CN102406610A - Particle dosing system with long circulation performance and preparation method thereof - Google Patents
Particle dosing system with long circulation performance and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a particle dosing system for slightly soluble medicines and a preparation method thereof. A plurality of medicines for the present clinical application are slightly soluble medicines; in order to solve the problem of improving the solubility of the slightly soluble medicines to a certain degree and improving bioavailability, the invention provides a particle dosing system with a long circulation performance and a preparation method thereof, wherein the long circulation performance can be provided by PEG-chitosans. The medicines provided by the invention show slow release characteristics under in-vitro sink condition, and achieve the controlled release function. When entered into rabbit bodies through an intravenous fluid manner, the particle dosing system also shows a longer elimination half-life in comparison with the particle dosing system modified by pure medical solutions or chitosans, and the bioavailability is obviously improved.
Description
Technical field
The present invention relates to medical technical field, specifically relate to particulate delivery system of a kind of insoluble drug and preparation method thereof.
Background technology
Many medicines of clinical practice are insoluble drug mostly.They are because highly lipophilic, and solubility property is poor in water-soluble medium, and self receive that relatively large molecular weight, small intestinal transmitance are low, the restriction of liver and gastrointestinal tract mucous factors such as first pass effect, make bioavailability present great individual variation.Therefore; People hope through modified form, comprise galenic pharmacy technology such as solubilising, hydrotropy and employing particulate delivery system, improve the dissolubility of insoluble drug to a certain extent; Auxiliary different route of administration is improved transhipment, distribution, the absorption of medicine, improves drug effect.The bioavailability that improves insoluble drug is to realize one of key issue that safe and efficient insoluble drug novel formulation need solve, and is the only way which must be passed that research and development has the independent intellectual property right medical product.
Chitosan is naturally occurring, hydrophilic, cationic, biodegradable polysaccharide, has nontoxic, excellent biological compatibility, low immunological rejection, is suitable as the control slow-released carrier of medicine, is widely used in preparation research.Yet, because between chitosan molecule, the existence of interior hydrogen bond, make it be insoluble to general organic solvent and water, only could be dissolved in acetum.This is very big difficulty for its extensive use has caused.In order to improve its dissolubility; People have carried out many modification work to hydroxyl on its glucosides and amino; The advantage that keeps chitosan; Improved its shortcoming,, obtained the soluble derivative of many chitosans as to modification means such as its toluenesulfonic acidization, amination, esterification, carboxylated, aldehyde radicalization, sulfonation.
Polyethylene Glycol (PEG) is a kind of purposes macromolecular compound very widely, can be dissolved in water and the many solvents, has excellent biocompatibility, can be dissolved in vivo in the tissue fluid, can got rid of rapidly external and does not produce any toxic side effects by body.After research is illustrated in microparticle surfaces grafting PEG, replace the overlapping microparticle surfaces that covers, form fine and close conformation cloud.This sterically hindered protection microgranule makes microgranule eliminate speed and slows down not by the identification of the opsonin in the blood, picked-up, and residence time prolongs in the blood, and drug treating time prolongs.Through the effect of hydrogen bond, the PEGization chitosan is attracted to the phospholipid carrier surface, and the PEG long-chain reduces the possibility that particulate delivery system is engulfed by the mononuclear cell in human body reticuloendothelial system and the blood at the hydration shell that microparticle surfaces forms.And the PEGization chitosan is wrapped in the particulate delivery system surface, microgranule stably is present in the medium and does not assemble, and plays stable effect.
Biomedical engineering's magazine 2007; 24 (4): disclose a kind of polyethyleneglycol modified liposome that is connected by Polyethylene Glycol or with part in " progress of long circulating liposomes and the application in nuclear medicine thereof " in 941～945 pages of Ma Chao, the Anren of rectifying; It is long circulating liposomes; As a kind of drug-supplying system, but this drug-supplying system form by liposome, liposome is mainly formed skeleton by lecithin and cholesterol; PEG forms PEGization phospholipid or PEGization cholesterol through chemical reaction.The less stable of liposome, memory time is short, and storage condition is high.Commercial PEGization phospholipid or PEGization cholesterol price are high simultaneously.
