CN1557282A - Modified water-soluble medicine and vaccine embedded macromolecule microsphere preparation method - Google Patents
Modified water-soluble medicine and vaccine embedded macromolecule microsphere preparation method Download PDFInfo
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention is the preparation process of improved polymer microsphere for embedding water soluble medicine and vaccine. The system has initial emulsion comprising water phase and oil phase, the water phase is medicine aqua or buffering salt solution, the oil phase is polymer solution, and coagulant or non-solvent is petroleum ether or n-hexane or n-heptane containing certain amount of oil soluble emulsifier. During the preparation, certain amount of water phase is emulsified in oil phase to obtain water-in-oil emulsion, certain amount of coagulant is added into the emulsion under stirring to obtain multi-phase suspension system containing semi-solidified microsphere, the suspension is added into certain amount of petroleum ether and stirred magnetically for some time, and the completely solidified microsphere is separated centrifugally and washed with petroleum ether.
Description
Technical field
The present invention relates to the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug and vaccine.Especially the preparation method of medicine microspheres such as 5-fluorouracil, amycin, insulin, bovine serum albumin, human serum albumin, human chorionic gonadotropin, clostridium tetani vaccine.
Background technology
In recent years, the medicine controlled releasing microsphere has obtained to use widely at field of medicaments.The first, as the controlled release and the multipath drug-delivery preparation of various medicines, as can be used as multipath administrations such as injection, oral, nasal cavity suction, dosing eyes; The second, as chemoembolization preparation performance thromboembolism and controlled release dual-use function; The 3rd, realize the effect that single administration reaches long-time performance curative effect, stimulates immunity of organism to respond as the carrier of biological active substanceies such as hormone, vaccine.
The carrier material that is used to prepare control-release microsphere at present has multiple, by sources can be divided into (1) natural macromolecular material, as cellulose and derivant, chitosan and derivant thereof, protein, sodium alginate, the most degradable of this class material and have excellent biological compatibility; (2) synthesized polymer material can be divided into again by biodegradation character: non-biodegradation type macromolecular material, as polyacrylate and derivant thereof, polyvinyl acetate, polyurethane; The Biodegradable macromolecular material, mainly contain polyester, poly-anhydride, poe, Merlon and poly phosphazene etc., polylactic acid wherein, poly-(lactide-co-glycolide) since its excellent biological compatibility and biological degradability by drugs approved by FDA as the clinical use of medical material.
Biological active substances in the control-release microsphere preparation can be fat-soluble, also can be water miscible.The degradability microsphere that wherein is loaded with cancer therapy drug, polypeptide protein class medicine and vaccine causes people's great attention as a class newtype drug dosage form with biotechnology and engineered fast development.In this novel slow release formulation, the listing of the conduct product that has has been used for diseases such as clinical treatment carcinoma of prostate, endometriosis and leiomyoma of uterus as leuprorelin acetate, music score of Chinese operas Rayleigh sustained-release micro-spheres dosage form; The microball preparation that has is carrying out clinical trial, carry out clinical trial at research group of France as the 5-fluorouracil of anti-glioma/poly-(lactide-co-glycolide) microsphere, be used for the treatment of the hormone-dependent type dwarfism and the childhood period undergrown recombinant human somatropin's sustained release microsphere agents just carry out clinical trial in the U.S.; Though what have is preliminary basic research, has demonstrated application prospects, as Macrulin, be loaded with the slow releasing preparation of subunit vaccine or viral vaccine.By making the sustained-release micro-spheres dosage form, both can avoid the degraded of bioactive substance receptor endoenzyme and the destruction inactivation of other material, but significant prolongation medicine release time in vivo again reaches the permanently effective purpose of single administration.
