CN1720902A - The supercritical anti-dissolving agent process prepares the method for biological degradable polymer drug-carried fine particle - Google Patents
The supercritical anti-dissolving agent process prepares the method for biological degradable polymer drug-carried fine particle Download PDFInfo
- Publication number
- CN1720902A CN1720902A CNA2005100270730A CN200510027073A CN1720902A CN 1720902 A CN1720902 A CN 1720902A CN A2005100270730 A CNA2005100270730 A CN A2005100270730A CN 200510027073 A CN200510027073 A CN 200510027073A CN 1720902 A CN1720902 A CN 1720902A
- Authority
- CN
- China
- Prior art keywords
- drug
- polymer
- solution
- dissolved
- pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 239000010419 fine particle Substances 0.000 title description 6
- 229920006237 degradable polymer Polymers 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 51
- 229940079593 drug Drugs 0.000 claims abstract description 29
- 229920000642 polymer Polymers 0.000 claims abstract description 29
- 239000002245 particle Substances 0.000 claims abstract description 23
- 238000001808 supercritical antisolvent technique Methods 0.000 claims abstract description 6
- 239000013557 residual solvent Substances 0.000 claims abstract description 3
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract 7
- 239000004621 biodegradable polymer Substances 0.000 claims abstract 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 22
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 19
- 239000004626 polylactic acid Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 229920001610 polycaprolactone Polymers 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 4
- 238000004140 cleaning Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000000178 monomer Substances 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 238000013022 venting Methods 0.000 claims 1
- 238000001556 precipitation Methods 0.000 abstract description 8
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 239000011859 microparticle Substances 0.000 abstract description 3
- 238000005507 spraying Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 239000011882 ultra-fine particle Substances 0.000 abstract description 2
- 238000005538 encapsulation Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
- 239000004005 microsphere Substances 0.000 description 23
- 239000012530 fluid Substances 0.000 description 16
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 11
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical compound C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 description 9
- 239000011246 composite particle Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- -1 polysiloxane Polymers 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000012296 anti-solvent Substances 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 229940098773 bovine serum albumin Drugs 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 229960002297 fenofibrate Drugs 0.000 description 5
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000008021 deposition Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000517 particles from gas-saturated solution Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 238000001046 rapid expansion of supercritical solution Methods 0.000 description 3
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000001056 aerosol solvent extraction system Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229920006125 amorphous polymer Polymers 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000005025 nuclear technology Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001432 poly(L-lactide) Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000002466 solution-enhanced dispersion by supercritical fluid Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Landscapes
- Medicinal Preparation (AREA)
Abstract
本发明属化学和生物医学工程领域，涉及到用一种超临界流体抗溶剂过程制备可生物降解聚合物载药微粒的方法。其过程主要包括以下步骤：A.首先将CO2通入结晶反应釜中，并达到预定温度和压力；B.将溶有药物的聚合物溶液通过一个特制的喷嘴喷入反应釜中，粒子沉析出来；C.收集到一定量的粒子之后停止喷射溶液，继续通入CO2清洗残留的溶剂，这一过程持续90～120分钟；D.最后在操作温度下减压放空。本发明工艺合理、操作简单、低成本、产品清洁且药物包封率高，CO2可循环使用。所制得的超细微粒产品粒径范围0.5～5μm。The invention belongs to the field of chemical and biomedical engineering, and relates to a method for preparing biodegradable polymer drug-loaded microparticles by using a supercritical fluid antisolvent process. The process mainly includes the following steps: A. Firstly, CO 2 is passed into the crystallization reactor to reach the predetermined temperature and pressure; B. The polymer solution containing the drug is sprayed into the reactor through a special nozzle, and the particles settle. Precipitation; C. After collecting a certain amount of particles, stop spraying the solution, and continue to pass through CO 2 to clean the residual solvent. This process lasts for 90 to 120 minutes; D. Finally, depressurize and vent at the operating temperature. The invention has the advantages of reasonable process, simple operation, low cost, clean product, high drug encapsulation rate, and CO2 can be recycled. The particle size range of the prepared ultrafine particle product is 0.5-5 μm.