Application number is that 200610099318.5 Chinese patent discloses a kind of novel long circulation alprostadil liposome drug feeding system for injection and preparation method thereof; This invention is wrapped in pharmaceutical pack in the bilayer lipid membrane of formation, is prepared into the prostaglandin E 1 liposome drug-supplying system that can supply inject.This polyethylene glycol long chain is provided by DSPE one Polyethylene Glycol (PEG-DSPE).After forming liposome; The surface that its polyethylene glycol long chain can be distributed in microgranule forms hydrophilic protective films; Prevent the mutual gathering between the microgranule on the one hand; Can avoid by reticuloendothelial system identification in the body on the other hand, engulf, prolong particulate delivery system, reach macrocyclic effect in sanguimotor retention time.The pH of this liposome is a citrate buffer solution, and pH is between 4.0-5.0, and this pH scope is significantly less than blood pH7.4, though added analgesic---and tert-butyl group hydroxy-methylbenzene (BHT), after the said preparation injection, patient possibly produce and not accommodate pain.In addition,---lactose and analgesic---tert-butyl group hydroxy-methylbenzene adjuvants such as (BHT) that added a large amount of freeze drying protectants in this lyophilized formulations brings toxicity.
Summary of the invention
Many medicines of clinical practice at present are insoluble drug mostly; Improve the dissolubility of insoluble drug for solution; Improve the existing problem of bioavailability; The present invention proposes a kind of particulate delivery system with long cycle performance and preparation method thereof, medicine of the present invention shows slow release characteristic under external sink conditions, play control-release function.When getting in the rabbit body with the intravenous fluid mode, this particulate delivery system also showed than simple liposome or chitosan-modified longer elimination half-life of particulate delivery system, and bioavailability is significantly increased.
The present invention realizes through following technical scheme: a kind of particulate delivery system with long cycle performance; Described particulate delivery system with long cycle performance is the load amycin; The particulate delivery system that PEGization is chitosan-modified; Long cycle performance is provided by the PEGization chitosan, and the representative general structure of PEGization chitosan is:
Wherein n is the degree of polymerization; The molecular weight of chitosan is 1～100kDa, and deacetylation is 70-100%; Part free amino group on the chitosan chain is replaced by Polyethylene Glycol (PEG), and amino group substitution degree is 1～80%.
We introduce the amino of chitosan glucose unit through the synthetic reaction of mild condition with hydrophilic Polyethylene Glycol 5000 segments, synthesize the PEGization chitosan, and modify the particulate delivery system that load has insoluble drug with it.Simultaneously to this particulate delivery system in vivo, outer performance characterizes.
A kind of particulate delivery system method for preparing with long cycle performance, described method for preparing with particulate delivery system of long cycle performance is following steps:
(1) oil phase: take by weighing amycin, lecithin, with dichloromethane and the dissolving of acetone mixed liquor, the amount of mixed liquor is for making the consoluet quantity of solvent of solute;
(2) water: take by weighing PEGization chitosan, Poloxmer (poloxamer), use water dissolution, the amount of water is for making the consoluet quantity of solvent of solute;
When (3) oil phase being injected water, inject while stirring, adding the final concentration that water is settled to amycin is 0.5 ~ 10mg/ml; 2 ~ 8 ℃ of ultra-sonic dispersion, reuse water washing behind the dichloromethane is removed in room temperature evaporation (room temperature is 18 ~ 32 ℃); Centrifugal 15 ~ 50 minutes of centrifugal speed 6000 ~ 16000g, 2 ~ 8 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.3 ~ 0.6 μ m is removed big microsphere and is assembled standardize solution behind the thing; Drying is the load amycin, the particulate delivery system of the long cycle performance that PEGization is chitosan-modified; As preferably, water washed twice or more than twice.