Phase separation method or coacervation are one of methods the most commonly used of medicine microspheresization.Be equipped with in the microsphere process in this legal system, silicone oil is high score subclass flocculating agent or non-solvent, especially dimethicone the most commonly used.Use the shortcoming of such flocculating agent to be: first, when using such flocculating agent, must better controlled water oil phase volume ratio, the volume of polymer concentration, flocculating agent and rate of addition thereof so that system be in ' stability window ', otherwise microsphere is easy to assemble in preparation process, and is more difficult to get the medicine carrying microballoons of high embedding rate.The second, many studies show that, flocculating agent such as silicone oil can be embedded in the microsphere in the microsphere preparation process, after washing process also be difficult to thoroughly remove.And silicone oil has certain toxicity, its in vivo non-degradable also be difficult to excrete by metabolism, thereby influence the application of final products; The existence of such material simultaneously can influence the physicochemical property of microsphere again, and then influence the release behavior of medicine, makes that to influence the factor of microsphere Chinese medicine release more complicated, and this appropriate design for microball preparation has increased difficulty.The 3rd, the use of such flocculating agent, the viscosity of suspension system increases much in causing preparing, and is difficult in this case obtain the small particle diameter microsphere, and requires microsphere to have very little particle diameter for the controlled release of some route of administration or some bioactive substances.This makes the application of traditional phase separation method be subjected to certain restriction.The 4th, when using such emulsifying agent, because the bigger viscosity of system makes organic solvent extraction not thorough.And these organic solvents often have stronger toxicity, the halogenated hydrocarbons commonly used such as dichloromethane, chloroform etc. has carcinogenecity, makes abnormal property, mutability and certain neurotoxicity, and American Pharmacopeia and European Pharmacopoeia stipulate that all the residual volume of these two kinds of solvents in microsphere is less than 500ppm and 50ppm respectively.
In view of above reason, a lot of research groups improve traditional phase separation method.People such as Leelarasamee use mineral oil to replace silicone oil as flocculating agent, and use different big small-bore injection devices to prepare the microsphere of different-grain diameter.The limitation of this method is that requirement has special device, and mineral oil also has certain residual quantity in microsphere simultaneously.People such as McGee join the emulsion of ovalbumin and polymer formation in the silicon oil solution that contains certain emulsifying agent, have obtained the very little microsphere of particle diameter.But the shortcoming of this method is owing to the silicone oil that has used a large amount of volumes, thereby proteic loss amount is big, and this embedding for expensive polypeptide, protein medicaments or vaccine is inapplicable.In order to reduce solvent residual amount in the last microsphere, the PLGA microsphere that people such as Lewis adopt less solvent/flocculating agent recently to prepare to be loaded with histrelin, they also advise using Oleum sesami as new flocculating agent.People such as Lawter are that flocculating agent prepares music score of Chinese operas Rayleigh microsphere to be easy to evaporable six dimethylsilane.
Although existing research has been done no small improvement to traditional phase separation method, but still there are many problems, such as the use of difficult volatility flocculating agent, the control and the organic solvent residue of particle diameter.Petroleum ether with different boiling ranges is that a class is easy to evaporable organic solvent, and this kind solvent also is divided into three grades of solvents by International Coordinating Committee (ICH) simultaneously, promptly is allowed to the low-toxic solvent that uses in medicament industry.Department's class's class or phospholipid oil soluble emulsifying agent are the materials in being usually used in preparation, and the safety of using in its body is proved to be already.We use the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution to replace silicone oil commonly used to prepare the polymer microsphere of soluble small molecular medicine, polypeptide protein class medicine and vaccine as flocculating agent.This method both can obtain the small particle diameter microsphere of high embedding rate, even nanosphere, can reduce organic solvent residue amount in the microsphere again.And the work of this respect does not see in the bibliographical information so far yet.
Summary of the invention
The preparation method that the purpose of this invention is to provide the polymer microsphere of a kind of improved occluded water soluble drug and vaccine.