Description
Technical field
The invention belongs to chemistry and biomedical engineering field, be specifically related to a kind of preparation method of polymer drug-carried fine particle, particularly relate to the method that a kind of supercritical anti-dissolving agent process prepares biological degradable polymer drug-carried fine particle.
Technical background
1984, Krukonis propose first supercritical fluid become nuclear technology (Krukonis VJ.Supercritical FluidNucleation of Difficult to Comminute Solids[C] .Paper Presented at AIChE Meeting, SanFrancisco, CA, 1984,11), principle is earlier solid chemical compound to be dissolved in the supercritical fluid (SCF), after system pressure reduced, this chemical compound was that the nucleation crystallization is separated out.Compare with traditional method such as grinding, vapour deposition, liquid deposition, mist projection granulating etc., adopt plurality of advantages such as the supercritical fluid deposition technology has crystallization purity height, epigranular, good fluidity, the super-refinement that is applicable to particular matters such as thermal sensitivity and biological activity, particle size distribution is adjustable.Supercritical fluid deposition technology (Supercritical Solution Precipitation) is used to prepare the main method of the ultrafine particle of uniform particle diameter in recent ten years: supercritical solution fast expansion (Rapid Expansion from Supercritical Solution, RESS), supercritical anti-dissolving agent process (Supercritical Anti-solvent, SAS) and the gas saturated solution method (Particles from Gas SaturatedSolutions, PGSS).
The SAS method (Reverchon E.Supercritical antisolvent precipitation of micro and nanoparticles[J] .J.Supercritical Fluids.1999,15, need to use conventional solvent 1-21), and RESS and PGSS only relate to the binary system of solid solute and supercritical fluid, do not relate to the use of conventional solvent.But RESS and PGSS have very big limitation, the former is fit to the material (for example fluorine-containing amorphous polymer and polysiloxane) that processing can be dissolved in supercritical fluid preferably, the dissolubility that the latter be fit to handle in SCF is bigger, and fusing point is lower and do not have a heat-labile material.And SAS has exactly solved the problem that many medicines, high-molecular organic material etc. can not be dissolved in SCF, utilizes this technology can study, develop and produce the functional particulate product.
The SAS ratio juris is that the solution that is dissolved with the solute that needs the making superfine powder is mixed with certain shooting flow bulk phase, though this supercritical fluid is to the solvability of solute in the solution very poor (or insoluble at all), the organic solvent in the solution can dissolve each other with supercritical fluid.When solution mixed with this supercritical fluid, volumetric expansion can take place in solution, reduced the viscosity energy density, causes the solvability of former solvent to descend greatly, thereby solute is separated out.The maximum characteristics of SAS method are, select suitable supercritical fluid and operating condition, solvent in the solution can be dissolved fully by supercritical fluid, mixing rate by control anti-solvent of supercritical and solution, just can control the precipitation rate of solute, thereby the size and shape of powder body is separated out in control, and the mean diameter of powder granule can reach the submicron order of magnitude.For the SAS method, the field that attracted attention by researcher is aspects such as biological preparation and the preparation of medicine controlled releasing microgranule.
The SAS method implement multiple different process arrangement and device, many authors have used various title to represent these processes (having write a Chinese character in simplified form ASES, GAS, SEDS and PCA).Hanna and York use a kind of coaxial nozzle to play to mix simultaneously and the effect (US 6440337) of anti-solvent of the supercritical fluid that atomizes and liquid solution.A kind of GAS technology that proposed Krukonis etc. has successfully realized the super-refinement of RDX (cyclonite), be characterized in supercritical fluid as anti-solvent, handle the material that those can not be dissolved in supercritical fluid, this process be with pending material dissolution in organic solvent, feeding supercritical fluid then expands organic solvent, reduce the active force between it and the solid solute, cause solid supersaturation precipitation particles (US5389263).1992, Debenedetti etc. have invented a kind of ASES method and have been used for preparing protein microbeads, its main feature is to utilize special nozzle---the platinum rounding dish of laser boring, organic solution is ejected in the anti-solvent of supercritical, carry out solvent expansion, the particle precipitating has obtained catalase and the insulin microparticles of 1～5 μ m.
