CN1742706A - Water-soluble medicine degradable polymer microcapsule injecta and preparing method - Google Patents
Water-soluble medicine degradable polymer microcapsule injecta and preparing method Download PDFInfo
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- CN1742706A CN1742706A CN 200510060925 CN200510060925A CN1742706A CN 1742706 A CN1742706 A CN 1742706A CN 200510060925 CN200510060925 CN 200510060925 CN 200510060925 A CN200510060925 A CN 200510060925A CN 1742706 A CN1742706 A CN 1742706A
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- polylactic acid
- water soluble
- water
- injecta
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Links
- 239000003814 drug Substances 0.000 title claims abstract description 32
- 239000003094 microcapsule Substances 0.000 title claims abstract description 32
- 229920006237 degradable polymer Polymers 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title abstract description 3
- 239000004626 polylactic acid Substances 0.000 claims abstract description 97
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 59
- 238000002360 preparation method Methods 0.000 claims abstract description 45
- 150000004676 glycans Chemical class 0.000 claims abstract description 22
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 22
- 239000005017 polysaccharide Substances 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims description 32
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical group C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 16
- 239000000839 emulsion Substances 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 10
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 10
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 10
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 9
- 229920001661 Chitosan Polymers 0.000 claims description 9
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 9
- -1 allyloxy ethylene glycol Chemical compound 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000001119 stannous chloride Substances 0.000 claims description 9
- 235000011150 stannous chloride Nutrition 0.000 claims description 9
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 150000001718 carbodiimides Chemical class 0.000 claims description 8
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 claims description 8
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 7
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 6
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 6
- 239000003431 cross linking reagent Substances 0.000 claims description 6
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 6
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 5
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 claims description 5
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 claims description 5
- 229920001503 Glucan Polymers 0.000 claims description 5
- 229940112869 bone morphogenetic protein Drugs 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 5
- 102000009027 Albumins Human genes 0.000 claims description 4
- 108010088751 Albumins Proteins 0.000 claims description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000006392 deoxygenation reaction Methods 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229940050528 albumin Drugs 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 239000002775 capsule Substances 0.000 abstract description 3
- 238000007720 emulsion polymerization reaction Methods 0.000 abstract 1
- 239000011257 shell material Substances 0.000 abstract 1
- 238000013019 agitation Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000008307 w/o/w-emulsion Substances 0.000 description 9
- 230000005540 biological transmission Effects 0.000 description 6
- 239000011162 core material Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 206010011732 Cyst Diseases 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 238000012688 inverse emulsion polymerization Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
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Abstract
The present invention discloses a degradable polymer microcapsule injection preparation of water soluble medicine and its preparation method. It uses polysaccharide containing double-bond and polylactic acid which have good biological compatibility and biological degradability as capsule shell material, utilizes the control of ratio of mixing polysaccharide and polylactic acid and adopts W10/w emulsion polymerization technique to obtain the medicine microcapsule injection preparation whose grain size is 100-2000nm.
Description
Technical field
The present invention relates to degradable polymer microcapsule injection reagent of a kind of water soluble drug and preparation method thereof, especially a kind of a kind of and multiple degradable polymer with medical grade polylactic acid and double bond containing polysaccharide and polylactic acid is a clad material, and water soluble drug is the capsule of nano type ejection preparation and the technology of preparing thereof of core materials.
Background technology
Biodegradable polymeric carrier occupies extremely important status because of its unique good characteristic (good degradation characteristic and less bio-toxicity) in the controlled release drug delivery system field.Compare with common biodegradable polymer microspheres carrier, microcapsule has following advantage: lower density and material consumption can reduce physiology toxicity to a certain extent; Relative bigger medicine carrying space; Simultaneously, by can realize the multi-level regulation and control of carrier sustained release performance to the change of microcapsule performance (as cyst material composition and molecular weight, microcapsule form, wall thickness etc.).Numerous researcheres have been reported the functionalization of preparation, release behavior and surface group thereof that biodegradable polymers (as polyester polymer and copolymer thereof and albumen, polysaccharide natural macromolecular) is microsphere supported.For the polyesters synthetic high polymer, molecular backbone is made of hydrophobic C-C key and ester bond, its relative chemical inertness makes it be difficult to directly obtain microcapsule by the method for chemical reaction, thus about the research report of the drug release carrier of hollow microcapsule-type with use less.And the microcapsule-type pharmaceutical carrier of natural polymer is difficult to obtain the performance of long-acting slow-release owing to capsule material good water-solubility and permeability.