Amycin wherein: lecithin: the mass ratio of PEGization chitosan: Poloxmer is 1:0.5 ~ 2.0:0.1 ~ 1:0.3 ~ 2, and the volume ratio of dichloromethane and acetone is 0.1 ~ 5:1.
The resulting microgranule of the present invention with particulate delivery system of long cycle performance be 5～1000nm, zeta current potential for-30mV～+ microgranule of 30mV.Particulate delivery system through emulsifying-solvent evaporation method preparation; The PEGization chitosan is adsorbed on the phospholipid carrier surface; Utilize the soft long-chain of PEG to form hydration shell, thereby reduce the possibility that drug microparticles is engulfed by the mononuclear cell in human body reticuloendothelial system and the blood at microparticle surfaces.Simultaneously the PEGization chitosan is wrapped in the particulate delivery system surface, microgranule stably is present in the medium and does not assemble, and plays stable effect.
The resulting particulate delivery system of the present invention, envelop rate is between 30%-100%, and drug loading is between 1%-50%.Show sustained releasing character in release in vitro, play the control slow-release function.Also show in animal body than simple liposome and chitosan-modified longer half-life of particulate delivery system, bioavailability is significantly increased.
Particulate delivery system involved in the present invention, stretching and flexibility because of the PEG chain of microparticle surfaces can form tight impermeable form cloud on the surface; Obviously increase the sterically hindered of microgranule; Make microgranule have crypticity, reduced the interaction of plasma protein and microparticle surfaces, reduced by the identification of monokaryon macrophage and engulf; Prolonged holdup time, improved bioavailability greatly in blood circulation.Because PEG is hydrophilic,, reduces the netted picked-up of engulfing system of endothelium, thereby reach macrocyclic purpose again so this hydrated sheath can reduce proteic absorption.
Compared with prior art, the invention has the beneficial effects as follows:
(1) the PEGization chitosan among the present invention, in conjunction with the two advantage of PEG and chitosan, wherein PEG has " crypticity " that excellent hydrophilic and soft long-chain produce; Chitosan has cation, biocompatibility and biological degradability.Therefore, the PEGization chitosan is wrapped in the particulate delivery system surface, microgranule stably is present in the medium and does not assemble, and plays stable effect.
(2) the chitosan-modified particulate delivery system of PEGization of the present invention, method for preparing is simple.
Description of drawings
Fig. 1 for the TEM of the chitosan-modified particulate delivery system of PEGization figure (Bar, 50nm);
Fig. 2 is the zeta potential diagram of the chitosan-modified particulate delivery system of PEGization;
Fig. 3 is medicine release graphics from the chitosan-modified particulate delivery system of PEGization under the release in vitro condition;
Fig. 4 for the chitosan-modified particulate delivery system of PEGization with intravenously administrable after, different time points is at the intravital blood drug level of rabbit.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explain.
Embodiment 1
(a) oil phase: take by weighing amycin 0.1g, lecithin 0.12g uses volume ratio to be 3:1 dichloromethane and acetone mixed liquor 6ml dissolving,
(b) water: take by weighing 0.05g PEGization chitosan, 0.08g Poloxmer, use the 20ml water dissolution;
(c) oil phase is slowly injected the aqueous phase of magnetic agitation, adding the final concentration that water is settled to amycin is 1mg/ml, 4 ℃ of ultra-sonic dispersion; The room temperature rotary evaporation is removed reuse 20ml water washing twice behind the dichloromethane, centrifugal speed 12; Centrifugal 30 minutes of 000g, 4 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.45 μ m is removed big microsphere and is assembled standardize solution behind the thing, and lyophilization is the particulate delivery system of long cycle performance.
