CN1887273A - Prepn process of polysaccharide vitreous particle - Google Patents
Prepn process of polysaccharide vitreous particle Download PDFInfo
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- CN1887273A CN1887273A CNA2006100291267A CN200610029126A CN1887273A CN 1887273 A CN1887273 A CN 1887273A CN A2006100291267 A CNA2006100291267 A CN A2006100291267A CN 200610029126 A CN200610029126 A CN 200610029126A CN 1887273 A CN1887273 A CN 1887273A
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Abstract
The present invention relates to biomedicine technology, and is especially preparation process of vitreous polysaccharide particle. The preparation process includes the following steps: 1. dissolving polyethylene glycol, polyethylene oxide or polypyrrolidone and polysaccharide in water to compound solution, and forming emulsion at low temperature; 2. adding bioactive matter; 3. freezing the emulsion; 4. freeze drying; and 5. washing with solvent to eliminate continuous polyethylene glycol, polyethylene oxide or polypyrrolidone phase to obtain dispersed polysaccharide grains. The present invention has mild condition, long term maintenance of bioactive matter, low cost, high curative effect and other advantages.
Description
Technical field
What the present invention relates to is the preparation method in a kind of biological medicine technology field.Particularly a kind of method for preparing polysaccharide vitreous particle.
Background technology
Gene recombination technology be used for the treatment of proteic expression and production 20 for many years, up to the present, existing more than 30 protein drug product drops into clinical use, nearly 200 examine with R﹠D process in, emerge and a collection ofly enter (Amgen), gene technology a collection of new large-scale medical companies such as (Genentech) such as peace.With respect to the fast development of protein macromolecule medicine itself, its dosage form technical progress is slow.On the one hand, the protein macromolecule drug oral does not absorb, the interior half-life of body is short, needs drug administration by injection; On the other hand, the protein drug Drug therapy cycle of many He Ermeng, cytokine class is long, and injection for a long time and continually becomes necessary, also influences the main cause of patient's compliance.The research and development of the dosage form of slow release protein drug are owing to cause active loss such as W/O/W method etc. in preparation microgranule process.It is imperative that development prepares the protein particle with active protection.And glucosan and PEG are freeze drying protectant and the proteic reagent of separation and purification that is commonly used to protein drug.Hennink utilizes the glucosan of modifying to prepare the report of albumen sustained-release micro-spheres, but the author uses strong oxidizer such as potassium peroxydisulfate, Ammonium persulfate. etc., reach polymerization initiator and make the dextran molecule generation crosslinked, these do not react with albumen unavoidably, cause proteic inactivation or increase immunogenicity.Yet there are no up till now under aqueous environments, prepare polymer particulates method report without cross-linking agent or firming agent.
Find by prior art documents, find by prior art documents [Hennink.W.E.and Franssen.O.PROCESS FOR THE PREPARATION OF A CONTROLLED RELEASESYSTEM.Publication No.:WO/1998/022093 International Application No:PCT/NL1997/000625], (the preparation method of a Hennink.W.E.and Franssen.O. controlled release system, publication number .:WO/1998/022093. international application no: PCT/NL1997/000625), this patent report water-water binary system prepare polyoses grain.But they have used polysaccharide that can be crosslinked, and a little crosslinked groups be to obtain by chemical modification.So not only can change the character of polysaccharide own, might increase the immunogenicity of polysaccharide, these crosslinked groups also may be crosslinked with protein and polypeptide generation simultaneously, because crosslinked group does not have special selectivity.We have avoided using, and crosslinked that unsettled aqueous phase-aqueous phase emulsion is prepared is polysaccharide vitreous.
Patent of the prior art [CHEN, Li; ZHU, Hua; JIN, Tuo THE PREPARATIONMETHOD OF A STABLE POLYMER AQUEOUS PHASE-AQUEOUS PHASE EMULSION AND ITSUSE, Publication Number International:WO/2002/000778 Application No.:PCT/CN2001/001033] (Chen Li; Zhu Hua; The preparation of the polymer aqueous phase-aqueous phase emulsion that Jin Tuo is stable and application publication number thereof are, WO/2002/000778 international application no PCT/CN2001/001033), this patent discloses a kind of novel stable emulsion (polymer aqueous phase-aqueous phase emulsion) and preparation method thereof and in pharmacy and Application in Biotechnology.The fundamental difference of this emulsion and conventional emulsions is that its decentralized photo and continuous phase are aqueous solution.Promptly produce diffuse double layer, thereby developed the material system of a uniqueness: stable do not need continuous stirring or (to decentralized photo) to solidify macromolecule water-water Emulsion immediately by polyelectrolyte being introduced two systems of high molecular weight hydrophilic (aqueous two-phase system).This system is used for the preparation of protein macromolecule medicament slow-release microsphere dosage form, has obtained ideal results.Yet some protein molecular may interact with polyelectrolyte, causes gathering.