Summary of the invention
The objective of the invention is to propose the preparation method that a kind of supercritical anti-dissolving agent process prepares biological degradable polymer drug-carried fine particle.
A kind of supercritical anti-dissolving agent process that the present invention proposes prepares the preparation method of biological degradable polymer drug-carried fine particle, and its concrete steps are as follows:
(1) reactor pretreatment
With CO
2Feed in the reactor, and reach predetermined temperature and pressure; Temperature is room temperature～50 ℃, and pressure is 5～20MPa, and room temperature is since 5 ℃;
(2) preparation is dissolved with the polymer solution of medicine
Polymer and medicine are dissolved in the solvent, obtain being dissolved with the polymer solution of medicine; The concentration of polymer solution is 5～60mg/ml, and drug level is 0.1～10mg/ml;
(3) polymer solution that is dissolved with medicine that obtains in the step (2) is passed through high-pressure pump, spray into nozzle in the reactor of step (1), make polymer in the solution, medicine supersaturation form crystallization, precipitating; Being dissolved with the flow velocity that the polymer solution of medicine sprays into by nozzle is 0.5～3ml/min;
(4) solution sprays and finishes, and continues to feed CO
2Clean residual solvent, temperature is room temperature～50 ℃, and pressure is 5～20MPa, and scavenging period is 90～120 minutes;
(5) about decompression emptying 30min, obtain product.
(6) above-mentioned polymer is polylactic acid, polyglycolic acid, poly-epsilon-caprolactone, poly-β-hydroxy butyl ester, Polyethylene Glycol or any two monomeric copolymers a kind of among them.For example gather (lactic acid-glycolic), poly-(lactic acid-caprolactone), poly-(caprolactone-ethylene glycol) etc.
(7) said medicine can be oil-soluble or water soluble drug.
Among the present invention, described water soluble drug can be dispersed in it and form suspension in polymer solution by ultrasonic instrument.
Among the present invention, described oil-soluble medicine kind is very extensive.Be the oil-soluble medicine (as norcantharidin, the FENOBRATE top grade) that dissolves in chloroform, dichloromethane, ethyl acetate, dimethyl sulfoxine, acetone and other organic solvent, can be mixed with uniform solution with polymer.
Among the present invention, described organic solvent requires its boiling point lower, and in no thermal decomposition phenomenon below 120 ℃, for example a kind of among dichloromethane, acetone, ethyl acetate, dimethyl sulfoxine, the chloroform.
Among the present invention, described medicine can also be some easily heat-sensitive substances of degraded or biologically active, i.e. protein, and polypeptide etc., as be bovine serum albumin (BSA), con A, phytohaemagglutinin, glutathione or the like.
Among the present invention, described reactor pressure is 8～14MPa, and its regularity of medicine composite particles of preparing is better, and particle size distribution is even, and entrapment efficiency is higher.
Among the present invention, the described working flow that is used to spray the high-pressure pump of the polymer solution that is dissolved with medicine is 0.01～9.99ml/min.
Among the present invention, the described nozzle that is used to spray the polymer solution that is dissolved with medicine, its aperture is 20 μ m～500 μ m, length is 0.1mm～0.2mm.
The biological degradation polyalcohol medicine composite particles mean diameter that is made by the present invention is generally between 1.5～3.5 μ m, and particle size distribution is narrower, and its standard deviation is generally between 0.3～0.6 μ m.