Biodegradable polymeric two big component part---natural polymer and synthetic high polymer performance are totally different, differ from one another, and the preparation method of its microcapsule carrier also differs widely.Find a kind of microcapsule preparation method that can be suitable for this two classes material simultaneously, and may they are organic compound, obtain the polymer support of mutual supplement with each other's advantages, be to have challenging work.
Summary of the invention
The object of the invention provides degradable polymer microcapsule injection reagent of a kind of water soluble drug and preparation method thereof.
The degradable polymer microcapsule injecta of the water soluble drug of invention comprises water soluble drug, one or more mixture in medical grade polylactic acid, double bond containing polylactic acid and the double bond containing polysaccharide of coating water soluble drug.
Above-mentioned water soluble drug is ciprofloxacin hydrochloride, albumin (BSA), bone morphogenetic protein (BMP) or fibroblast growth factor (bFGF); Said medical grade polylactic acid is the commercial polylactic acid of medical grade, and its molecular weight is 5,000～400,000; Said double bond containing polysaccharide is grafting methacrylic acid or acrylic acid diethylin ethyl glucosan and chitosan; The particle diameter of microcapsule is at 100～2000nm.
The preparation method of the degradable polymer microcapsule injecta of water soluble drug of the present invention may further comprise the steps:
(1) with lactide and stannous chloride crystal grind into powder, adds a certain amount of allyloxy ethylene glycol, place reaction vessel, deoxygenation is towards nitrogen, closed container, wherein the consumption of stannous chloride is 0.8 of lactide weight～10 ‰, the mol ratio of lactide/allyloxy ethylene glycol is 6～300;
(2) above-mentioned reaction unit places 140～200 ℃ oil bath, and constant temperature is lowered the temperature after 4 hours at least, is that solvent, deionized water are precipitant with acetone, by dissolving-deposition and purification, remove impurity, 40 ℃ of vacuum dryings obtain double bond containing polylactic acid to constant weight or lyophilization;
(3) 0～40 ℃, pH value 2～8 times, with concentration is that methacrylic acid or the acrylic acid of 0.01-1g/ml is dissolved in the aqueous solution that contains the water solublity carbodiimide, the weight ratio of methacrylic acid or acrylic acid and carbodiimide is 1: 1.5～1: 10, after the stirring, polysaccharide solution dropwise is added dropwise in the above-mentioned solution, polysaccharide and methacrylic acid or acrylic acid weight ratio are 1: 0.2～1: 10, dropwise back constant temperature 0.5～2 round the clock, the gained solution centrifugal filters, and lyophilizing after placing tri-distilled water to dialyse 1～7 day, obtain double bond containing polysaccharide;
(4) under the room temperature, with the medical grade polylactic acid, contain two key polylactic acid and cross-linking agent is dissolved in the organic solvent, the consumption of medical grade polylactic acid is to contain 0～80% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 5～50mg/ml, and the consumption of cross-linking agent is to contain 0～20% of two key polylactic acid weight; After being dissolved in water soluble drug in the aqueous solution that contains 0.2% tween 20, join in the solution of above-mentioned organic solvent, ultrasonic after, form water/fat liquor; Again water/fat liquor is joined in the aqueous solution by polyvinyl alcohol that contains two key polysaccharide and 0.002～0.01mg/ml or Triton x-100 preparation, perhaps join in the aqueous solution of the polyvinyl alcohol of 0.002～0.01mg/ml or Triton x-100, obtain water/oil/aqueous emulsion, the consumption that contains two key polysaccharide is 0～50% of a polylactic acid gross weight, drug weight is 0.1～50% of a polylactic acid gross weight, water/oil/water volume ratio 1: 2: 4～1: 10: 50;
(5) logical nitrogen and keep nitrogen atmosphere in the said vesse stirs down 10～50 ℃ of constant temperature, water soluble oxidized is reduced initiator add in the above-mentioned system, stirs and reduces to room temperature at least after 2 hours rapidly;
(6) worn-out mouth is stirred to the organic solvent volatilization and finishes lyophilization.