The content of invention
The objective of the invention is to overcome deficiency of the prior art, a kind of method for preparing polysaccharide vitreous particle is provided.Make the smooth rounding of microparticle surfaces of its preparation, good evenness, the no adhesion of granule rule is at complete organic solvent-free, do not add especially polyelectrolyte class surfactant of any cross-linking agent, polymerization initiator and surfactant, to avoid these function influences to the treatment of medicine.
The present invention is achieved by the following technical solutions: the present invention is-2 ℃-4 ℃ condition, two or more the water-soluble polymer that does not describe mutually, under external condition as forming emulsion under the effects such as homogeneity, Voterx, ultrasonic mechanical agitation, lyophilizing and remove to loose continuously and obtain polysaccharide vitreous particle mutually then.Need not use organic facies (or claiming oil phase) emulsifying, need not use cross-linking agent, firming agent, surfactant, not have the tensile interfaces of strong interface such as water-oil, water-gas.
The present invention specifically may further comprise the steps:
1. with Polyethylene Glycol (PEG), poly(ethylene oxide) (PEO) or polypyrrole alkane ketone (PVP) etc. and polysaccharide wiring solution-forming soluble in water, mixed according to ratio under cryogenic condition greater than 1: 1 (W/W), under the effect of external force, form emulsion;
2. bioactive substance is added wherein, or add in the lump, or do not add medicine with polysaccharide, Polyethylene Glycol;
3. completing steps Emulsion 2. is freezing;
4. with completing steps sample lyophilizing 3.;
5. completing steps sample is 4. removed PEG, PEO or PVP continuous phase acquisition polysaccharide dispersion particle with solvent wash.
Described PEG, PEO or PVP, its molecular weight are 1,000-30,000.
Described PEG, PEO or PVP, its concentration is between the 0.2%-50%.
Described polysaccharide, its molecular weight are 50,000-500,000.
Described polysaccharide, its concentration are 2%-20%.
Described polysaccharide is glucosan or glucosan, starch, cellulose and derivant thereof, agarose and water soluble polymer polysaccharide.
Described PEG, PEO or PVP are used to remove PEG, PEO or PVP, and the organic solvent of continuous phase is dissolving PEG and do not dissolve the solvent of polysaccharide.
Described polysaccharide dispersion particle contains buffer substance, salt and micromolecule saccharide material.
Described buffer substance is Mg (OH)
2, ZnCO
3, and MgCO
3, salt is Zn (AC)
2, ZnCl
2, CaSO
4, MgSO
4In a kind of; The micromolecule saccharide is a kind of in trehalose, sucrose, glucose, sorbitol, the mannitol.
Described polysaccharide dispersion particle can be used for the therapeutant of microencapsulation fragile structure--can be supported among the polysaccharide microgranule such as protein, polypeptide, genetic stew, antibody, vaccine, virus and liposome etc.;
Described polysaccharide dispersion particle can be used for the sustained-release micro-spheres dosage form and the inhalant dosage form of its therapeutant that supports;
Described sustained-release micro-spheres dosage form, the polysaccharide microparticulate that is loaded with therapeutant is in the substrate of degradable macromolecule microsphere; By the polysaccharide microparticulate is formed colostrum (S/O) in degradable macromolecule solution, redispersion forms the i.e. method of oil bag solid-oil-in-water (S/O/W) of emulsion at aqueous phase, perhaps form colostrum (S/O) by polysaccharide vitreous particle being dispersed in the molten degradable macromolecule solution of oil, redispersion forms the i.e. method of oil bag solid-oil bag oil (S/O/O) of emulsion in another oil phase.
Described inhalant dosage form is the polysaccharide itself that is loaded with therapeutant, and its particle diameter is 1 μ m-5 μ m.
One, blank polysaccharide vitreous preparation
1. prepare PEG and polysaccharide solution
Prepare 10% PEG and 10% polysaccharide solution respectively with ultra-pure water, accurately taking by weighing 10 gram PEG and 10 gram polysaccharide water is placed on respectively in 100 milliliters the beaker and adds water 90 grams, then two beakers are placed on the magnetic agitation 30min of heating, it is stand-by to treat that cooling is taken off in the whole dissolvings of PEG and polysaccharide.
