CN1887276A - Frozen phase separating process of preparing polysaccharide vitreous particle - Google Patents
Frozen phase separating process of preparing polysaccharide vitreous particle Download PDFInfo
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- CN1887276A CN1887276A CNA2006100291303A CN200610029130A CN1887276A CN 1887276 A CN1887276 A CN 1887276A CN A2006100291303 A CNA2006100291303 A CN A2006100291303A CN 200610029130 A CN200610029130 A CN 200610029130A CN 1887276 A CN1887276 A CN 1887276A
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Abstract
The present invention is frozen phase separating process of preparing vitreous polysaccharide particle. Two or more kinds of polymer aqua containing polysaccharide are frozen to produce phase separation during lowering temperature and make polysaccharide become dispersed phase, and through subsequent freeze drying to eliminate continuous phase, vitreous polysaccharide particle is obtained. The process includes the following steps: 1. dissolving PEG and polysaccharide in water and controlling concentration to form homogeneous solution; 2. adding protein and medicines; 3. lowering the temperature of the solution; 4. freeze drying; and 5. washing with solvent to eliminate continuous PEG phase and obtain dispersed phase polysaccharide particle. The said process has no influence on the treating effect of the medicines.
Description
Technical field
What the present invention relates to is a kind of formulation preparation method of biological technical field, especially a kind ofly utilizes freezing being separated to prepare the method for 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, [Van T.S.R., Van S.M.J., Van N.C.F.andHennink W.E.GEL COMPOSITION COMPRISING CHARGED POLYMERS.PublicationNumber:WO/2005/110377, International Application No.:PCT/NL2005/000365.], (Van T.S.R., Van S.M.J., the gel combination of Van N.C.F.and Hennink W.E. Ionomer, publication number is, WO/2005/110377, international application no PCT/NL2005/000365).People such as Van T.S.R. at this patent report utilize the crosslinked pharmaceutical carrier that is prepared into gel of opposite ionic charge.This patent utilization carries protein and polypeptide drugs in the interaction preparation of water miscible two kinds of oppositely chargeds.But protein and polypeptide drugs are also all electrically charged, and the glue material of medicine carrying is also electrically charged, and electric charge has only both positive and negative, and gelatigenous material is so inevitably crosslinked with albumen or polypeptide generation.Also inevitable inactivation of protein after crosslinked and polypeptide and increase immunogenicity.
The content of invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of and utilize freezing being separated to prepare the method for polysaccharide vitreous particle.Make the smooth rounding of microparticle surfaces of its preparation, good evenness, the granule regular without adhesion is at complete organic solvent-free with do not add any cross-linking agent and polymerization initiator, to avoid these function influences to the treatment of medicine.
The present invention is achieved by the following technical solutions, and it is freezing that the present invention will contain two or more aqueous solutions of polymers of polysaccharide, is separated in temperature-fall period and makes polysaccharide become decentralized photo, then lyophilizing and remove to loose continuously and obtain polysaccharide vitreous particle mutually.Need not use organic facies (or claiming oil phase) emulsifying, need not use cross-linking agent, firming agent, surfactant to stablize, not have the tensile interfaces of strong interface such as water-oil, water-gas.
The present invention specifically may further comprise the steps:
1. form homogeneous phase solution with Polyethylene Glycol (PEG) or with polysaccharide is soluble in water by control concentration;
2. bioactive substance is added wherein, or add in the lump with polysaccharide, Polyethylene Glycol;
3. with completing steps solution 2. in temperature-fall period, avoid freezing under the quick-freezing condition;
4. with completing steps sample lyophilizing 3.;
5. completing steps sample is 4. removed PEG continuous phase with solvent wash and obtain the polysaccharide dispersion particle.
Described PEG, its molecular weight are 1,000-30,000; With 6,000 to 10,000, be good.
Described PEG, its weight percent concentration is between the 0.2%-50%; With 1%-20% is good.
Described polysaccharide, its molecular weight are 10,000-2,000,000; With 50,000-500,000 is good.
Described polysaccharide, its weight percent concentration are 1%-50%; With 1%-20% is good.
Described polysaccharide is good with glucosan;
Described PEG, the organic solvent that is used to remove PEG continuous phase are dissolving PEG and do not dissolve the solvent of polysaccharide.