Technology of the present invention is simple, easy to operate, yield is high, non-environmental-pollution and can keep higher biological activity when handling the medicine of biologically active.Products obtained therefrom can be widely used in fields such as medicament slow release, controlled release preparation and medicine super-refinement.
Description of drawings
Fig. 1 is polylactic acid/norcantharidin complex microsphere SEM figure, this microsphere preparation condition: temperature=34 ℃, pressure=14MPa, PLA concentration=20mg/ml, norcantharidin drug level=2mg/ml, solution flow rate=1ml/min.
Fig. 2 is polylactic acid/fenofibrate complex microsphere SEM figure, this microsphere preparation condition: temperature=34 ℃, pressure=14MPa, PLA concentration=20mg/ml, fenofibrate drug level=2mg/ml, solution flow rate=1ml/min.
Fig. 3 is that Fig. 2 thus obtained microsphere is tested gained particle diameter and scattergram thereof with laser particle analyzer, and wherein abscissa is a particle diameter, and vertical coordinate is a quantity percent.
The specific embodiment
Embodiment 1:
In reactor, feed CO
2, regulate pressure and temperature to steady statue (34 ℃, 14MPa).(can be used for treating primary hepatocarcinoma, character is for being white crystalline powder with 1g polylactic acid (L-PLA) and 0.1g norcantharidin; Aqueous solution shows acid reaction, and is easily molten in acetone or hot water, molten at ethanol or cold water part omitted.) be dissolved in the 50ml dichloromethane, form uniform and stable solution, wherein PLA concentration is 20mg/ml, the norcantharidin drug level is 2mg/ml.Subsequently above-mentioned solution is sprayed in the autoclave, spraying flow velocity is 1ml/ minute, and organic solvent expands in course of injection, and solvability reduces, and original solute supersaturation forms crystal powder powder precipitation in the organic solvent thereby make.After treating that the solution injection finishes, in reactor, feed CO
2, keep original pressure and temperature, in order to the wash residual organic solvent, this process continues 100 minutes.Product is collected in about 30 minutes of last slowly blood pressure lowering, shows through scanning electron microscope and laser particle analyzer analysis result, the mean diameter of medicine composite particles is 1.852 μ m, standard deviation 0.603 μ m, and the thus obtained microsphere regularity is better, entrapment efficiency can reach 40.1%, has certain slow-releasing.
Embodiment 2:
In reactor, feed CO
2, regulate pressure and temperature to steady statue (room temperature, 20MPa).1g polylactic acid (L-PLA) and 0.5g norcantharidin are dissolved in the 50ml dichloromethane, form uniform and stable solution, wherein PLA concentration is 20mg/ml, and the norcantharidin drug level is 10mg/ml.Subsequently above-mentioned solution is sprayed in the autoclave, spraying flow velocity is 1ml/ minute, and organic solvent expands in course of injection, and solvability reduces, and original solute supersaturation forms crystal powder powder precipitation in the organic solvent thereby make.After treating that the solution injection finishes, in reactor, feed CO
2, keep original pressure and temperature, in order to the wash residual organic solvent, this process continues 100 minutes.Product is collected in about 30 minutes of last slowly blood pressure lowering, shows through scanning electron microscope and laser particle analyzer analysis result, the mean diameter of medicine composite particles is 2.784 μ m, standard deviation 1.748 μ m, the thus obtained microsphere regularity is relatively poor, and adhesion between the microsphere, agglomeration are more serious.
Embodiment 3:
Poly-L-lactic acid (L-PLA) concentration becomes 60mg/ml, and other condition is with embodiment 1, and the thus obtained microsphere mean diameter is 3.562 μ m, standard deviation 0.793 μ m, and entrapment efficiency is 37.6%.