2. prepare PEG and polysaccharide low temperature aqueous phase-aqueous phase emulsion
Under 0 ℃-4 ℃ condition, polysaccharide with 1. and PEG aqueous solution are respectively 1: 5,1: 10,1: 20,1: 40 at the abundant mixing of cillin bottle vortex 30s-60s according to volume ratio, form aqueous phase-aqueous phase emulsion; Or to take by weighing mass ratio according to polysaccharide and PEG be to add water again at cillin bottle elder generation mixing in 1: 5,1: 10,1: 20,1: 40, makes it dissolving and form aqueous phase-aqueous phase emulsion.
3. cryopreparation PEG and polysaccharide low temperature aqueous phase-aqueous phase emulsion
PEG and polysaccharide low temperature aqueous phase-aqueous phase emulsion will be prepared in the refrigerator freeze overnight, and also can quick-freezing Vitrea size can be do not influenced.
With the sample of completing steps 3 in the vacuum freeze drier lyophilizing;
5. the sample of completing steps 4 is removed PEG continuous phase for three times with washed with dichloromethane and obtain the polysaccharide dispersion particle.
Two, the polysaccharide vitreous preparation of medicine carrying
1. prepare PEG and polysaccharide solution
All according to the polysaccharide vitreous preparation method of blank.
2. under 0 ℃-4 ℃ condition,, or medicine and PEG and polysaccharide solution are mixed together the PEG and the polysaccharide low temperature aqueous phase-aqueous phase emulsion of preparation medicine carrying medicine and polysaccharide solution mix homogeneously.
3. freezing polysaccharide, medicine and PEG low temperature aqueous phase-aqueous phase emulsion
4. will prepare polysaccharide, medicine and PEG low temperature aqueous phase-aqueous phase emulsion freeze overnight.
5. to obtain medicine carrying polysaccharide vitreous according to preparing blank polysaccharide vitreous 4 and 5 methods of carrying out then.
The medicine carrying of the present invention's preparation is polysaccharide vitreous can be directly used in inhalant dosage form, the biological reagent such as the medicines such as protein and polypeptide of protection fragile structure; By the polysaccharide microparticulate is formed colostrum (S/O) in degradable macromolecule solution, redispersion forms the i.e. method of oil bag solid-oil-in-water (S/O/W) of emulsion at aqueous phase, perhaps form colostrum (S/O) by polysaccharide vitreous particle being dispersed in the molten degradable macromolecule solution of oil, redispersion forms the i.e. method of oil bag solid-oil bag oil (S/O/O) of emulsion in another oil phase.
The present invention has avoided with an organic solvent fully, high shear force, interface and cross-linking agent etc., at the following bioactive substance of the condition of gentleness, be written into polysaccharide vitreously as protein, polypeptide, vaccine, DNA, RNA, virus and liposome, can keep active for a long time.Reduce the expense of preserving greatly and improve curative effect.Zhi Bei polysaccharide vitreous particle diameter is little simultaneously, and therefore active height is being prepared into other dosage form such as sustained-release micro-spheres, can reduce prominent releasing and not exclusively release.
The specific embodiment
Embodiment one: blank polysaccharide vitreous preparation
1. under 0 ℃ of-4 ℃ of condition, be mixed with 10% Dex70,000 and 10% PEG8,000 solution; According to getting 0.500gDex70,000; 2.500gPEG8,000, the abundant mixing of (w/w) vortex 30s-60s formed aqueous phase-aqueous phase emulsion in promptly 1: 5,-26 ℃ of one evenings of refrigerator pre-freeze, vacuum drying 24 hours, get dichloromethane 3ml-4ml with dropper and splash into cillin bottle again, vortex 5min, at the centrifugal 5min of 12000RPM, remove supernatant, three times back and forth, wave most dichloromethane at vacuum drying, collect microgranule, what take a morsel examines under a microscope, or it is suspended in the dichloromethane measures its particle diameter with PCS granularity scatterometer.Particle diameter is at 2 μ m-10 μ m, and mean diameter is 5.7 μ m.