Described temperature-fall period, be instigate sample temperature from single phase aqueous solution to being reduced to process below freezing more than two-phase or multiphase the phase transition temperature, phase transition temperature then changes with the kind and the concentration of hydrophilic polymer.
The weight ratio of described polysaccharide and described PEG is in the scope of 1: 1 and 1: 200; With 1: 4 to 1: 80 was good.
Described polysaccharide dispersion particle contains buffer substance, salt and micromolecule saccharide material, and its concentration is the 0.1-10% of the percentage by weight of polysaccharide.
Described buffer substance is Mg (OH)
2, ZnCO
3, and MgCO
3, salt is Zn (AC)
2, ZnCl
2, CaSO
4, MgSO
4, the micromolecule saccharide is trehalose, sucrose, glucose, sorbitol, 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, it is the method for water/oil/solid (S/O/W) that redispersion forms 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 emulsion in another oil phase be the method for oil/oil/solid (S/O/O);
Described inhalant dosage form is the polysaccharide itself that is loaded with therapeutant, and its particle diameter is 1 μ m-5 μ m.
The present invention adopts the solution methods of conventional prepared polymer.The formation solution that respectively glucosan and PEG is dissolved in the water earlier mixes two kinds of solution mutually and forms homogeneous phase.Freezing then this homogeneous phase solution, continuous phase is removed in lyophilizing again, gets the polysaccharide microgranule.Under control concentration, PEG and polysaccharide can be miscible, and are separated when freezing, and lyophilizing then goes continuous phase to collect microgranule with solvent.
Provide a kind of, reach the microgranule method that polymerization initiator and firming agent prepare various particle diameters (0.1 μ m-10 μ m) without potassium peroxydisulfate or Ammonium persulfate. strong oxidizer.Adopt the smooth rounding of microparticle surfaces of the inventive method preparation, the granule regular without adhesion, particle diameter can be regulated and control from 0.1 μ m as required to 10 μ m.
The present invention has selected suitable hydrophilic polymer homogeneous phase aqueous solution freezing method to prepare the polysaccharide microgranule, can and not add any cross-linking agent and polymerization initiator at complete organic solvent-free.Can avoid these function influences to the treatment of medicine, especially those physicochemical properties are unsettled, as biopharmaceutical macromolecular drug protein drug, polypeptide etc.The smooth surface rounding of microgranule, the granule regular without adhesion, particle diameter can be regulated and control from 0.1 μ m as required to 10 μ m, the span narrow distribution, its freeze dried powder is that white is fine and smooth, and is loose, do not subside, adhesion, redispersibility is good.Can apply to the preparation of various medicament slow-release microspheres and the adjuvant of vaccine.
The specific embodiment
One, blank polysaccharide vitreous preparation
1. prepare PEG and polysaccharide solution
Prepare 8% PEG and 8% polysaccharide solution respectively with ultra-pure water, accurately taking by weighing 8 gram PEG and 8 gram polysaccharide water is placed on respectively in 100 milliliters the beaker and adds water 92 grams, then two beakers are placed on the magnetic agitation 30min of heating, the polysaccharide for the treatment of PEG and 8% all dissolving to take off cooling stand-by.
2. preparation PEG and polysaccharide homogeneous phase are total to aqueous solution
The polysaccharide and the PEG aqueous solution of step 1. 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 homogeneous phase solution; 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 homogeneous phase solution.
3. freezing PEG and polysaccharide homogeneous phase be aqueous solution altogether
To prepare the common aqueous solution of PEG and polysaccharide homogeneous phase and be separated in temperature-fall period, and make polysaccharide become decentralized photo, PEG becomes continuous phase.But avoid freeze overnight under the quick-freezing condition.
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
2. preparation PEG and polysaccharide homogeneous phase are total to aqueous solution
All according to the polysaccharide vitreous preparation method of blank.
3. be total to aqueous solution medicine and polysaccharide solution mix homogeneously, or the PEG and the polysaccharide homogeneous phase of medicine and PEG and the common aqueous solution uniform preparation medicine carrying of polysaccharide homogeneous phase
4. freezing polysaccharide, medicine and PEG homogeneous phase be aqueous solution altogether
To prepare the common aqueous solution of polysaccharide, medicine and PEG homogeneous phase and be separated in temperature-fall period, medicine is arrived in the polysaccharide decentralized photo by priority allocation, PEG becomes continuous phase.But avoid freezing under the quick-freezing condition.
