CN101773466B - Oral administration nanometer polymer micelle medicine carrying system and preparation method thereof - Google Patents
Oral administration nanometer polymer micelle medicine carrying system and preparation method thereof Download PDFInfo
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- CN101773466B CN101773466B CN201010120171.XA CN201010120171A CN101773466B CN 101773466 B CN101773466 B CN 101773466B CN 201010120171 A CN201010120171 A CN 201010120171A CN 101773466 B CN101773466 B CN 101773466B
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Abstract
The invention discloses an oral administration nanometer polymer micelle medicine carrying system, which comprises copolymers with hydrophilic and hydrophobic embedded sections, wherein the hydrophilic sections are chitosan, and the hydrophobic sections are glycerin monostearate, monopalmitin or glyceryl monooleate. The polymer micelle can be obtained through a method of carrying out ultrasonic processing after direct dissolution in water. A hydrophobic medicine bag can be loaded in an inner core of the polymer micelle, the polymer micelle has the grain diameter between 50 and 500 nm, and the medicine carrying quantity is between 5 and 70 percent. The prepared micelle exists in the state of water dispersing liquid or powder. Experiments show that the medicine can be slowly released from the polymer micelle, the effective acting time of the medicine in the body is prolonged, and the bioavailability of the oral administration absorption of the hydrophobic medicine is obviously improved. A medicine transmission system has the advantages of simple preparation and safe use, can be used as oral administration absorption carriers of the anticancer medicine, and can also be used as oral administration absorption carriers of other hydrophobic medicine.
Description
Technical field
The invention belongs to biological medicine technology field, relate to a kind of oral administration nanometer polymer micelle medicine carrying system and preparation method thereof.
Background technology
In the clinical treatment of tumor, chemotherapy is most important treatment means except operation.But current chemotherapy be take drug administration by injection as main, patient's poor compliance not only, and after drug administration by injection, dense in body circulation at starting stage medicine on the one hand, cause the infringement of normal tissue, and at the later stage of dosing interval drug level lower than valid density, can not bring into play therapeutical effect.And, because medicine distributes at whole body, when killing and wounding cancerous cell, normal cell is also had to same lethal effect, often there is the minimizing of leukocyte, erythrocyte and platelet counts in the cancer patient of accepting chemotherapy, feel sick, the side effect such as vomiting and alopecia, even threat to life.On the other hand, drug resistance (multidrugresistance due to tumor (cancerous cell), MDR), although most of cancer patient reacted medicine to some extent at the chemotherapy initial stage, the mechanism of drug resistance of final tumor has often caused failed, the patient death of chemotherapy.Therefore the drug-supplying system that, multidrug resistance can be avoided or overcome again to research oral sustained release is the inevitable development trend of oncotherapy.Yet, because most of cancer therapy drugs have very strong hydrophobicity, and in gastrointestinal tract, there is a large amount of efflux pumps, cause the oral absorption poor effect of cancer therapy drug, make people more rely on drug administration by injection and ignored oral administration this most easily by patient accept, route of administration the most easily.Use polymer micelle as pharmaceutical carrier, for the oral administration biaavailability that improves hydrophobic drug, there is following advantage: the apparent solubility that 1) can increase hydrophobic drug, in polymer micelle is hydrophobic, endorse and load hydrophobic medicine, drug loading is large, and can be used as the slow Slow release of release reservoir; 2) medicine is wrapped into hydrophobic inner core and can be improved the stability of medicine; 3) micelle can be avoided multidrug resistance.