In the preparation process of the present invention, said cross-linking agent is divinylbenzene or Polyethylene Glycol double methacrylate.Organic solvent in the step 4) is immiscible dichloromethane of water or chloroform.Said water soluble oxidized reduction initiator is K
2S
2O
8Or (NH
4)
2S
2O
8With NaHSO
3Or Na
2SO
3System is to the concentration and the K of system
2S
2O
8Or (NH
4)
2S
2O
8With NaHSO
3Or Na
2SO
3Ratio do not have specific (special) requirements, generally make K
2S
2O
8Or (NH
4)
2S
2O
8With NaHSO
3Or Na
2SO
3Weight ratio be 1: 1.Said polysaccharide is a kind of or its mixture in diethylin ethyl glucosan and the chitosan.
Utilization of the present invention has excellent biological compatibility and the biodegradable two key polysaccharide and polylactic acid and medical grade polylactic acid of containing are coating material, ratio by control polysaccharide/poly-lactic acid mixture, the emulsifying agent kind and the consumption of mechanical agitation speed, system water oil volume ratio, use, adopt the technology of W/O/W emulsion polymerisation, obtain the drug microcapsule type ejection preparation of particle diameter 100～2000nm.Beneficial effect of the present invention is:
(1) avirulence.The material that the present invention adopts is without any physiology toxicity.
(2) excellent biological compatibility and degradability.Material of the present invention has good biocompatibility and degradability.
(3) performance is controlled.By the mechanical agitation speed of the ratio between simple control clad material, preparation process, emulsifying agent kind and the consumption that polymerization system water oil volume compares, uses, can obtain the microcapsule-type preparation of different sustained release performances, different grain size, different structure composition.Have adjustable sustained release performance and hydrophilic and hydrophobic surface.
(4) You Yi stability.By the inverse emulsion polymerization technology, the dosage surface coating material has cross-linked structure, thereby has good stable.Applied widely.
(5) preparation technology is simple, mild condition.
Description of drawings
Fig. 1 is double bond containing polylactic acid
1The HNMR picture.The molecular formula of product sees among the figure that the H atom chemistry displacement at corresponding letter place in the absworption peak at the letter place of the labelling difference molecular formula can be known and find out the absworption peak that has two keys on the AOE segment on the spectrogram among the figure.It is 2100 that gel permeation chromatography (GPC) is measured its number-average molecular weight.
Fig. 2 is the transmission electron microscope picture of the preparation of example 1 preparation.As seen from the figure, microcapsule has hollow-core construction, and particle diameter is 200～500nm.
Fig. 3 be example 2 preparation preparation transmission electron microscope picture and atomic force microscope figure.As seen from the figure, microcapsule has hollow-core construction, is evenly distributed, and particle diameter is 150～250nm.
Fig. 4 is atomic force microscope (AFM) figure of the ejection preparation of example 4 preparations.Can know by figure and to see that the particle of acquisition has uniform particle diameter, the about 300nm of size.
Fig. 5 is the ejection preparation of example 5 preparations.Figure a is a transmission electron microscope, figure b, and c is atomic force microscope figure.Can know by figure and to see that the particle of acquisition has uniform particle diameter, the about 150nm of size.
Fig. 6 is the transmission electron microscope and the atomic force microscope figure of the ejection preparation of example 6 preparations.Can know by figure and to see that the part particle has hollow-core construction, the about 400nm of size.
Fig. 7 is the granularity and the particle size distribution figure of the ejection preparation of example 7 preparations.The particle diameter of preparation is 200～500nm.
Fig. 8 is the transmission electron microscope picture of the ejection preparation of example 8 preparations.The particle diameter of preparation is～150nm.
