CN110101680A - A kind of preparation method for the PLGA biodegradable microspheres loading disulfiram drug - Google Patents
A kind of preparation method for the PLGA biodegradable microspheres loading disulfiram drug Download PDFInfo
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- CN110101680A CN110101680A CN201910392712.5A CN201910392712A CN110101680A CN 110101680 A CN110101680 A CN 110101680A CN 201910392712 A CN201910392712 A CN 201910392712A CN 110101680 A CN110101680 A CN 110101680A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The present invention provides a kind of preparation method of PLGA biodegradable microspheres for loading disulfiram drug, includes the following steps: that poly lactide-glycolide acid and disulfiram drug are dissolved in methylene chloride by (1), and acquired solution is transferred in syringe；(2) syringe needle of syringe is submerged in the water being vigorously stirred, water temperature is higher than methylene chloride boiling point, is then added drop-wise to disulfiram/PLGA mixed solution in water dropwise；(3) after being added dropwise to complete stirring gained lotion, obtain the microballoon of different-grain diameter, be classified, take micron order microballoon freeze-drying to get.This method combines the advantages of emulsion process and precipitation method, while avoiding respective disadvantage, and compared with emulsion process, this method stablizes emulsion droplet without using surfactant, avoids influence of the surfactant of microsphere surface absorption to drugloading rate；Compared with the precipitation method, water-miscible organic solvent is not used in this method, is avoided later period cumbersome removing step, is reduced dissolvent residual.
Description
Technical field
The present invention relates to a kind of preparation method of PLGA biodegradable microspheres, in particular to a kind of load disulfiram drug
The preparation method of PLGA biodegradable microspheres, belongs to field of biomedical polymer materials.
Background technique
Disulfiram (disulfiram, DSF) is used for more than 60 years as treatment alcohol addiction disease drug, is studied recently
It was found that disulfiram has very high specificity to tumour cell, tumour cell is only killed, normal cell is not injured.DSF energy
Tumor stem cell is killed in targeting, also not fully aware of at present to the mechanism of action of tumor stem cell.Disulfide bond in DSF molecule
It is easy to be destroyed by gluathione peptides reducing agent during blood transportation, half-life period in blood less than 4 minutes, makes DSF
It has just been inactivated before tumor tissues have not yet been reached.Nanoparticle-loaded DSF can slow down its degradation inactivation.Pass through liposome
Package can extend the half-life period of DSF in vivo, however 18 minutes half-life period of DSF liposome from clinical application there are also it is very long away from
From.Distinctive parent-hydrophobic the core-shell structure of macromolecule micelle can be effectively protected during blood conveys be carried on it is hydrophobic
DSF in core.The DSF of poly lactide-glycolide acid (PLGA) nanoparticle package has the half-life period up to 4 hours.
Due to the limited space in inside of DSF strong hydrophobicity and nanoparticle, it is difficult to largely load DSF.Document report
Drugloading rate of the DSF in nanoparticle it is all very low, generally 3% or less.PLGA microballoon has hollow spherical shell structure, wherein
Empty internal structure is greatly improved the load capacity of DSF drug.The PLGA microsphere surface of conventional emulsification method preparation is adsorbed with largely
Surfactant, although the surfactants of partial adsorbates can be removed by repeatedly washing, remove and be not thorough.
Surfactant can adsorb the DSF not being wrapping to inside microballoon, cause the drugloading rate of DSF higher, error is up to 50% or more.
Surfactant can not be had to precipitation method preparation PLGA microballoon.The precipitation method need for PLGA to be dissolved in miscible with water
Organic solvent (such as DMF and DMSO) obtains PLGA microballoon using the quick diffusion of water-miscible organic solvent in water, however,
Water-miscible organic solvent is difficult to remove completely, and the residual quantity in microballoon is high, is needed through cumbersome, complicated, prolonged processing
Process can just thoroughly remove.
Summary of the invention
Goal of the invention: high and heavy for the residual of surfactant existing for existing emulsion process height, microsphere surface drugloading rate
The high problem of Determination of Residual Organic Solvents existing for the method for shallow lake, it is micro- that the present invention provides a kind of PLGA biodegrade for loading disulfiram drug
The preparation method of ball.
Technical solution: a kind of preparation method for the PLGA biodegradable microspheres loading disulfiram drug of the present invention,
Include the following steps:
(1) poly lactide-glycolide acid (abbreviation PLGA) and disulfiram drug are dissolved in methylene chloride, and by gained
Solution is transferred in syringe；
(2) syringe needle of syringe is submerged in the water being vigorously stirred, water temperature is higher than methylene chloride boiling point, then by double sulphur
Logical sequence/PLGA mixed solution is added drop-wise in water dropwise；
(3) stirring gained lotion, obtains the microballoon of different-grain diameter after being added dropwise to complete, and to thus obtained microsphere classification, takes micron order
Microballoon freeze-drying is to get the PLGA biodegradable microspheres for loading disulfiram drug.
Preferably, in step (1), the intrinsic viscosity of poly lactide-glycolide acid is 0.1~0.5dL/g；Wherein,
The molar ratio of lactic acid and hydroxyacetic acid is 10:1~1:1.Further, poly lactide-glycolide acid and disulfiram drug
Methylene chloride is dissolved according to the mass ratio of 50:1~10:1.
In above-mentioned steps (2), the stirring rate that the water being vigorously stirred generally refers to water is more than or equal to 1000r/min.Into one
Step, water temperature is preferably 40~70 DEG C.Wherein, preferably meet such as between the solvent volume used in the volume and step (1) of water
Lower proportionate relationship: the volume ratio of methylene chloride and water is 1:100~1:10.