Polymer micelle refers to the micelle that a class is comprised of amphipathic nature block polymer, and this amphipathic copolymer is comprised of hydrophobic fragment and hydrophilic segment, can be in water the spontaneous core-shell type structure that is arranged in, hydrophobic fragment forms micelle kernel, hydrophilic segment forms micelle shell.The material of the formation block copolymer hydrophilic area of reporting is at present mainly Polyethylene Glycol (PEG) or polyoxyethylene (PEO), and the material that forms hydrophobic region is mainly polyoxypropylene, polystyrene, polyamino acid, polylactic acid, spermine, short-chain phospholipid etc.And chitosan is as a kind of biodegradable natural macromolecular material, not only there is water solublity and biocompatibility, and there is stronger bioadhesive and absorption enhancement effect, be the preferred vector of gastrointestinal administration.Therefore, chitosan is the hydrophilic group material that desirable oral administration polymer micelle designs.In the selection of hydrophobic region material, consider that on the one hand it should can be reacted and be formed micelle by self aggregation with hydrophilic chain, has biodegradability and safety; On the other hand, should there is the good compatibility with medicine, preferably can avoid or the multidrug resistance of reversing tumor cell, to meet the demand of hydrophobic anticancer drug drug-supplying system.Glyceryl monostearate, monopalmitin or glyceryl monooleate are as nonionic surfactant, and safety non-toxic, is widely used as pharmaceutical excipient in drug-supplying system field.There are some researches show recently, glyceryl monostearate, monopalmitin or glyceryl monooleate are the substrates of P-glycoprotein, and can reduce the activity of other drug-resistant proteins such as multidrug-associated protein (MRP).Therefore, glyceryl monostearate, monopalmitin or glyceryl monooleate are the hydrophobic group materials of comparatively ideal oral administration polymer micelle design.
Summary of the invention
The object of this invention is to provide a kind of oral administration nanometer polymer micelle medicine carrying system and preparation method thereof, this micelle medicine carrying system is the multi-functional oral polymer micelle system that integrates biocompatibility, bioadhesive, absorption enhancement, avoids/reverse multidrug resistance, improves medicine stability, slow release etc.
The present invention is achieved through the following technical solutions:
Micelle medicine carrying system of the present invention comprises the block copolymer with hydrophilic and hydrophobicity block, and at least one is embedded in the intrafascicular hydrophobic drug of this polymer latex.Wherein, hydrophilic block is chitosan, and hydrophobicity block is glyceryl monostearate, monopalmitin or glyceryl monooleate.Hydrophobic drug refers to that the dissolubility in 1000ml aqueous medium is less than or equal to the medicine of a gram.
Described block copolymer is formula (I) and the copolymer of one of formula (II), formula (III), formula (IV).
The preparation process of described block copolymer is:
1) intermediate of preparation as shown in (V)
2) then above intermediate (V) is grafted on chitosan under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and N-hydroxy-succinamide (NHS) catalysis.
Intermediate (V) is grafted on chitosan with 10～25% substitution value.
Described hydrophobic drug is embedded in the intrafascicular method of this polymer latex:
1) direct dissolution method: block copolymer is directly dissolved in water, according to the dissolution characteristics of medicine and pKa value, prepare medicine aqueous solution under given conditions or the aqueous suspension of medicine, join in above-mentioned block copolymer aqueous solution ultrasonic, stirring certain hour.
2) non-aqueous solvent method: hydrophobic drug is dissolved in to the solution for preparing medicine in the solvent not miscible with water.The solution of hydrophobic drug is added drop-wise in block copolymer aqueous solution, then to mixed solution stir, the processing such as heating, ultrasonic and solvent evaporates.
The particle diameter of polymer micelle prepared by the present invention is 50-500nm, and drug loading is 5-70%.The micelle of preparation exists with aqueous dispersions or pulverulence.The carrier that can be used for the oral absorption of cancer therapy drug, also can be used as the carrier of other hydrophobic drug oral absorption.
Advantage of the present invention is:
1) nano-micelle has increased the dissolubility of hydrophobic drug;
2) bio-adhesive properties of chitosan has extended micelle in the gastrointestinal holdup time;
3) the absorption enhancement effect of chitosan can increase carrier micelle and effectively absorbs at gastrointestinal;
4) introducing of glyceryl monostearate, monopalmitin or glyceryl monooleate can reduce outer row's effect of P-glycoprotein;
5) outer row's effect of P-glycoprotein can be avoided or reduce to nanometer particle size;
6) drug encapsulation can improve the stability of medicine in micelle;
7) the long-lasting of drug-supplying system given in the slow release of medicine from micelle.