The specific embodiment
Below in conjunction with example the present invention is elaborated:
Example 1:
(1) with lactide and stannous chloride crystal grind into powder, adds a certain amount of allyloxy ethylene glycol, place reaction vessel, remove oxygen and filling nitrogen, closed container, wherein the consumption of stannous chloride is 0.8 ‰ of a lactide weight, the mol ratio of lactide/allyloxy ethylene glycol is 55;
(2) above-mentioned reaction unit places 140 ℃ oil bath, and constant temperature was lowered the temperature after 8 hours, is that solvent, deionized water are precipitant with acetone, by dissolving-deposition and purification, removes impurity, and 40 ℃ of vacuum dryings obtain double bond containing polylactic acid to constant weight, its H
1NMR sees Fig. 1;
(3) 25 ℃, pH value 7.0 times, with concentration is that the methacrylic acid of 1g/ml is dissolved in the aqueous solution that contains the water solublity carbodiimide, the weight ratio of methacrylic acid and carbodiimide is 1: 2, stir after 2 hours, diethylin ethyl glucosan (deae dextran) aqueous solution dropwise is added dropwise in the above-mentioned solution, the weight ratio of deae dextran and methacrylic acid is 1: 1, dropwise back constant temperature 1 round the clock, the gained solution centrifugal filters, and place tri-distilled water dialysis lyophilizing after 7 days, obtain double bond containing deae dextran (MADdex);
(4) under the room temperature, with medical grade polylactic acid (molecular weight 100,000), containing two key polylactic acid and divinylbenzene is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 10% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 25mg/ml, and the consumption of divinylbenzene is to contain 1% of two key polylactic acid weight.Ciprofloxacin hydrochloride is dissolved in the aqueous solution that contains 0.2% tween 20 to join in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, form the W/O emulsion, again the W/O emulsion is joined in the aqueous solution by the Triton x-100 preparation of MADdex and 0.05%, obtain the W/O/W emulsion.The consumption of MADdex is 50% of a polylactic acid gross weight, and the consumption of ciprofloxacin hydrochloride is 20% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 25;
(5) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 1000rmp, 40 ℃ of constant temperature are with K
2S
2O
8With NaHSO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 8h;
(6) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
The transmission electron microscope picture of the microcapsule injecta of preparation is seen Fig. 2.
Example 2:
(1) with lactide and stannous chloride crystal grind into powder, adds a certain amount of allyloxy ethylene glycol, place reaction vessel, remove oxygen and filling nitrogen, closed container, wherein the consumption of stannous chloride is 2 ‰ of a lactide weight, the mol ratio of lactide/allyloxy ethylene glycol is 200;
(2) above-mentioned reaction unit places 200 ℃ oil bath, and constant temperature was lowered the temperature after 24 hours, is that solvent, deionized water are precipitant with acetone, by dissolving-deposition and purification, removes impurity, and 40 ℃ of vacuum dryings obtain double bond containing polylactic acid to constant weight;
(3) under the room temperature, will contain two key polylactic acid and divinylbenzene (DVB) and be dissolved in the dichloromethane, polylactic acid concentration in dichloromethane is 17mg/ml, and DVB weight accounts for and contains 5% of two key polylactic acid weight.Ciprofloxacin hydrochloride is dissolved in adds in the aqueous solution that contains 0.2% tween 20 in the above-mentioned solution, behind the ultrasonic 0.5min, form the W/O emulsion; Again the W/O emulsion is joined in the aqueous solution of 0.05% Triton x-100, obtain the W/O/W emulsion.The consumption of ciprofloxacin hydrochloride is 5% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 4: 32;
(4) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 600rmp, 35 ℃ of constant temperature are with K
2S
2O
8With Na
2SO
3(1: 1 weight ratio, concentration is 0.05mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 8h;
(5) uncovered stirring is spent the night to organic solvent volatilization and is finished, and preserves after the lyophilization.The polymer microcapsule preparation that is obtained is seen Fig. 3, and as seen from the figure, microcapsule has hollow-core construction, is evenly distributed, and particle diameter is 150～250nm.