2. under 0 ℃ of-4 ℃ of condition, be mixed with 10% Dex70,000 and 10% PEG8,000 solution; According to getting 0.250gDex70,000; 2.500gPEG8,000, promptly 1: 10 (w/w), the abundant mixing of vortex 30s-60s forms aqueous phase-aqueous phase emulsion ,-26 ℃ of one evenings of refrigerator pre-freeze, again vacuum drying 24 hours, get dichloromethane 3ml-4ml with dropper and splash into cillin bottle, vortex 5min is at the centrifugal 5min of 12000RPM, remove supernatant, three times back and forth, wave most dichloromethane at vacuum drying, collect microgranule, what take a morsel examines under a microscope, or it is suspended in the dichloromethane measures its particle diameter with PCS granularity scatterometer.Particle diameter is at 1 μ m-5 μ m, and mean diameter is 2.652 μ m.
3. under 0 ℃～4 ℃ conditions, be mixed with 10% Dex70,000 and 10% PEG8,000 solution; According to getting 0.125gDex70,000; 2.500gPEG8,000, promptly 1: 20 (w/w), the abundant mixing of vortex 30s-60s forms aqueous phase-aqueous phase emulsion ,-26 ℃ of one evenings of refrigerator pre-freeze, again vacuum drying 24 hours, get dichloromethane 3ml-4ml with dropper and splash into cillin bottle, vortex 5min is at the centrifugal 5min of 12000RPM, remove supernatant, three times back and forth, wave most dichloromethane at vacuum drying, collect microgranule, what take a morsel examines under a microscope, or it is suspended in the dichloromethane measures its particle diameter with PCS granularity scatterometer.Particle diameter is at 0.5 μ m-5 μ m, and mean diameter is 1.562 μ m.
4. under 0 ℃ of-4 ℃ of condition, be mixed with 8% Dex70,000 and 8% PEG8,000 solution; According to getting 0.080g Dex70,000; 3.200g PEG8,000, promptly 1: 40 (w/w), the abundant mixing of vortex 30s-60s forms aqueous phase-aqueous phase emulsion ,-26 ℃ of one evenings of refrigerator pre-freeze, again vacuum drying 24 hours, get dichloromethane 3ml-4ml with dropper and splash into cillin bottle, vortex 5min is at the centrifugal 5min of 12000RPM, remove supernatant, three times back and forth, wave most dichloromethane at vacuum drying, collect microgranule, what take a morsel examines under a microscope, or it is suspended in the dichloromethane measures its particle diameter with PCS granularity scatterometer.Particle diameter is at 0.3 μ m-5 μ m, and mean diameter is 309nm.
Embodiment two: it is polysaccharide vitreous that bovine serum albumin is carried in preparation
1. prepare bovine serum albumin, PEG and polysaccharide solution
Prepare 10% PEG and 10% polysaccharide solution respectively with ultra-pure water, accurately taking by weighing 10 gram PEG and 10 gram polysaccharide water is placed on respectively in 100 milliliters the beaker and adds water 90 grams, then two beakers are placed on the magnetic agitation 30min of heating, the polysaccharide for the treatment of PEG and 10% all dissolving to take off cooling stand-by.Accurately taking by weighing 800 milligrams of bovine serum albumin with electronic balance is dissolved in 7.2 ml waters stand-by.
2. bovine serum albumin, PEG and polysaccharide aqueous phase-aqueous phase emulsion
Under 0 ℃ of-4 ℃ of condition, the polysaccharide with 1., bovine serum albumin and PEG aqueous solution are respectively 1: 1: 5,1: 1: 10,1: 1: 20,1: 1: 40 at the abundant mixing of cillin bottle vortex 30s-60s according to volume ratio, form aqueous phase-aqueous phase emulsion; Or to take by weighing mass ratio according to polysaccharide and PEG be to be dissolved in water at cillin bottle elder generation mixing in 1: 1: 5,1: 1: 10,1: 1: 20,1: 1: 40 again, weight ratio according to polysaccharide and bovine serum albumin is adding in 1: 1 again, makes it to form aqueous phase-aqueous phase emulsion.
3. freeze bovine serum albumin, PEG and polysaccharide aqueous phase-aqueous phase emulsion
To prepare bovine serum albumin, PEG and polysaccharide and form aqueous phase-aqueous phase emulsion, some are not assigned to the protein of polysaccharide phase, are redistributed in the polysaccharide decentralized photo freeze overnight in temperature-fall period.
4. the sample of completing steps 3 is in the vacuum freeze drier lyophilizing;
5. the sample of completing steps 4 is removed PEG continuous phase for three times with washed with dichloromethane to carry bovine serum albumin polysaccharide vitreous.