Accompanying drawing explanation
The infared spectrum of Fig. 1 chitosan graft glyceryl monostearate
The release in vitro curve of the polymer micelle system that is loaded with hydroxy camptothecin that Fig. 2 embodiment 12 is prepared
In Fig. 3 embodiment 19, be loaded with the blood drug level-time graph (n=3) after the polymer micelle Oral Administration in Rats administration of hydroxy camptothecin
Blood drug level-time graph (n=3) in Fig. 4 embodiment 19 after hydroxy-camptothecin aqueous slkali rat tail vein drug administration by injection
The specific embodiment
Embodiment 1: prepare succinylation glyceryl monostearate intermediate
By glyceryl monostearate 2.2g and succinic anhydrides 0.6g in 10ml oxolane, 70 ℃ of magnetic agitation back flow reaction 4h.Reactant liquor is transferred in beaker, is cooled to room temperature, adds 90ml distilled water, and adularescent solid is separated out.Sucking filtration, and wash three times with distillation, collecting precipitation thing, is succinylation glyceryl monostearate.
Embodiment 2: prepare succinylation monopalmitin intermediate
By monopalmitin 2.0g and succinic anhydrides 0.6g in 10ml oxolane, 70 ℃ of magnetic agitation back flow reaction 4h.Reactant liquor is transferred in beaker, is cooled to room temperature, adds 90ml distilled water, and adularescent solid is separated out.Sucking filtration, and wash three times with distillation, collecting precipitation thing, is succinylation monopalmitin.
Embodiment 3: prepare succinylation glyceryl monooleate intermediate
By glyceryl monooleate 2.19g and succinic anhydrides 0.6g in 10ml oxolane, 70 ℃ of magnetic agitation back flow reaction 4h.Reactant liquor is transferred in beaker, is cooled to room temperature, adds 90ml distilled water, and adularescent solid is separated out.Sucking filtration, and wash three times with distillation, collecting precipitation thing, is succinylation glyceryl monooleate.
Embodiment 4: the chitosan graft glyceryl monostearate block copolymer of preparing substitution value 15%
Get succinylation glyceryl monostearate 0.28g and EDC, NHS is dissolved in 20ml dichloromethane, stir-activating 15min.Get 0.1g chitosan (molecular weight 50kDa; substitution value 85%) add 4mL 0.1M hydrochloric acid stirring and dissolving after adding distil water be diluted to 50mL; the succinylation glyceryl monostearate solution that under agitation adds activation, reacts 6 hours under room temperature 400r/min magnetic agitation condition.Reaction finishes, and pours reactant liquor into separatory funnel, and organic facies is removed in separation, collects water.Water is put in beaker, and magnetic agitation 2 hours, volatilizes after organic solvent, removes by filter unreacted succinylation glyceryl monostearate.In the aqueous phase solution of product, add the dehydrated alcohol of 3 times of amounts, product is separated out, sucking filtration use dehydrated alcohol cyclic washing, obtains glyceryl monostearate substitution value and is 15% block copolymer.The infared spectrum feature of chitosan graft glyceryl monostearate is shown in Fig. 1.
Embodiment 5: the chitosan graft glyceryl monostearate block copolymer of preparing substitution value 25%
Get succinylation glyceryl monostearate 0.56g and EDC, NHS is dissolved in 20ml dichloromethane, stir-activating 15min.Get 0.1g chitosan (molecular weight 50kDa; substitution value 85%) add 4mL 0.1M hydrochloric acid stirring and dissolving after adding distil water be diluted to 50mL; the succinylation glyceryl monostearate solution that under agitation adds activation, reacts 6 hours under room temperature 400r/min magnetic agitation condition.Reaction finishes, and pours reactant liquor into separatory funnel, and organic facies is removed in separation, collects water.Water is put in beaker, and magnetic agitation 2 hours, volatilizes after organic solvent, removes by filter unreacted succinylation glyceryl monostearate.In the aqueous phase solution of product, add the dehydrated alcohol of 3 times of amounts, product is separated out, sucking filtration use dehydrated alcohol cyclic washing, obtains glyceryl monostearate substitution value and is 25% block copolymer.