Example 3:
(1) contain step (1) and (2) in the synthetic repetition example 1 of two key polylactic acid, it is 10 ‰ of lactide weight that difference is in the consumption of stannous chloride;
(2) 25 ℃, pH value 7.0 times, with concentration is that the acrylic acid of 1g/ml is dissolved in the aqueous solution that contains the water solublity carbodiimide, the weight ratio of acrylic acid and carbodiimide is 1: 2, stir after 2 hours, the HCl aqueous solution (pH 3.0) of chitosan dropwise is added dropwise in the above-mentioned solution, the weight ratio of chitosan and methacrylic acid is 1: 10, dropwise back constant temperature 1 round the clock, the gained solution centrifugal filters, and places tri-distilled water dialysis lyophilizing after 7 days, obtains double bond containing chitosan;
(3) under the room temperature, with medical grade polylactic acid (molecular weight 50,000), containing two key polylactic acid and Polyethylene Glycol double methacrylate is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 30% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 50mg/ml, and the consumption of Polyethylene Glycol double methacrylate is to contain 1% of two key polylactic acid weight.Albumin is dissolved in the aqueous solution that contains 0.2% tween 20 to join in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, form the W/O emulsion, again the W/O emulsion is joined in the aqueous solution by the Triton x-100 preparation of double bond containing chitosan and 0.05%, obtain the W/O/W emulsion.The consumption of double bond containing chitosan is 50% of a polylactic acid gross weight, and albuminous consumption is 5% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 25;
(4) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 10000rmp, constant temperature 30% is with (NH
4)
2S
2O
8With NaHSO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 12h;
(5) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
Example 4:
(1) contains the synthetic of two key polylactic acid with step (1) in the example 1 and (2);
(2) under the room temperature, with medical grade polylactic acid (molecular weight 5,000), containing two key polylactic acid and DVB is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 30% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 50mg/ml, and the consumption of DVB is to contain 1% of two key polylactic acid weight.Albumin is dissolved in the aqueous solution that contains 0.2% tween 20 joins in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, form the W/O emulsion, again the W/O emulsion is added in the aqueous solution of 0.05% Triton x-100, obtain the W/O/W emulsion.Albuminous consumption is 2% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 25;
(3) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 600rmp, 30 ℃ of constant temperature are with K
2S
2O
8With NaHSO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 12h;
(4) worn-out mouth is stirred to the organic solvent volatilization and finishes lyophilization.
The gained ejection preparation is seen Fig. 4, can be known by figure and see that the particle of acquisition has uniform particle diameter, the about 300nm of size.
Example 5:
(1) contains the synthetic of two key polylactic acid with step (1) in the example 2 and (2);
(2) under the room temperature, with medical grade polylactic acid (molecular weight 10,000), containing two key polylactic acid and DVB is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 30% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 50mg/ml, and the consumption of DVB is to contain 1% of two key polylactic acid weight.Ciprofloxacin hydrochloride is dissolved in the aqueous solution that contains 0.2% tween 20 joins in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, form the W/O emulsion, again it is added in the aqueous solution of 0.05% polyvinyl alcohol, obtain the W/O/W emulsion.The consumption of ciprofloxacin hydrochloride is 0.2% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 25;
(3) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 600rmp, 40 ℃ of constant temperature are with K
2S
2O
8With NaHSO
3(1: 2 weight ratio, concentration is 0.04mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 12h;
(4) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
Gained the results are shown in Figure 5.
Example 6:
(1) contains the synthetic of two key polylactic acid with step (1) in the example 1 and (2);
(2) under the room temperature, with medical grade polylactic acid (molecular weight 10,000), containing two key polylactic acid and DVB is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 30% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 50mg/ml, and the consumption of DVB is to contain 1% of two key polylactic acid weight.Bone morphogenetic protein is dissolved in the aqueous solution that contains 0.2% tween 20 joins in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, the W/O emulsion of formation in it being added the aqueous solution of 0.05% polyvinyl alcohol, obtains the W/O/W emulsion.The consumption of bone morphogenetic protein is 0.2% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 50;
(3) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 1000rmp, 40 ℃ of constant temperature are with (NH
4)
2S
2O
8With NaHSO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 12h;
(4) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
Gained the results are shown in Figure 6.
Example 7:
(1) contains the synthetic of two key polylactic acid with step (1) in the example 1 and (2);
(2) under the room temperature, with medical grade polylactic acid (molecular weight 10,000), containing two key polylactic acid and DVB is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 30% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 50mg/ml, and the consumption of DVB is to contain 1% of two key polylactic acid weight.Fibroblast growth factor is dissolved in the aqueous solution that contains 0.2% tween 20 joins in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, the W/O emulsion of formation in it being added the aqueous solution of 0.05% polyvinyl alcohol, obtains the W/O/W emulsion.The consumption of fibroblast growth factor is 0.1% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 50;
(3) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 1000rmp, 40 ℃ of constant temperature are with (NH
4)
2S
2O
8With Na
2SO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 12h;
(4) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
Gained the results are shown in Figure 7.