At first water soluble drug and vaccine are dissolved in aqueous solution or the buffer salt solution and obtain water, the degradability carrier material is that high molecular polymer is dissolved in dichloromethane or the chloroform and obtains oil phase, department's class's class or phospholipid emulsifying agent and petroleum ether or normal hexane, the solution that normal heptane is formed is as flocculating agent or non-solvent, change under the high-speed stirred with per minute 500-40000 or under the ultrasound wave effect water is emulsifiable in ice bath neutralization then and form water-in-oil emulsion in the oil phase, under 500-40000 rev/min of stirring, flocculating agent or non-solvent are dripped the heterogeneous suspension system that obtains containing the semi-solid preparation microsphere in this emulsion, again this suspension is joined in the petroleum ether to extract the organic solvent of removing oil phase, and at room temperature magnetic agitation 30-60 minute, after treating the microsphere sclerosis, centrifugalize, petroleum ether or normal heptane washing, lyophilization.
Advantage of the present invention is:
1) uses the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution to replace silicone oil commonly used, can avoid containing in the thus obtained microsphere silicone oil toxicant as flocculating agent.
2) use the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution as flocculating agent, both can avoid the reunion or the gathering of microsphere in the preparation process, can obtain the very microsphere of small particle diameter again; Adopt suitable preparation technology, can obtain nanosphere.
3) use the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution as flocculating agent, can effectively reduce (lowering 5-100 doubly) microsphere toxic organic solvent residue amount.
4) use the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution as flocculating agent, can obtain the microsphere of high medicine embedding rate (75-100%), and microsphere yield higher (75-100%).
The specific embodiment
The present invention uses the petroleum ether contain a certain amount of department class's class or phospholipid oil soluble emulsifying agent or normal hexane, n-heptane solution to replace silicone oil commonly used as flocculating agent, adopts phase separation method to prepare the polymer microsphere of water soluble drug and vaccine.In order to prevent the gathering of microsphere, reduce microspherulite diameter and reduce organic solvent residue amount in the microsphere, the present invention takes following measure.This method water is aqueous solution or the buffer salt solution that is dissolved with medicine, and wherein drug level is 0.01-100mg/ml.Oil phase is for being dissolved with the dichloromethane or the chloroformic solution of polylactic acid, poly-(lactide-co-glycolide), poly-(lactide-be total to-trimethylene carbonate), and wherein polymer concentration is 1-200mg/ml.The solution that department's class's class or phospholipid emulsifying agent and petroleum ether or normal hexane, normal heptane are formed is as flocculating agent, wherein the concentration of department's class's class or phospholipid emulsifying agent is 0.05-20% (g/ml), the volume of flocculating agent is 0.5-5 a times of oil phase volume, and its rate of addition is a per minute 0.5-20 milliliter.The volume of petroleum ether that uses in the curing schedule or normal hexane, normal heptane is 1-50 times of the oil phase volume.Change under the high-speed stirred with per minute 500-40000 or under the ultrasound wave effect water is emulsifiable in ice bath neutralization and form water-in-oil emulsion in the oil phase, under 500-40000 rev/min of stirring, flocculating agent (or non-solvent) dripped the heterogeneous suspension system that in this emulsion, obtains containing the semi-solid preparation microsphere, again this suspension is joined in a certain amount of petroleum ether, and at room temperature magnetic agitation 30-60 minute organic solvent with extraction removal oil phase, after treating the microsphere sclerosis, centrifugalize, petroleum ether or normal heptane washing, lyophilization gets final product.
Be described in further detail below in conjunction with embodiment.