Embodiment 6: prepare chitosan graft monopalmitin block copolymer
Get succinylation monopalmitin 0.52g and EDC, NHS is dissolved in 20ml dichloromethane, stir-activating 15min.Get 0.1g chitosan (molecular weight 3kDa; substitution value 95%) add 4mL 0.1M hydrochloric acid stirring and dissolving after adding distil water be diluted to 50mL; the succinylation monopalmitin solution that under agitation adds activation, reacts 6 hours under room temperature 400r/min magnetic agitation condition.Reaction finishes, and pours reactant liquor into separatory funnel, and organic facies is removed in separation, collects water.Water is put in beaker, and magnetic agitation 2 hours, volatilizes after organic solvent, removes by filter unreacted succinylation monopalmitin.In the aqueous phase solution of product, add the dehydrated alcohol of 3 times of amounts, product is separated out, sucking filtration use dehydrated alcohol cyclic washing, obtains substitution value and is 20% chitosan graft monopalmitin block copolymer.
Embodiment 7: prepare chitosan graft glyceryl monooleate block copolymer
Get succinylation glyceryl monooleate 0.55g and EDC, NHS is dissolved in 20ml dichloromethane, stir-activating 15min.Get 0.1g chitosan (molecular weight 80kDa; substitution value 60%) 50kDa; after adding 4mL0.1M hydrochloric acid stirring and dissolving, adding distil water is diluted to 50mL, under agitation adds the succinylation glyceryl monooleate solution of activation, under room temperature 400r/min magnetic agitation condition, reacts 6 hours.Reaction finishes, and pours reactant liquor into separatory funnel, and organic facies is removed in separation, collects water.Water is put in beaker, and magnetic agitation 2 hours, volatilizes after organic solvent, removes by filter unreacted succinylation glyceryl monooleate.In the aqueous phase solution of product, add the dehydrated alcohol of 3 times of amounts, product is separated out, sucking filtration use dehydrated alcohol cyclic washing, obtains substitution value and is 24% chitosan graft glyceryl monooleate block copolymer.
Embodiment 8: prepare chitosan graft glyceryl monostearate micelle
Adopt direct dissolution method.Take the chitosan graft glyceryl monostearate in 40mg above-described embodiment 4, add distilled water 15mL, after magnetic agitation is fully dissolved it, in ice bath, use the ultrasonic 20min (200W of Ultrasonic cell smash, work 3s, stops 3s), obtain chitosan graft glyceryl monostearate micellar solution.
Embodiment 9: prepare chitosan graft monopalmitin micelle
Adopt direct dissolution method.Take the chitosan graft monopalmitin in 40mg above-described embodiment 6, add distilled water 15mL, after magnetic agitation is fully dissolved it, in ice bath, use the ultrasonic 20min (200W of Ultrasonic cell smash, work 3s, stops 3s), obtain chitosan graft monopalmitin micellar solution.
Embodiment 10: prepare chitosan graft glyceryl monooleate micelle
Adopt direct dissolution method.Take the chitosan graft glyceryl monooleate in 40mg above-described embodiment 7, add distilled water 15mL, after magnetic agitation is fully dissolved it, in ice bath, use the ultrasonic 20min (200W of Ultrasonic cell smash, work 3s, stops 3s), obtain chitosan graft glyceryl monooleate micellar solution.
Embodiment 11: the polymer micelle of preparing hydroxy camptothecin drug loading 8%
The chitosan graft monopalmitin taking in 10mg above-described embodiment 6 is put in cillin bottle, add 5mg/mL10-hydroxy-camptothecin aqueous alkali (pH=12) 200 μ L, add appropriate 1M hydrochloric acid and adjust pH to 6, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains micelle medicine carrying amount and is about 8.43%.
Embodiment 12: the polymer micelle system of preparing hydroxy camptothecin drug loading 30%
The chitosan graft monoleate taking in 10mg above-described embodiment 7 is put in cillin bottle, add 5mg/mL10-hydroxy-camptothecin aqueous alkali (pH=12) 1.2mL, add appropriate 1M hydrochloric acid and adjust pH to 6, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains micelle medicine carrying amount and is about 32.94%.