Example 8:
(1) contains the synthetic of two key polylactic acid with step (1) in the example 1 and (2);
(2) double bond containing deae dextran (MADdex) is synthetic with step (3) in the example 1;
(3) under the room temperature, with medical grade polylactic acid (molecular weight 100,000), containing two key polylactic acid and divinylbenzene is dissolved in the chloroform, the consumption of medical grade polylactic acid is to contain 20% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 17mg/ml, and the consumption of divinylbenzene is to contain 0.5% of two key polylactic acid weight.Fibroblast growth factor is dissolved in the aqueous solution that contains 0.2% tween 20 to join in the solution of above-mentioned organic solvent, behind the ultrasonic 0.5min, the W/O emulsion that forms in the aqueous solution that it is joined by the Triton x-100 preparation of MADdex and 0.05%, obtains the W/O/W emulsion.The consumption of MADdex is 50% of a polylactic acid gross weight, and the consumption of fibroblast growth factor is 0.15% of a polylactic acid gross weight, and the W/O/W volume ratio is 1: 5: 25;
(4) logical nitrogen and keep nitrogen atmosphere in the said vesse, mechanical agitation speed 600rmp, 40 ℃ of constant temperature are with K
2S
2O
8With NaHSO
3(1: 1 weight ratio, concentration is 0.02mg/ml in the water) adds in the above-mentioned system, reduces to room temperature rapidly behind the stirring 8h;
(5) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
Gained the results are shown in Figure 8.
Claims (10)
1. the degradable polymer microcapsule injecta of a water soluble drug is characterized in that it comprises water soluble drug, one or more mixture in medical grade polylactic acid, double bond containing polylactic acid and the double bond containing polysaccharide of coating water soluble drug.
2. the degradable polymer microcapsule injecta of water soluble drug according to claim 1, the particle diameter that it is characterized in that microcapsule is at 100～2000nm.
3. the degradable polymer microcapsule injecta of water soluble drug according to claim 1 is characterized in that said water soluble drug is ciprofloxacin hydrochloride, albumin, bone morphogenetic protein or fibroblast growth factor.
4. the degradable polymer microcapsule injecta of water soluble drug according to claim 1, the molecular weight that it is characterized in that the medical grade polylactic acid is 5,000～400,000.
5. the degradable polymer microcapsule injecta of water soluble drug according to claim 1 is characterized in that said double bond containing polysaccharide is grafting methacrylic acid or acrylic acid diethylin ethyl glucosan and chitosan.
6. the preparation method of the degradable polymer microcapsule injecta of water soluble drug according to claim 1 is characterized in that may further comprise the steps:
(1) with lactide and stannous chloride crystal grind into powder, adds a certain amount of allyloxy ethylene glycol, place reaction vessel, deoxygenation is towards nitrogen, closed container, wherein the consumption of stannous chloride is 0.8 of lactide weight～10 ‰, the mol ratio of lactide/allyloxy ethylene glycol is 6～300;
(2) above-mentioned reaction unit places 140～200 ℃ oil bath, and constant temperature is lowered the temperature after 4 hours at least, is that solvent, deionized water are precipitant with acetone, by dissolving-deposition and purification, remove impurity, 40 ℃ of vacuum dryings obtain double bond containing polylactic acid to constant weight or lyophilization;
(3) 0～40 ℃, pH value 2～8 times, with concentration is that methacrylic acid or the acrylic acid of 0.01-1g/ml is dissolved in the aqueous solution that contains the water solublity carbodiimide, the weight ratio of methacrylic acid or acrylic acid and carbodiimide is 1: 1.5～1: 10, after the stirring, polysaccharide solution dropwise is added dropwise in the above-mentioned solution, polysaccharide and methacrylic acid or acrylic acid weight ratio are 1: 0.2～1: 10, dropwise back constant temperature 0.5～2 round the clock, the gained solution centrifugal filters, and lyophilizing after placing tri-distilled water to dialyse 1～7 day, obtain double bond containing polysaccharide;
(4) under the room temperature, with the medical grade polylactic acid, contain two key polylactic acid and cross-linking agent is dissolved in the organic solvent, the consumption of medical grade polylactic acid is to contain 0～80% of two key polylactic acid weight, total polylactic acid concentration in organic solvent is 5～50mg/ml, and the consumption of cross-linking agent is to contain 0～20% of two key polylactic acid weight; After being dissolved in water soluble drug in the aqueous solution that contains 0.2% tween 20, join in the solution of above-mentioned organic solvent, ultrasonic after, form water/fat liquor; Again water/fat liquor is joined in the aqueous solution by polyvinyl alcohol that contains two key polysaccharide and 0.002～0.01mg/ml or Triton x-100 preparation, perhaps join in the aqueous solution of the polyvinyl alcohol of 0.002～0.01mg/ml or Triton x-100, obtain water/oil/aqueous emulsion, the consumption that contains two key polysaccharide is 0～50% of a polylactic acid gross weight, drug weight is 0.1～50% of a polylactic acid gross weight, water/oil/water volume ratio 1: 2: 4～1: 10: 50;
(5) logical nitrogen and keep nitrogen atmosphere in the said vesse stirs down 10～50 ℃ of constant temperature, water soluble oxidized is reduced initiator add in the above-mentioned system, stirs and reduces to room temperature at least after 2 hours rapidly;
(6) uncoveredly be stirred to organic solvent volatilization and finish lyophilization.