Embodiment 4:
Polymer be poly-dl-lactide (D, L-PLA), organic solvent is an acetone, other condition is with embodiment 1, the thus obtained microsphere mean diameter is 2.652 μ m, standard deviation 0.703 μ m, the thus obtained microsphere regularity is better, entrapment efficiency is 42.6%.
Embodiment 5:
Polymer is poly-(caprolactone-ethylene glycol), and other condition is with embodiment 1, and the thus obtained microsphere mean diameter is 2.652 μ m, standard deviation 1.203 μ m, and the thus obtained microsphere regularity is better, and entrapment efficiency is 47.6%.
Embodiment 6:
Polymer is for being poly-(caprolactone-glycolic), and other conditions are with embodiment 1, and the thus obtained microsphere mean diameter is 2.052 μ m, standard deviation 0.403 μ m, and the thus obtained microsphere regularity is better, and entrapment efficiency is 45.2%.
Embodiment 7:
Organic solvent is a dimethyl sulfoxine, and other condition is with embodiment 1, and the thus obtained microsphere mean diameter is 2.452 μ m, standard deviation 1.041 μ m, and the thus obtained microsphere regularity is better, and entrapment efficiency is 27.6%.
Embodiment 8:
In reactor, feed CO
2, regulate pressure and temperature to steady statue (34 ℃, 14MPa).With 1g polylactic acid (L-PLA) and 0.1g fenofibrate (a kind of clofibrate lipid lowerers, character be for being white crystalline powder, odorless, bitter in the mouth dissolves in acetone, chloroform and ether.) be dissolved in the 50ml chloroform, forming that PLA concentration is 20mg/ml in the uniform and stable organic solution, the fenofibrate drug level is 2mg/ml.Subsequently above-mentioned solution is sprayed in the autoclave, the injection flow velocity is 1ml/min, and organic solvent expands in course of injection, and solvability reduces, and original solute supersaturation forms crystal powder powder precipitation in the organic solvent thereby make.After treating that the solution injection finishes, in reactor, feed CO
2, keep original pressure and temperature, in order to the wash residual organic solvent, this process continues 100min.The last slowly about 30min of blood pressure lowering collects product, shows through scanning electron microscope and laser particle analyzer analysis result, the mean diameter of medicine composite particles is 1.652 μ m, standard deviation 0.573 μ m, and the thus obtained microsphere regularity is better, entrapment efficiency can reach 54.06%, has certain slow-releasing.
Embodiment 9:
Polymer is poly-(lactic acid-glycolic), and other condition is with embodiment 8, and the thus obtained microsphere mean diameter is 2.852 μ m, standard deviation 0.593 μ m, and the thus obtained microsphere regularity is better, and entrapment efficiency is 31.6%.
Embodiment 10:
Polymer is a poly-epsilon-caprolactone, and other condition is with embodiment 8, and the thus obtained microsphere mean diameter is 2.752 μ m, standard deviation 0.473 μ m, and the thus obtained microsphere regularity is better, and entrapment efficiency is 32.4%.
Embodiment 11:
In reactor, feed CO
2, regulate pressure and temperature to steady statue (34 ℃, 14MPa).1g polylactic acid (L-PLA) is dissolved in the 50ml dichloromethane, simultaneously 50mg bovine serum albumin (BSA) is dissolved in the phosphate buffered solution that 2ml concentration is 0.1mol/l (PBS) (pH value is about 7.4), both are mixed and sonic oscillation 5min, form water in oil homogeneous latex emulsion.Subsequently above-mentioned solution is sprayed in the autoclave, the injection flow velocity is 1ml/min, and solvent expands in course of injection, and solvability reduces by CO
2Take away, original solute supersaturation forms Powdered precipitation in the organic solvent thereby make.After treating that the solution injection finishes, in reactor, feed CO
2, keep original pressure and temperature, in order to the wash residual organic solvent, this process continues 100 minutes.About 30 minutes of last slowly blood pressure lowering, collect product, show through scanning electron microscope and laser particle analyzer analysis result, the mean diameter of medicine composite particles is 2.452 μ m, standard deviation 0.683 μ m, the thus obtained microsphere regularity is better, and entrapment efficiency can reach 74.06%, BSA can keep higher biological activity, has certain slow-releasing.