Embodiment 2
(a) oil phase: take by weighing amycin 0.1g, lecithin 0.05g uses volume ratio to be 0.5:1 dichloromethane and acetone mixed liquor 6ml dissolving,
(b) water: take by weighing 0.01g PEGization chitosan, 0.03g Poloxmer, use the 10ml water dissolution;
(c) oil phase is slowly injected the aqueous phase of magnetic agitation, adding the final concentration that water is settled to amycin is 1mg/ml, 4 ℃ of ultra-sonic dispersion; The room temperature rotary evaporation is removed behind the dichloromethane reuse 10ml water washing three times, centrifugal speed 16; Centrifugal 30 minutes of 000g, 4 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.30 μ m is removed big microsphere and is assembled standardize solution behind the thing, and lyophilization is the particulate delivery system of long cycle performance.
Embodiment 3
(a) oil phase: take by weighing amycin 0.1g, lecithin 0.2g uses volume ratio to be 5:1 dichloromethane and acetone mixed liquor 6ml dissolving,
(b) water: take by weighing 0.1g PEGization chitosan, 0.2g Poloxmer, use the 50ml water dissolution;
(c) oil phase is slowly injected the aqueous phase with magnetic agitation, adding the final concentration that water is settled to amycin is 1mg/ml, 4 ℃ of ultra-sonic dispersion; The room temperature rotary evaporation is removed behind the dichloromethane reuse 50ml water washing three times, centrifugal speed 8; Centrifugal 30 minutes of 000g, 4 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.6 μ m is removed big microsphere and is assembled standardize solution behind the thing, and lyophilization is the particulate delivery system of long cycle performance.
Embodiment 4
(a) oil phase: take by weighing amycin 0.1g, lecithin 0.15g uses volume ratio to be 1:1 dichloromethane and acetone mixed liquor 6ml dissolving,
(b) water: take by weighing 0.02g PEGization chitosan, 0.1g Poloxmer, use the 20ml water dissolution;
(c) oil phase is slowly injected the aqueous phase with magnetic agitation, adding the final concentration that water is settled to amycin is 3mg/ml, 5 ℃ of ultra-sonic dispersion; The room temperature rotary evaporation is removed reuse 20ml water washing twice behind the dichloromethane, centrifugal speed 10; Centrifugal 40 minutes of 000g, 5 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.4 μ m is removed big microsphere and is assembled standardize solution behind the thing, and lyophilization is the particulate delivery system of long cycle performance.
Embodiment 5
(a) oil phase: take by weighing amycin 0.1g, lecithin 0.18g uses volume ratio to be 4:1 dichloromethane and acetone mixed liquor 6ml dissolving,
(b) water: take by weighing 0.08g PEGization chitosan, 0.15g Poloxmer, use the 20ml water dissolution;
(c) oil phase is slowly injected the aqueous phase with magnetic agitation, adding the final concentration that water is settled to amycin is 7mg/ml, 3 ℃ of ultra-sonic dispersion; The room temperature rotary evaporation is removed reuse 20ml water washing twice behind the dichloromethane, centrifugal speed 15; Centrifugal 20 minutes of 000g, 3 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.5 μ m is removed big microsphere and is assembled standardize solution behind the thing, and lyophilization is the particulate delivery system of long cycle performance.
The embodiment evaluation
(1) seals the mensuration of productive rate and drug loading
Precision take by weighing among the embodiment 1 preparation microgranule lyophilization article, dissolve with high performance liquid chromatogram mobile phase, filter paper filtering is removed insoluble matter, after getting subsequent filtrate and being diluted to the detectable concentration scope of standard curve, measures concentration with HPLC, the calculating medicament contg.
Seal medication amount/prescription dosage * 100% of productive rate=record.
Drug loading=medication amount/prescription dosage * 100%
Measure through HPLC, the entrapment efficiency of the particulate delivery system that PEGization is chitosan-modified is 69.22%, and drug loading is 37.04%.