It is polysaccharide vitreous to obtain medicine carrying according to the blank polysaccharide vitreous preparation method of preparation then.
Use: the medicine carrying of 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; Medicine carrying polysaccharide vitreous can also be dispersed in the degradable macromolecule solution redispersion in the method for aqueous phase (S-O-W), perhaps by polysaccharide microparticulate redispersion method of (S-O-O) in another oil phase in degradable macromolecule solution is prepared sustained-release micro-spheres.
Advantage of the present invention: avoided fully with an organic solvent, 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.
Embodiment one: polysaccharide vitreous preparation
(1) under 25 ℃, is mixed with 8% Dex70,000 and 8% PEG8,000 solution; According to getting 0.500gDex70,000; 2.500gPEG8,000, (w/w) was mixed with solution under 25 ℃ in promptly 1: 5, the abundant mixing of vortex 30s-60s is-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 2 μ m-10 μ m, and mean diameter is 5.7 μ m.
(2) under 25 ℃, be mixed with 8% Dex70,000 and 8% PEG8,000 solution; According to getting 0.250gDex70,000; 2.500gPEG8,000, (w/w) was mixed with solution under 25 ℃ in promptly 1: 10, the abundant mixing of vortex 30s-60s is-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 25 ℃, be mixed with 8% Dex70,000 and 8% PEG8,000 solution; According to getting 0.125gDex70,000; 2.500gPEG8,000, (w/w) was mixed with solution under 25 ℃ in promptly 1: 20, the abundant mixing of vortex 30s-60s is-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 25 ℃, be mixed with 8% Dex70,000 and 8% PEG8,000 solution; According to getting 0.080g Dex70,000; 3.200g PEG8,000, (w/w) was mixed with solution under 25 ℃ in promptly 1: 40, the abundant mixing of vortex 30s-60s is-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: the preparation medicine carrying is polysaccharide vitreous
It is polysaccharide vitreous that bovine serum albumin is carried in preparation
1. prepare bovine serum albumin, PEG and polysaccharide solution
Prepare 8% PEG and 8% polysaccharide solution respectively with ultra-pure water, accurately taking by weighing 8 gram PEG and 8 gram polysaccharide water is placed on respectively in 100 milliliters the beaker and adds water 92 grams, then two beakers are placed on the magnetic agitation 30min of heating, the polysaccharide for the treatment of PEG and 8% 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 homogeneous phase are total to aqueous solution
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 homogeneous phase solution; 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: 1: 5,1: 1: 10,1: 1: 20,1: 1: 40, makes it dissolving and form homogeneous phase solution.
3. freezing bovine serum albumin, PEG and polysaccharide homogeneous phase be aqueous solution altogether
To prepare the common aqueous solution of bovine serum albumin, PEG and polysaccharide homogeneous phase and be separated in temperature-fall period, and make polysaccharide become decentralized photo, PEG becomes continuous phase.But avoid freeze overnight under the quick-freezing condition.
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.
Embodiment three: the preparation medicine carrying is polysaccharide vitreous
It is polysaccharide vitreous that Myoglobin is carried in preparation
1. prepare Myoglobin, PEG and polysaccharide solution
Prepare 8% PEG and 8% polysaccharide solution respectively with ultra-pure water, accurately taking by weighing 8 gram PEG and 8 gram polysaccharide water is placed on respectively in 100 milliliters the beaker and adds water 92 grams, then two beakers are placed on the magnetic agitation 30min of heating, the polysaccharide for the treatment of PEG and 8% all dissolving to take off cooling stand-by.Accurately taking by weighing 10 milligrams of bovine serum albumin with electronic balance is dissolved in 990 ml waters stand-by.
2. Myoglobin, PEG and polysaccharide homogeneous phase are total to aqueous solution
Polysaccharide with 1., Myoglobin 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 homogeneous phase solution; 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: 10: 50,1: 10: 100,1: 10: 200,1: 10: 400, makes it dissolving and form homogeneous phase solution.