Embodiment 1
It is the bovine serum albumin (BSA of 50mg/ml that water adopts 0.5ml concentration, molecular weight is 67000) aqueous solution, oil phase is that (mol ratio is 75: 25 for poly-(lactide-co-glycolide) of 50mg/ml for 4.0ml concentration, weight average molecular weight is 45000) dichloromethane solution, flocculating agent is that viscosity is the dimethicone of 1000cs, during preparation water is emulsifiable in the oil phase under 2800 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 5.0ml flocculating agent joined this Ruzhong just, its rate of addition is 4.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the 50ml petroleum ether (boiling range: 60-90 ℃) and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 30 minutes, after treating the microsphere sclerosis, centrifugalize, petroleum ether, lyophilization gets final product.The embedding rate of thus obtained microsphere 5-fluorouracil is 88.7%, and the microsphere yield is 85%, and the microsphere number average bead diameter is 46.0 μ m.Solvent residual amount is 4.4 μ l/mg.
Embodiment 2
It is the hydrochloric acid solution (0.1N) of the 5-fluorouracil of 50mg/ml that water adopts 0.5ml concentration, oil phase is that (mol ratio is 60: 40 for poly-(lactide-co-glycolide) of 50mg/ml for 5.0ml concentration, weight average molecular weight is 35000) dichloromethane solution, flocculating agent is for containing petroleum ether (boiling range: the 60-90 ℃) solution of class of 2.5% (weight/volume) department 20, during preparation with water at ultrasound wave effect (200w, be emulsifiable in the oil phase 10s), the Water-In-Oil colostrum that forms, under 2800 rev/mins of stirrings the 10ml flocculating agent is joined this Ruzhong just then, its rate of addition is 5.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the 50ml petroleum ether (boiling range: 60-90 ℃) and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 30 minutes, after treating the microsphere sclerosis, centrifugalize, petroleum ether, lyophilization gets final product.Thus obtained microsphere 5-fluorouracil embedding rate is 80.7%, and the microsphere yield is 90%, and the microsphere number average bead diameter is 6.0 μ m.Solvent residual amount is 0.4 μ l/mg.
Embodiment 3
It is the aqueous solution of the bovine insulin (molecular weight is 5800) of 10mg/ml that water adopts 0.5ml concentration, oil phase is that (mol ratio is 50: 50 for poly-(lactide-co-glycolide) of 50mg/ml for 4.0ml concentration, weight average molecular weight is 40000) dichloromethane solution, flocculating agent is for containing petroleum ether (boiling range: the 60-90 ℃) solution of class of 5.0% (weight/volume) department 20, during preparation water is emulsifiable in the oil phase under 4000 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 10ml flocculating agent joined this Ruzhong just, its rate of addition is 10.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the petroleum ether (boiling range: 60-90 ℃) of 50ml and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 45 minutes, after treating the microsphere sclerosis, centrifugalize, the normal heptane washing, lyophilization gets final product.Thus obtained microsphere bovine insulin embedding rate is 90.5%, and the microsphere yield is 85%, and the microsphere number average bead diameter is 4.0 μ m.Solvent residual amount is 0.15 μ l/mg.
Embodiment 4
It is the human chorionic gonadotropin (HCG of 5.0mg/ml that water adopts 0.5ml concentration, immunocompetence is 14000IU/mg) phosphate buffered saline(PBS) (0.1M, pH7.4), oil phase is that (mol ratio is 50: 50 for poly-(lactide-co-glycolide) of 50mg/ml for 4.0ml concentration, weight average molecular weight is 30000) dichloromethane solution, flocculating agent is for containing petroleum ether (boiling range: the 30-60 ℃) solution of class of 10.0% (weight/volume) department 80, during preparation water is emulsifiable in the oil phase under 3000 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 10ml flocculating agent joined this Ruzhong just, its rate of addition is 2.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the petroleum ether (boiling range: 30-60 ℃) of 50ml and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 60 minutes, treat the microsphere sclerosis after, centrifugalize, the normal hexane washing, lyophilization gets final product.Thus obtained microsphere HCG embedding rate is 90.3%, and the microsphere yield is 95%, and the microsphere number average bead diameter is 2.5 μ m.Solvent residual amount is 0.06 μ l/mg.