2) delivery of particulate form and particle size determination
Quantitatively the delivery of particulate lyophilization article that PEGization is chitosan-modified are scattered in the quantitative normal saline; Obtain suspension, thin up to 2.5%, with special-purpose copper mesh dip in get after; With 1% phosphotungstic acid dyeing a moment, place transmission electron microscope under its form of observation and particle diameter roughly.The drug microparticles drug-supplying system dry product that quantitative PEGization is chitosan-modified is water-soluble, and ZETASIZE 3000 HSa measure particle diameter and zeta potential down.
The TEM figure and the Zeta-potential of delivery of particulate are like Fig. 1 and Fig. 2.
From last visible, the chitosan-modified delivery of particulate particle diameter of PEGization about 100nm, the mutual adhesion of microgranule, particle size distribution is even.
Can know that from the Zeta-potential figure of the chitosan-modified particulate delivery system of PEGization Zeta-potential is-8.5mv.Use is+15.2 mv with the Zeta-potential of the chitosan-modified particulate delivery system of method preparation, and the Zeta-potential of simple phospholipid administration surface is-17.5mv.The clear chitosan of these tables of data is as the positive charge donor, and lecithin is electronegative material, and they can both make the microparticle surfaces electric charge change; Simultaneously; Maybe be because in this microgranule prescription, the amount of lecithin be bigger than the amount of PEGization chitosan, therefore; The chitosan-modified particulate delivery system surface charge of PEGization is negative slightly, near neutral.This shows from the another side that also the PEGization chitosan has been wrapped in microparticle surfaces really.
Under the room temperature, the delivery of particulate lyophilization article that a certain amount of PEGization is chitosan-modified are suspended in 100mLPBS (pH7.4) release medium, place brown bottle to do release in vitro, make to meet sink conditions.Interval certain hour quantitative sampling, the fresh release medium of additional equivalent simultaneously.The sample of getting in different time points is 12, and centrifugal 30 minutes of 000g, 4 ℃ get supernatant, measure the drug concentrations in the supernatant sample, calculating cumulative burst size with the HPLC method.
The delivery of particulate release in vitro that contains the PEGization chitosan is seen Fig. 3.Visible from release graphics, the release of microgranule is not prominent releases phenomenon, in 48 hours, from microgranule, has discharged medicine about 30%.
Dilute the chitosan-modified particulate delivery system dried frozen aquatic products of PEGization of accurate weighing with the quantitative aseptic normal saline, obtain the injection of this delivery of particulate.
Get the rabbit about 2 kilograms, test fasting in preceding 12 hours, but can't help water.Earlier get blank blood from the rabbit auricular vein; By the chitosan-modified particulate delivery system injection of the PEGization of rabbit per kilogram of body weight drug 5mg,, at 2min, 5min, 10min, 20min, 40min, 1h, 2h, 4h, 8h, 12h, 24h time point blood sampling, use the organic solvent extraction medicine respectively; Analyze through HPLC; Obtain the blood drug level of each time point,, calculate the moving parameter of medicine the moving software of blood drug level data input medicine.
Measure the blood drug level that obtains each time point by HPLC and see Fig. 4.
With the moving software of blood drug level data input medicine, calculate the moving parameter of medicine.Can know that from the moving parameter of medicine the elimination half-life of chitosan-modified delivery of particulate, AUC are 13 times, 1.38 times of simple drug solution; The elimination half-life of the delivery of particulate that PEGization is chitosan-modified, AUC are 21 times, 25.8 times of simple drug solution.Therefore, it is slightly longer than chitosan-modified microgranule that the chitosan-modified microgranule of PEGization is eliminated the half-life, and bioavailability is 18.6 times of chitosan-modified microgranule, and significant difference is arranged.In sum, the chitosan-modified delivery of particulate solution of PEGization is compared with chitosan-modified delivery of particulate solution, simple drug solution, eliminates half-life t
1/2betaProlong; AUC increases.