Embodiment 12:
In reactor, feed CO
2, regulate pressure and temperature to steady statue (50 ℃, 5MPa).The 0.5g norcantharidin is dissolved in the 50ml dichloromethane, and polymer and solution thereof form uniform and stable organic solution with embodiment 2.Subsequently above-mentioned solution is sprayed in the autoclave, the injection flow velocity is 1ml/min.After treating that the solution injection finishes, in original pressure and temperature downhill reaction still, feed CO
2, the wash residual organic solvent, this process continues 120 minutes.Product is collected in about 30 minutes of last slowly blood pressure lowering, shows that through scanning electron microscope and laser particle analyzer analysis result the mean diameter of gained norcantharidin microgranule is 1.252 μ m, standard deviation 0.325 μ m.
The prepared polymeric medicine composite particles of the foregoing description all has certain slow-releasing.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100270730A CN1302766C (en) | 2005-06-23 | 2005-06-23 | Method for preparing biological degradable polymer drug-carried fine particle by supercritical anti-solvent process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100270730A CN1302766C (en) | 2005-06-23 | 2005-06-23 | Method for preparing biological degradable polymer drug-carried fine particle by supercritical anti-solvent process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1720902A true CN1720902A (en) | 2006-01-18 |
| CN1302766C CN1302766C (en) | 2007-03-07 |
Family
ID=35911742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100270730A Expired - Fee Related CN1302766C (en) | 2005-06-23 | 2005-06-23 | Method for preparing biological degradable polymer drug-carried fine particle by supercritical anti-solvent process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1302766C (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857227B (en) * | 2006-03-07 | 2010-05-19 | 大连大学 | Supercritical Fluid-Assisted Dual-Cycle Method for Drug Loading on Polymer Microspheres |
| CN101972212A (en) * | 2010-10-29 | 2011-02-16 | 华侨大学 | Method for preparing core-shell type composite microspheres by supercritical fluid technology |
| CN102327186A (en) * | 2011-09-30 | 2012-01-25 | 四川大学 | A method for preparing water-soluble drug slow-release microparticles using supercritical CO2 fluid technology |
| CN101185868B (en) * | 2006-12-15 | 2012-07-18 | 国家纳米技术与工程研究院 | Technique for preparing lomoxicam ultra-fine particles using by supercritical fluid crystallization technology |
| CN105073841A (en) * | 2013-02-22 | 2015-11-18 | Vaim有限公司 | Method for preparing polymer microparticles by spray process |
| CN105687141A (en) * | 2016-03-04 | 2016-06-22 | 中国药科大学 | Technical study for preparing Nim-PLLA (nimesulide-poly-l-lactic acid) composite microsphere with supercritical anti-solvent method |
| CN108478784A (en) * | 2018-05-25 | 2018-09-04 | 扬子江药业集团广州海瑞药业有限公司 | A kind of pharmaceutical composition containing thymalfasin |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4223282A1 (en) * | 2022-02-08 | 2023-08-09 | Servizo Galego de Saude | Microspheres for extended release of fenofibrate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128172C (en) * | 2000-01-28 | 2003-11-19 | 中国科学院广州化学研究所 | Method of enhancing adsorptive capacity of small molecules into high polymer in supercritical carbon dioxide medium |
| KR100887429B1 (en) * | 2001-10-22 | 2009-03-09 | 돔페 파르마 에스.피.에이. | Supercritical Fluid Process: Preparation and Stabilization of Protein Microparticles |
| CN1498675A (en) * | 2002-11-06 | 2004-05-26 | 尹恩华 | Method and device for producing ultramicron by using supercritical gas saturation solution |