Embodiment 5
It is the bovine serum albumin (BSA of 50mg/ml that water adopts 0.5ml concentration, Mw=67000) aqueous solution, (mol ratio is 80: 20 to poly-(lactide-altogether-trimethylene carbonate) of the 40mg/ml that oil phase for 5.0ml concentration is, weight average molecular weight is 28000) dichloromethane solution, flocculating agent is for containing petroleum ether (boiling range: the 30-60 ℃) solution of class of 5.0% (weight/volume) department 80, during preparation water is emulsifiable in the oil phase under 2800 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 12.5ml flocculating agent joined this Ruzhong just, its rate of addition is 2.5ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the petroleum ether (boiling range: 30-60 ℃) of 100ml and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 60 minutes, after treating the microsphere sclerosis, centrifugalize, petroleum ether (boiling range: 30-60 ℃) washing, lyophilization gets final product.Thus obtained microsphere BSA embedding rate is 99.0%, and the microsphere yield is 90%, and the microsphere number average bead diameter is 8.5 μ m.Solvent residual amount is 0.1 μ l/mg.
Embodiment 6
It is the human serum albumin's (HSA) of 50mg/ml aqueous solution that water adopts 0.5ml concentration, (mol ratio is 75: 25 to poly-(lactide-co-glycolide) of the 50mg/ml that oil phase for 4.0ml concentration is, weight average molecular weight is 38000) dichloromethane solution, flocculating agent is for containing petroleum ether (boiling range: the 30-60 ℃) solution of class of 10.0% (weight/volume) department 80, during preparation water is emulsifiable in the oil phase under 2800 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 7.5ml flocculating agent joined this Ruzhong just, its rate of addition is 7.5ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the petroleum ether (boiling range: 30-60 ℃) of 50ml and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 60 minutes, after treating the microsphere sclerosis, centrifugalize, petroleum ether (boiling range: 30-60 ℃) washing, lyophilization gets final product.Thus obtained microsphere HSA embedding rate is 90.5%, and the microsphere yield is 85%, and the microsphere number average bead diameter is 4.5 μ m.Solvent residual amount is 0.12 μ l/mg.
Embodiment 7
It is the human serum albumin's (HSA) of 50mg/ml aqueous solution that water adopts 0.5ml concentration, (mol ratio is 50: 50 to poly-(lactide-co-glycolide) of the 40mg/ml that oil phase for 5.0ml concentration is, weight average molecular weight is 58000) dichloromethane solution, flocculating agent is for containing the n-heptane solution of class of 10.0% (weight/volume) department 80, during preparation water is emulsifiable in the oil phase under 10000 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 10ml flocculating agent joined this Ruzhong just, its rate of addition is 10.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added under mechanical agitation in the petroleum ether (boiling range: 30-60 ℃) of 75ml and remove the oil phase solvent to extract, the room temperature lower magnetic force stirred 60 minutes, after treating the microsphere sclerosis, centrifugalize, the normal hexane washing, lyophilization gets final product.Thus obtained microsphere HSA embedding rate is 77.6%, and the microsphere yield is 75%, and the microsphere number average bead diameter is 500nm.Solvent residual amount is 0.17 μ l/mg.
Embodiment 8
Water adopts the aqueous solution (15000IU/ml) of 0.5ml clostridium tetani vaccine, the dichloromethane solution of the polylactic acid (weight average molecular weight is 36000) of the 50mg/ml that oil phase for 5.0ml concentration is, flocculating agent is for containing the hexane solution of 0.1% (weight/volume) lecithin, during preparation water is emulsifiable in the oil phase under 5600 rev/mins of stirrings, the Water-In-Oil colostrum that forms, under identical mixing speed, the 7.5ml flocculating agent joined this Ruzhong just, its rate of addition is 4.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added in the petroleum ether of 200ml (boiling range: 30-60 ℃) and remove the oil phase solvent under mechanical agitation to extract, the room temperature lower magnetic force stirred 60 minutes, after treating the microsphere sclerosis, centrifugalize, petroleum ether, lyophilization gets final product.The embedding rate of clostridium tetani vaccine is 85.7%, and the microsphere yield is 80%, and the microsphere number average bead diameter is 3.5 μ m.Solvent residual amount is 0.12 μ l/mg.