Above presentation of results, the chitosan-modified delivery of particulate of PEGization has long cycle performance, and obvious variation has taken place in the pharmacokinetics characteristic of medicine and carrier.Mainly show as drug metabolism and elimination is slowed down, bioavailability improves greatly.These effects all are because PEG is grafted to the PEGization microgranule that forms on the chitosan skeleton chain, and the PEG chain stretching and the flexibility on surface can form tight impermeable form cloud (conformational cloud) at microparticle surfaces; Obviously increase the sterically hindered of microgranule; Make microgranule have crypticity, reduced the interaction of plasma protein and microparticle surfaces, reduced by the identification of monokaryon macrophage and engulf; Prolonged holdup time, improved bioavailability greatly in blood circulation.Because PEG is hydrophilic,, reduces the netted picked-up of engulfing system of endothelium, thereby reach macrocyclic purpose again so this hydrated sheath can reduce proteic absorption.
Claims (6)
1. particulate delivery system with long cycle performance; It is characterized in that; Described particulate delivery system with long cycle performance is the load amycin; The particulate delivery system that PEGization is chitosan-modified, long cycle performance is provided by the PEGization chitosan, and the representative general structure of PEGization chitosan is:
Wherein n is the degree of polymerization; The molecular weight of chitosan is 1～100kDa, and deacetylation is 70～100%; Part free amino group on the chitosan chain is replaced by Polyethylene Glycol (PEG), and amino group substitution degree is 1～80%.
2. a kind of particulate delivery system with long cycle performance according to claim 1 is characterized in that, the microgranule of particulate delivery system be 5～1000nm, zeta current potential for-30mV～+ microgranule of 30mV.
3. a kind of particulate delivery system with long cycle performance according to claim 1 is characterized in that described particulate delivery system, envelop rate are between 30%～100%, and drug loading is between 1%～50%.
4. an a kind of method for preparing with particulate delivery system of long cycle performance as claimed in claim 1 is characterized in that, described method for preparing with particulate delivery system of long cycle performance is following steps:
(1) oil phase: take by weighing amycin, lecithin, with dichloromethane and the dissolving of acetone mixed liquor, the amount of mixed liquor is for making the consoluet quantity of solvent of solute;
(2) water: take by weighing PEGization chitosan, Poloxmer, use water dissolution, the amount of water is for making the consoluet quantity of solvent of solute;
When (3) oil phase being injected water, inject while stirring, adding the final concentration that water is settled to amycin is 0.5～10mg/ml; 2～8 ℃ of ultra-sonic dispersion, reuse water washing behind the dichloromethane is removed in room temperature evaporation; Centrifugal 15～50 minutes of centrifugal speed 6000～16000g, 2～8 ℃, abandoning supernatant, the precipitate water that obtains after centrifugal is resuspended; The film of crossing 0.3～0.6 μ m is removed big microsphere and is assembled standardize solution behind the thing, and drying is the particulate delivery system of long cycle performance;
Amycin wherein: lecithin: the mass ratio of PEGization chitosan: Poloxmer is 1:0.5～2.0:0.1～1:0.3～2, and the volume ratio of dichloromethane and acetone is 0.1～5:1.
5. a kind of method for preparing with particulate delivery system of long cycle performance according to claim 4 is characterized in that, the particulate delivery system microgranule that obtains in the step (3) be 5～1000nm, zeta current potential for-30mV～+ microgranule of 30mV.
6. a kind of method for preparing with particulate delivery system of long cycle performance according to claim 4 is characterized in that, form have long cycle performance particulate delivery system, envelop rate is between 30%～100%, drug loading is between 1%～50%.
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| RU2642786C2 (en) * | 2015-01-30 | 2018-01-26 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Liposomal suspensions stabiliser |
| CN109223732A (en) * | 2018-09-29 | 2019-01-18 | 南通市第人民医院 | A kind of medical chitose nanosphere and preparation method thereof treated spinal cord injury and carry methylnaphthoquinone -4 |
| CN109223732B (en) * | 2018-09-29 | 2020-09-01 | 南通市第一人民医院 | Menadione-4-loaded medical chitosan nano-microsphere for treating spinal cord injury and preparation method thereof |
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