| CN1303133C (en) * | 2003-08-13 | 2007-03-07 | 同济大学 | Method for preparing bio-degraded polymer particles by supercritical crystallization |
-
2005
- 2005-06-23 CN CNB2005100270730A patent/CN1302766C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857227B (en) * | 2006-03-07 | 2010-05-19 | 大连大学 | Supercritical Fluid-Assisted Dual-Cycle Method for Drug Loading on Polymer Microspheres |
| CN101185868B (en) * | 2006-12-15 | 2012-07-18 | 国家纳米技术与工程研究院 | Technique for preparing lomoxicam ultra-fine particles using by supercritical fluid crystallization technology |
| CN101972212A (en) * | 2010-10-29 | 2011-02-16 | 华侨大学 | Method for preparing core-shell type composite microspheres by supercritical fluid technology |
| CN102327186A (en) * | 2011-09-30 | 2012-01-25 | 四川大学 | A method for preparing water-soluble drug slow-release microparticles using supercritical CO2 fluid technology |
| CN105073841A (en) * | 2013-02-22 | 2015-11-18 | Vaim有限公司 | Method for preparing polymer microparticles by spray process |
| US9850341B2 (en) | 2013-02-22 | 2017-12-26 | Vaim Co., Ltd. | Method for preparing polymer microparticles by spray process |
| CN105687141A (en) * | 2016-03-04 | 2016-06-22 | 中国药科大学 | Technical study for preparing Nim-PLLA (nimesulide-poly-l-lactic acid) composite microsphere with supercritical anti-solvent method |
| CN108478784A (en) * | 2018-05-25 | 2018-09-04 | 扬子江药业集团广州海瑞药业有限公司 | A kind of pharmaceutical composition containing thymalfasin |
| CN108478784B (en) * | 2018-05-25 | 2019-02-22 | 扬子江药业集团广州海瑞药业有限公司 | A kind of pharmaceutical composition containing thymalfasin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1302766C (en) | 2007-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100681213B1 (en) | Microsphere manufacturing method and manufacturing apparatus | |
| US7537803B2 (en) | Polymer coating/encapsulation of nanoparticles using a supercritical antisolvent process | |
| CA2474701C (en) | Preparation of biodegradeable microparticles containing a biologically active agent | |
| CN1273113C (en) | Powder processing with pressurized gaseous fluids | |
| WO2001078687A1 (en) | Injectable sustained release pharmaceutical composition and processes for preparing the same | |
| FR2691631A1 (en) | Compositions containing peptide salts formed with carboxy-terminated polyesters and processes for their production | |
| JPWO2001083594A1 (en) | Microsphere manufacturing method | |
| CN1302766C (en) | Method for preparing biological degradable polymer drug-carried fine particle by supercritical anti-solvent process | |
| JP2012515790A (en) | Continuous double emulsion process for fine particle production | |
| TW201834640A (en) | Preparation of microparticles of an active ingredient | |
| WO2001080835A1 (en) | Process for producing microsphere | |
| CN101035610A (en) | Method for coating powders | |
| JP2004035446A (en) | Method for producing microsphere and apparatus for producing the same | |
| JP2000239152A (en) | Method for removing organic solvent remaining in fine particles | |
| KR0146386B1 (en) | Manufacturing method of drug-containing microspheres | |
| CN1303133C (en) | Method for preparing bio-degraded polymer particles by supercritical crystallization | |
| CN118903021A (en) | Hydromorphone microsphere, preparation method and application thereof | |
| HK1014970A1 (en) | Polyester | |
| HK1014970B (en) | Polyester | |
| Kluge et al. | PRODUCTION OF POLYMER MICROPARTICLES FOR PHARMACEUTICAL APPLICATIONS BY SUPERCRITICAL FLUID EXTRACTION OF EMULSIONS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070307 Termination date: 20140623 |
|
| EXPY | Termination of patent right or utility model |