Embodiment 9
Water adopts the aqueous solution (10mg/ml) of 0.5ml amycin, the dichloromethane solution of the polylactic acid (weight average molecular weight is 36000) of the 50mg/ml that oil phase for 4.0ml concentration is, flocculating agent is for containing petroleum ether (boiling range: the 60-90 ℃) solution of class of 5.0% (weight/volume) department 80, during preparation with water at ultrasound wave effect (150w, be emulsifiable in the oil phase 15s), the Water-In-Oil colostrum that forms, under 2800 rev/mins of stirrings the 10ml flocculating agent is joined this Ruzhong just then, its rate of addition is 5.0ml/min, obtain containing the heterogeneous suspension system of semi-solid preparation microsphere, again this suspension is added in the petroleum ether of 100ml (boiling range: 60-90 ℃) and remove the oil phase solvent under mechanical agitation to extract, the room temperature lower magnetic force stirred 30 minutes, treat the microsphere sclerosis after, centrifugalize, petroleum ether, lyophilization gets final product.The embedding rate of amycin is 86.7% in the thus obtained microsphere, and the microsphere yield is 90%, and the microsphere number average bead diameter is 9.5 μ m.Solvent residual amount is 0.23 μ l/mg.
Claims (8)
1. the preparation method of the polymer microsphere of improved occluded water soluble drug and vaccine, it is characterized in that: at first water soluble drug and vaccine are dissolved in aqueous solution or the buffer salt solution and obtain water, the degradability carrier material is that high molecular polymer is dissolved in dichloromethane or the chloroform and obtains oil phase, department's class's class or phospholipid emulsifying agent and petroleum ether or normal hexane, the solution that normal heptane is formed is as flocculating agent or non-solvent, change under the high-speed stirred with per minute 500-40000 or under the ultrasound wave effect water is emulsifiable in ice bath neutralization then and form water-in-oil emulsion in the oil phase, under 500-40000 rev/min of stirring, flocculating agent or non-solvent are dripped the heterogeneous suspension system that obtains containing the semi-solid preparation microsphere in this emulsion, again this suspension is joined in the petroleum ether to extract the organic solvent of removing oil phase, and at room temperature magnetic agitation 30-60 minute, after treating the microsphere sclerosis, centrifugalize, petroleum ether or normal heptane washing, lyophilization.
2. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine, it is characterized in that the solution that said flocculating agent or non-solvent are formed for department class's class or phospholipid emulsifying agent and petroleum ether or normal hexane, normal heptane, the concentration of department's class's class or phospholipid emulsifying agent volume ratio by weight is expressed as 0.05-20%.
3. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine, the boiling range that it is characterized in that said petroleum ether are 30-60 ℃, 60-90 ℃, 90-120 ℃.
4. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine, the volume that it is characterized in that said flocculating agent or non-solvent are 0.5-5 times of oil phase volume.
5. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine, the rate of addition that it is characterized in that said flocculating agent or non-solvent is a per minute 0.5-20 milliliter.
6. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine, the volume that it is characterized in that the petroleum ether that uses in the said curing schedule are as the 1-50 of oil phase volume doubly.
7. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine is characterized in that said water soluble drug and vaccine are 5-fluorouracil, amycin, insulin, bovine serum albumin, human serum albumin, human chorionic gonadotropin, clostridium tetani vaccine.
8. the preparation method of the polymer microsphere of a kind of improved occluded water soluble drug according to claim 1 and vaccine is characterized in that said degradability carrier material is polylactic acid, poly-(lactide-be total to-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(lactide-be total to-trimethylene carbonate) biodegradated polymer materal.
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