Embodiment 13: the polymer micelle system of preparing hydroxy camptothecin drug loading 70%
The chitosan graft glyceryl monostearate taking in 10mg above-described embodiment 4 is put in cillin bottle, add 5mg/mL10-hydroxy-camptothecin aqueous alkali (pH=12) 4mL, add appropriate 1M hydrochloric acid and adjust pH to 6, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains micelle medicine carrying amount and is about 67.43%.
Embodiment 14: the polymer micelle system of preparing paclitaxel carried medicine amount 30%
The chitosan graft glyceryl monooleate taking in 10mg above-described embodiment 7 is put in cillin bottle, adds distilled water 7ml, adds 2mg/mL paclitaxel alcoholic solution 3mL, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains micelle medicine carrying amount and is about 30.2%.
Embodiment 15: the polymer micelle system of preparing vinpocetine drug loading 50%
The chitosan graft glyceryl monostearate taking in 10mg above-described embodiment 4 is put in cillin bottle, adds distilled water 8mL, adds 5mg/mL vinpocetine alcoholic solution 2mL, add appropriate 1M hydrochloric acid and adjust pH to 7,, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains micelle medicine carrying amount and is about 46.3%.
Embodiment 16: the polymer micelle system of preparing itraconazole drug loading 40%
The chitosan graft glyceryl monostearate taking in 10mg above-described embodiment 5 is put in cillin bottle, adds distilled water 6ml, adds 2mg/mL itraconazole acetone soln 4mL, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains carrier micelle drug loading and is about 27%.
Embodiment 17: the polymer micelle system of preparing silibinin drug loading 50%
The chitosan graft monopalmitin taking in 10mg above-described embodiment 6 is put in cillin bottle, adds distilled water 6ml, adds 3mg/mL silibinin alcoholic solution 4mL, and adding distil water is diluted to 10mL, after magnetic agitation 24h, Probe Ultrasonic Searching (200W, work 3s, stops 3s).Centrifugal (1000rpm, 20min), removes the medicine of unentrapped, obtains carrier micelle drug loading and is about 45%.
Embodiment 18: the release in vitro behavior of polymer micelle medicine carrying system
Adopt dialysis to investigate the release in vitro behavior of carrier micelle in embodiment 12.1mL polypeptide drug-loaded micelle solution is added in bag filter, immerse 400mL release medium (0.1M HCl, 0～2h; PBS, pH=6.8,2～72h) in, 37 ℃ of constant temperature oscillations.In certain hour point sampling 2mL supplementary same volume fresh medium.Release curve is shown in Fig. 2.
Embodiment 19: behavior in the body of polymer micelle medicine carrying system
Adopt the interior behavior of body of carrier micelle in serum level algoscopy Evaluation operation example 12.Get 3 of rats, fasting 10h before experiment, gavage gives polypeptide drug-loaded micelle solution, dosage is 5mg/kg, after administration 0.167,0.25,0.5,1,2,4,8,12,24,36,48,60,72,84,96h gets the about 0.25mL of blood, puts in the centrifuge tube that scribbles heparin, centrifugal 20min (4000r/min), separated plasma is preserved in-20 ℃ of refrigerators, until analyze.Separately get rat (3), fasting 10h before experiment, tail vein injection hydroxy-camptothecin aqueous slkali, dosage is 2mg/kg, after administration 0.033,0.083,0.25,0.5,0.75,1,2h gets the about 0.25mL of blood, puts in the centrifuge tube that scribbles heparin, centrifugal 20min (4000r/min), separated plasma is preserved in-20 ℃ of refrigerators, until analyze.Blood drug level-the time graph of two kinds of preparations is shown in Fig. 3, Fig. 4.