3. Myoglobin, PEG and polysaccharide homogeneous phase are total to aqueous solution
To prepare the common aqueous solution of Myoglobin, PEG and polysaccharide homogeneous phase and be separated in temperature-fall period, and make polysaccharide become decentralized photo, PEG becomes continuous phase.But avoid freeze overnight under the quick-freezing condition.
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 Myoglobin polysaccharide vitreous.
What obtain carries the Vitrea particle diameter of cattle Myoglobin 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 Myoglobin is obtained has been avoided at dosage form preparation process inactivation.
Claims (8)
1, a kind of preparation method of utilizing the freezing polysaccharide vitreous particle that is separated, it is characterized in that, two or more aqueous solutions of polymers that will contain polysaccharide are freezing, are separated in temperature-fall period and make polysaccharide become decentralized photo, then lyophilizing and remove to loose continuously and obtain polysaccharide vitreous particle mutually.
2, the preparation method of utilizing the freezing polysaccharide vitreous particle that is separated according to claim 1 is characterized in that, specifically may further comprise the steps:
1. make their form homogeneous phase solution with Polyethylene Glycol PEG or with polysaccharide is soluble in water by control concentration;
2. active substance is added wherein, or add in the lump, or bioactive substance does not add yet with polysaccharide, Polyethylene Glycol;
3. with completing steps solution 2. in temperature-fall period, avoid freezing under the quick-freezing condition;
4. with completing steps sample lyophilizing 3.;
5. completing steps sample is 4. removed PEG continuous phase with solvent wash and obtain the polysaccharide dispersion particle.
3, according to claim 1 or the 2 described preparation methoies of utilizing the freezing polysaccharide vitreous particle that is separated, it is characterized in that described PEG, its molecular weight are 1,000-30,000; Its weight percent concentration is 0.2%-50%.
4, the preparation method of utilizing the freezing polysaccharide vitreous particle that is separated according to claim 1 is characterized in that, described PEG, the organic solvent that is used to remove PEG continuous phase are dissolving PEG and do not dissolve the solvent of polysaccharide.
5, according to claim 1 or the 2 described preparation methoies of utilizing the freezing polysaccharide vitreous particle that is separated, it is characterized in that described polysaccharide is glucosan, starch; Its molecular weight is 10,000-2,000,000; Its weight percent concentration is 1%-50%.
6, describedly utilize freezing being separated to prepare the method for polysaccharide vitreous particle according to claim 1 or 2, it is characterized in that, described temperature-fall period, be instigate sample temperature from single phase aqueous solution to being reduced to process below freezing more than two-phase or multiphase the phase transition temperature, phase transition temperature then changes with the kind and the concentration of hydrophilic polymer.
7, describedly utilize freezing being separated to prepare the method for polysaccharide vitreous particle according to claim 1 or 2, it is characterized in that, the weight ratio of described polysaccharide and described PEG is in the scope of 1: 1 and 1: 200.
According to claim 1 or the 2 described preparation methoies of utilizing the freezing polysaccharide vitreous particle that is separated, it is characterized in that 8, described polysaccharide dispersion particle contains buffer substance, salt and micromolecule saccharide material.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100291303A CN1887276A (en) | 2006-07-20 | 2006-07-20 | Frozen phase separating process of preparing polysaccharide vitreous particle |
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|---|---|---|---|
| CNA2006100291303A CN1887276A (en) | 2006-07-20 | 2006-07-20 | Frozen phase separating process of preparing polysaccharide vitreous particle |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101934089A (en) * | 2010-09-01 | 2011-01-05 | 北京大学人民医院 | Application of in-situ crosslinking hydrogel capable of intraocular injection in preparing artificial vitreous bodies |
-
2006
- 2006-07-20 CN CNA2006100291303A patent/CN1887276A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101934089A (en) * | 2010-09-01 | 2011-01-05 | 北京大学人民医院 | Application of in-situ crosslinking hydrogel capable of intraocular injection in preparing artificial vitreous bodies |
| CN101934089B (en) * | 2010-09-01 | 2013-05-01 | 北京大学人民医院 | Application of in-situ crosslinking hydrogel capable of intraocular injection in preparing artificial vitreous bodies |
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