What obtain carries the Vitrea particle diameter of bovine serum albumin polysaccharide decentralized photo mostly at 300nm-5 μ m, obtains the smooth rounding of these vitreous body, and particle size distribution is even.The protection that the structure of bovine serum albumin is obtained has been avoided at dosage form preparation process inactivation.
Claims (8)
1, a kind of method for preparing polysaccharide vitreous particle is characterized in that, may further comprise the steps:
1. with Polyethylene Glycol, poly(ethylene oxide) or polypyrrole alkane ketone and polysaccharide wiring solution-forming soluble in water, mixed according to weight under cryogenic condition greater than 1: 1 ratio, under the effect of external force, form emulsion;
2. bioactive substance is added wherein, or add in the lump with polysaccharide, Polyethylene Glycol;
3. completing steps Emulsion 2. is freezing;
4. with completing steps sample lyophilizing 3.;
5. completing steps sample is 4. removed PEG, PEO or PVP continuous phase acquisition polysaccharide dispersion particle with solvent wash.
2, the method for preparing polysaccharide vitreous particle according to claim 1 is characterized in that, described Polyethylene Glycol, poly(ethylene oxide) or polypyrrole alkane ketone, and its molecular weight is 1,000-30,000.
3, according to claim 1 or the 2 described methods that prepare polysaccharide vitreous particle, it is characterized in that, described Polyethylene Glycol, poly(ethylene oxide) or polypyrrole alkane ketone, its concentration is 0.2%-50%.
4, the method for preparing polysaccharide vitreous particle according to claim 1 is characterized in that, described polysaccharide, its molecular weight are 50,000-500,000.
5, according to claim 1 or the 2 described methods that prepare polysaccharide vitreous particle, it is characterized in that, described polysaccharide, its concentration is 2%-20%.
According to claim 1 or the 2 described methods that prepare polysaccharide vitreous particle, it is characterized in that 6, described polysaccharide is glucosan or glucosan, starch, cellulose and derivant thereof, agarose and water soluble polymer polysaccharide.
7, according to claim 1 or the 2 described methods that prepare polysaccharide vitreous particle, it is characterized in that, described polysaccharide, its dispersion particle contains buffer substance, salt and micromolecule saccharide material.
According to claim 1 or the 2 described methods that prepare polysaccharide vitreous particle, it is characterized in that 8, described buffer substance is Mg (OH)
2, ZnCO
3, and MgCO
3, salt is Zn (AC)
2, ZnCl
2, CaSO
4, MgSO
4In a kind of; The micromolecule saccharide is a kind of in trehalose, sucrose, glucose, sorbitol, the mannitol.
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| CNA2006100291267A CN1887273A (en) | 2006-07-20 | 2006-07-20 | Prepn process of polysaccharide vitreous particle |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010480A (en) * | 2010-09-26 | 2011-04-13 | 广东工业大学 | Method for preparing micro-grade polymer gel microspheres capable of loading protein |
| CN102144977A (en) * | 2011-04-14 | 2011-08-10 | 上海交通大学 | Preparation method of growth hormone nanoparticles with biological activity |
| CN102908665A (en) * | 2012-10-26 | 2013-02-06 | 东华大学 | Preparation method of protein-grain-supported-in-beaded-fiber tissue engineering fiber support frame |
| CN103140145A (en) * | 2010-08-13 | 2013-06-05 | 高级生物营养公司 | Dry storage stabilizing composition for biological materials |
| CN107468653A (en) * | 2011-05-20 | 2017-12-15 | Sk 化学株式会社 | Initial stage with reduction the prominent polymer particles released preparation method and the particulate that thus prepares |
-
2006
- 2006-07-20 CN CNA2006100291267A patent/CN1887273A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103140145A (en) * | 2010-08-13 | 2013-06-05 | 高级生物营养公司 | Dry storage stabilizing composition for biological materials |
| CN102010480A (en) * | 2010-09-26 | 2011-04-13 | 广东工业大学 | Method for preparing micro-grade polymer gel microspheres capable of loading protein |
| CN102144977A (en) * | 2011-04-14 | 2011-08-10 | 上海交通大学 | Preparation method of growth hormone nanoparticles with biological activity |
| CN107468653A (en) * | 2011-05-20 | 2017-12-15 | Sk 化学株式会社 | Initial stage with reduction the prominent polymer particles released preparation method and the particulate that thus prepares |
| CN102908665A (en) * | 2012-10-26 | 2013-02-06 | 东华大学 | Preparation method of protein-grain-supported-in-beaded-fiber tissue engineering fiber support frame |
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