By rat pharmacokinetics experimental result, shown, after the administration of polymer latex beam system oral administration, blood drug level reaches peak and keeps constant at 72h (3d) at 4h.Compare with intravenous administration, oral administration polymer micelle can extend to 33.68h from 0.53h by the plasma half-life of medicine, and area under blood drug level/time graph (AUC) significantly increases, and safety evaluatio does not reveal any abnormalities.Illustrate that this polymer micelle oral administration has obvious slow releasing function, and significantly promoted the oral absorption of medicine, improved bioavailability.
Claims (5)
1. an oral administration nanometer polymer micelle medicine carrying system, it is characterized in that, it comprises the block copolymer with hydrophilic and hydrophobicity block, and at least one is embedded in the intrafascicular hydrophobic drug of this polymer latex, wherein, hydrophilic block is chitosan, hydrophobicity block is glyceryl monostearate, monopalmitin or glyceryl monooleate, substitution value with 10-25% is grafted on chitosan, described hydrophilic block is molecular weight 3-80kDa, the chitosan of deacetylation 60-95%, described block copolymer is formula (I) and formula (II), formula (III), the copolymer of one of formula (IV):
2. oral administration nanometer polymer micelle medicine carrying system according to claim 1, is characterized in that, hydrophobic drug refers to that the dissolubility in 1000ml aqueous medium is less than or equal to the medicine of a gram.
3. a kind of oral administration nanometer polymer micelle medicine carrying system according to claim 1, is characterized in that, the preparation process of described block copolymer is:
1) intermediate of preparation as shown in (V)
2) then intermediate (V) is grafted on chitosan under EDC and NHS catalysis
4. a preparation method for oral administration nanometer polymer micelle medicine carrying system as claimed in claim 1, is characterized in that, described hydrophobic drug is embedded in the intrafascicular method of this polymer latex and comprises:
Direct dissolution method: block copolymer is directly dissolved in water, prepare medicine aqueous solution under given conditions or the aqueous suspension of medicine according to the dissolution characteristics of medicine and pKa value, join in above-mentioned block copolymer aqueous solution, ultrasonic, stirring certain hour;
Non-aqueous solvent method: hydrophobic drug is dissolved in to the solution for preparing medicine in the solvent not miscible with water, the solution of hydrophobic drug is added drop-wise in block copolymer aqueous solution, then to mixed solution stir, heating, ultrasonic and solvent evaporates process.
5. a kind of oral administration nanometer polymer micelle medicine carrying system according to claim 1, it is characterized in that, prepared drug-carrying polymer micelle is drug solution, or the drug powder obtaining by spraying or Freeze Drying Technique, or add drug particles prepared by pharmaceutic adjuvant to pack the preparation obtaining in common or enteric capsule shell into.
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| CN102327208B (en) * | 2011-10-10 | 2012-10-03 | 广东药学院 | Vinpocetine polymer micelle preparation and preparation method thereof |
| CN110227059B (en) * | 2018-03-06 | 2022-11-01 | 沈阳药科大学 | Nasal cavity absorption enhancer and application thereof |
| CN113444250B (en) * | 2021-06-18 | 2022-10-25 | 绍兴文理学院附属医院 | Polyglycerol fatty acid ester derivative containing polyglutamic acid group, synthetic method thereof and application thereof in pharmaceutical preparation |
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| CN101066461A (en) * | 2007-05-29 | 2007-11-07 | 浙江大学 | Application of cell nucleus targeting chitosan-fatty acid graft as medicine carrier micelle |
| CN101524326A (en) * | 2009-03-30 | 2009-09-09 | 浙江大学 | Chlorin e6 chitosan-stearic acid graft micelle |
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| CN101066461A (en) * | 2007-05-29 | 2007-11-07 | 浙江大学 | Application of cell nucleus targeting chitosan-fatty acid graft as medicine carrier micelle |
| CN101524326A (en) * | 2009-03-30 | 2009-09-09 | 浙江大学 | Chlorin e6 chitosan-stearic acid graft micelle |
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| 蒙盼.壳聚糖硬脂酸嫁接物胶团的靶向修饰研究.《中国优秀硕士学位论文全文数据库 医药卫生科技辑（月刊）》.2009,(第07期), * |
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