage group liver coefficient of silibinin wheat gliadin nano-composition lyophilized injectable powder has reduction trend.Illustrate that silibinin wheat gliadin nano-composition lyophilized injectable powder causes the chmice acute hepatic injury to carbon tetrachloride tangible preventive and therapeutic effect is arranged.
Major advantage of the present invention is as follows:
1, the carrier material wheat gliadin is suitable for wrapping up poorly water soluble drugs, helps improving the envelop rate and the drug loading of medicine, and the envelop rate of the silibinin wheat gliadin nano-composition described in the present invention is 70～80%.
2, the preparation method of this carrier material wheat gliadin is simple, is fit to industrialization, is applied to the nanometer drug administration carrier and has certain novelty.
3, silibinin wheat gliadin nano-composition of the present invention has improved drug level in the liver, has certain meaning for the treatment hepatic disease.
4, the clinical efficacy of silibinin is definite, but it is insoluble in physical propertys such as water and has limited clinical practice, and the method has well solved this problem, makes the research and development of silibinin drug have wide space and bright development prospect.
Specific embodiment
Embodiment 1
Wheat gliadin 100mg and 15mg Poloxamer 188 are with 12ml 70% dissolve with ethanol solution, add 18.8mg silibinin (SN) again, 1500rpm speed magnetic agitation makes dissolving, add 1%Poloxamer188 solution 28ml rapidly, continue to stir 30min, rotary evaporation is removed part ethanol, promptly gets nano-composition colloid solution.In this solution, add glucose 400mg, mannitol 200mg, fully dissolving, lyophilizing promptly gets the nano-composition lyophilized injectable powder.Adding deionized water redissolution back mensuration particle diameter is 203nm, polydispersity index (PDI) 0.217.
Embodiment 2
Wheat gliadin 200mg and 30mg Poloxamer188 are with 15ml 70% dissolve with ethanol solution, add 10mg silibinin (SN) again, 2500rpm speed magnetic agitation makes dissolving, add dehydrated alcohol 36ml rapidly, continue to stir 20min, drip 1% glutaraldehyde solution 1.2ml, continue to stir curing 8-12h, rotary evaporation is removed part ethanol, promptly gets nano-composition colloid solution.In this solution, add glucose 200mg, mannitol 200mg, fully dissolving, lyophilizing promptly gets the nano-composition lyophilized injectable powder.Adding deionized water redissolution back mensuration particle diameter is 280nm, polydispersity index (PDI) 0.112.
Embodiment 3
Wheat gliadin 120mg and 16mg lecithin are with 6ml 70% dissolve with ethanol solution, add 2.4mg silibinin (SN) again, 500rpm speed magnetic agitation makes dissolving, add dehydrated alcohol 24ml rapidly, continue to stir 30min, drip 2% formalin 2.4ml, continue to stir curing 8-12h, rotary evaporation is removed part ethanol, promptly gets nano-composition colloid solution.In this solution, add glucose 100mg, mannitol 100mg, fully dissolving, lyophilizing promptly gets the nano-composition lyophilized injectable powder.Adding deionized water redissolution back mensuration particle diameter is 480nm, polydispersity index (PDI) 0.352.
Embodiment 4
Wheat gliadin 120mg and 8mg lecithin, 8mg Poloxamer 188 are with 10ml 70% dissolve with ethanol solution, add 2.4mg silibinin (SN) again, 500rpm speed magnetic agitation makes dissolving, add dehydrated alcohol 24ml rapidly, continue to stir 30min, drip 2% diacetyl solution 1.4ml, continue to stir curing 8-12h, rotary evaporation is removed part ethanol, promptly gets nano-composition colloid solution.In this solution, add glucose 100mg, mannitol 100mg, fully dissolving, lyophilizing promptly gets the nano-composition lyophilized injectable powder.Adding deionized water redissolution back mensuration particle diameter is 320nm, polydispersity index (PDI) 0.218.
Claims (8)
1, a kind of nano-composition is characterized in that being made up of silibinin and carrier material wheat gliadin, and particle diameter is 50～500 nanometers, and wherein the quality percentage composition of silibinin is 2%～20%.
2, nano-composition as claimed in claim 1 is characterized in that the carrier material wheat gliadin is the histone matter of molecular weight ranges at 200KD～30KD, derives from the Semen Tritici aestivi powder strength flour.
3, nano-composition as claimed in claim 1 or 2 is characterized in that this nano-composition obtains with aldehyde, the curing of ketone firming agent by the preparation of desolvation method and under the ethanol environment, and concrete steps are as follows:
A. silibinin and wheat gliadin are dissolved in 70% ethanol, form phase a;
B. dehydrated alcohol is poured into rapidly under the stirring a mutually in;
C. drip the aldoketones firming agent and solidify, rotary evaporation is removed ethanol, promptly gets silibinin wheat gliadin nano-composition colloid solution.
4, the preparation method of nano-composition as claimed in claim 3, it is characterized in that also being included in and add 2%～10% pharmaceutically acceptable lyophilizing caffolding agent in the silibinin wheat gliadin nano-composition colloid solution, obtained by freeze drying silibinin wheat gliadin nano-composition lyophilized injectable powder.
5, the preparation method of nano-composition as claimed in claim 3 is characterized in that, also comprises, adds surfactant or stabilizing agent in silibinin wheat gliadin nano-composition colloid solution.
6, the preparation method of nano-composition as claimed in claim 5 is characterized in that surfactant or stabilizing agent are one or more of lecithin, soybean phospholipid, poloxamer 188 (Poloxamer188), Tweens, spans, sodium lauryl sulphate, sucrose-fatty esters.
7, the preparation method of nano-composition as claimed in claim 3 is characterized in that the firming agent aldehyde, the ketone compounds that use comprise formaldehyde, glutaraldehyde or diacetyl, and concentration is 0.1%～1%.
8, the application of the described nano-composition of the arbitrary claim of claim 1～7 in preparation treatment hepatitis medicament.
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