7. according to the preparation method of the degradable polymer microcapsule injecta of claims 6 described water soluble drugs, it is characterized in that said cross-linking agent is divinylbenzene or Polyethylene Glycol double methacrylate.
8. according to the preparation method of the degradable polymer microcapsule injecta of claims 6 described water soluble drugs, it is characterized in that said organic solvent is immiscible dichloromethane of water or chloroform in the step 4).
9. according to the preparation method of the degradable polymer microcapsule injecta of claims 6 described water soluble drugs, it is characterized in that said water soluble oxidized reduction initiator is K
2S
2O
8Or (NH
4)
2S
2O
8With NaHSO
3Or Na
2SO
3System.
10. according to the preparation method of the degradable polymer microcapsule injecta of claims 6 described water soluble drugs, it is characterized in that said polysaccharide is a kind of or its mixture in diethylin ethyl glucosan and the chitosan.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110150746A (en) * | 2018-02-13 | 2019-08-23 | 湖南中烟工业有限责任公司 | It is a kind of for reducing the core-shell structure copolymer capsule of main flume harmful components and its preparation and application |
| CN110150742A (en) * | 2018-02-13 | 2019-08-23 | 湖南中烟工业有限责任公司 | A kind of packet capsule with diuresis promoting function and its one-step shaping preparation method and the application in cigarette |
| CN114773766A (en) * | 2022-05-25 | 2022-07-22 | 深圳华宝协同创新技术研究院有限公司 | Gel material, preparation method thereof, tobacco material and cigarette without burning after heating |
| CN116832213A (en) * | 2023-07-11 | 2023-10-03 | 杭州帕莱拉医疗科技有限公司 | Preparation method of injectable dextran/poly-L-lactic acid interpenetrating network microsphere composite hydrogel filler |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126589A (en) * | 1995-06-09 | 1996-07-17 | 中国科学院成都有机化学研究所 | Injecta of delayed hormone microcapsule and its prepn |
| AU722289B2 (en) * | 1996-10-01 | 2000-07-27 | Aptalis Pharmatech, Inc. | Taste-masked microcapsule compositions and methods of manufacture |
| CN1140263C (en) * | 2001-02-28 | 2004-03-03 | 中国科学院大连化学物理研究所 | Medicine release-controlled microcapsule with dual-layer membrane and its preparing process |
-
2005
- 2005-09-28 CN CNB2005100609256A patent/CN100364517C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110150746A (en) * | 2018-02-13 | 2019-08-23 | 湖南中烟工业有限责任公司 | It is a kind of for reducing the core-shell structure copolymer capsule of main flume harmful components and its preparation and application |
| CN110150742A (en) * | 2018-02-13 | 2019-08-23 | 湖南中烟工业有限责任公司 | A kind of packet capsule with diuresis promoting function and its one-step shaping preparation method and the application in cigarette |
| CN114773766A (en) * | 2022-05-25 | 2022-07-22 | 深圳华宝协同创新技术研究院有限公司 | Gel material, preparation method thereof, tobacco material and cigarette without burning after heating |
| CN114773766B (en) * | 2022-05-25 | 2023-11-03 | 深圳华宝协同创新技术研究院有限公司 | Gel material and preparation method thereof, tobacco material and heating non-burning cigarette |
| CN116832213A (en) * | 2023-07-11 | 2023-10-03 | 杭州帕莱拉医疗科技有限公司 | Preparation method of injectable dextran/poly-L-lactic acid interpenetrating network microsphere composite hydrogel filler |
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|---|---|
| CN100364517C (en) | 2008-01-30 |
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