Preferably, in step (3), gained lotion is continuously stirred 1~5 hour after being added dropwise to complete, and obtains different-grain diameter
Microballoon, including nanoscale microballoon and micron order microballoon.The mode that membrane filtration thus obtained microsphere can be used divides thus obtained microsphere
Grade, can filter off nanoscale microballoon by filter membrane, micron order microballoon is obtained on filter membrane, and the micron order microballoon is then taken to be freeze-dried
?.
The utility model has the advantages that the preparation method of the PLGA biodegradable microspheres of load disulfiram drug of the invention combines emulsification
The common advantage and characteristic of method and the precipitation method is dissolved in dichloro by the mixed solution of the PLGA Biodegradable high molecular and disulfiram
It in methane and is transferred in syringe, syringe needle submerges in the water of certain temperature, and disulfiram/PLGA mixed solution is added dropwise
Microballoon is directly formed into water, while low-boiling methylene chloride can quickly volatilize；On the one hand, compared with emulsion process, the present invention
Whole preparation process in stablize emulsion droplet without using surfactant, avoid the surfactant pair of microsphere surface absorption
The influence of drugloading rate；On the other hand, compared with the precipitation method, water-miscible organic solvent is not used in whole preparation process of the invention,
Later period cumbersome removing step is avoided, dissolvent residual is reduced.
Detailed description of the invention
Fig. 1 is the SEM photograph of the PLGA biodegradable microspheres of the load disulfiram drug obtained of embodiment 1.
Specific embodiment
Technical solution of the present invention is described further below with reference to embodiment.
Embodiment 1
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 2:1) and disulfiram medicine that intrinsic viscosity is 0.15dL/g
Object is dissolved in methylene chloride according to the mass ratio of 15:1, and transfers the solution into syringe, and the syringe needle of syringe submerges 45 DEG C of plays
In the distilled water of strong stirring, distilled water stirring rate 1000r/min, under the control of metering pump, by disulfiram/PLGA mixing
Solution is added drop-wise in distilled water dropwise, and the volume ratio of methylene chloride and water is 1:45.It is small that lotion continuously stirred 4 after being added dropwise to complete
Shi Hou, the membrane filtration for being 1 micron with aperture can be obtained load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried
PLGA biodegradable microspheres, SEM picture such as Fig. 1.
Embodiment 2
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 1:1) and disulfiram medicine that intrinsic viscosity is 0.5dL/g
Object is dissolved in methylene chloride according to the mass ratio of 10:1, and transfers the solution into syringe, and the syringe needle of syringe submerges 70 DEG C of plays
In the distilled water of strong stirring, distilled water stirring rate 5000r/min, under the control of metering pump, by disulfiram/PLGA mixing
Solution is added drop-wise in distilled water dropwise, and the volume ratio of methylene chloride and water is 1:10.It is small that lotion continuously stirred 5 after being added dropwise to complete
Shi Hou, the membrane filtration for being 1 micron with aperture can be obtained load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried
PLGA biodegradable microspheres.The SEM figure that gained loads the PLGA biodegradable microspheres of disulfiram drug is close with Fig. 1.
Embodiment 3
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 5:1) and disulfiram medicine that intrinsic viscosity is 0.3dL/g
Object is dissolved in methylene chloride according to the mass ratio of 20:1, and transfers the solution into syringe, and the syringe needle of syringe submerges 50 DEG C of plays
In the distilled water of strong stirring, distilled water stirring rate 3000r/min, under the control of metering pump, by disulfiram/PLGA mixing
Solution is added drop-wise in distilled water dropwise, and the volume ratio of methylene chloride and water is 1:50.It is small that lotion continuously stirred 3 after being added dropwise to complete
Shi Hou, the membrane filtration for being 1 micron with aperture can be obtained load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried
PLGA biodegradable microspheres.The SEM figure that gained loads the PLGA biodegradable microspheres of disulfiram drug is close with Fig. 1.
Embodiment 4
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 3:1) and disulfiram medicine that intrinsic viscosity is 0.4dL/g
Object is dissolved in methylene chloride according to the mass ratio of 30:1, and transfers the solution into syringe, and the syringe needle of syringe submerges 55 DEG C of plays
In the distilled water of strong stirring, distilled water stirring rate 1500r/min, under the control of metering pump, by disulfiram/PLGA mixing
Solution is added drop-wise in distilled water dropwise, and the volume ratio of methylene chloride and water is 1:20.Lotion is continuously stirred 3.5 after being added dropwise to complete
After hour, the membrane filtration for being 1 micron with aperture can be obtained load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried
PLGA biodegradable microspheres.The SEM figure that gained loads the PLGA biodegradable microspheres of disulfiram drug is close with Fig. 1.
Embodiment 5
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 10:1) and disulfiram medicine that intrinsic viscosity is 0.1dL/g
Object is dissolved in methylene chloride according to the mass ratio of 50:1, and transfers the solution into syringe, and the syringe needle of syringe submerges 40 DEG C of plays
In the distilled water of strong stirring, distilled water stirring rate 2000r/min, under the control of metering pump, by disulfiram/PLGA mixing
Solution is added drop-wise in distilled water dropwise, and the volume ratio of methylene chloride and water is 1:100.Lotion is continuously stirred 1 after being added dropwise to complete
After hour, the membrane filtration for being 1 micron with aperture can be obtained load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried
PLGA biodegradable microspheres.The SEM figure that gained loads the PLGA biodegradable microspheres of disulfiram drug is close with Fig. 1.
Comparative example 1
The PLGA biodegradable microspheres of load disulfiram drug are prepared using conventional emulsification method:
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 2:1) and disulfiram medicine that intrinsic viscosity is 0.15dL/g
Object is dissolved in methylene chloride according to the mass ratio of 15:1, is slowly dropped into the water containing 2wt%PVA, the volume ratio of methylene chloride and water
For 1:45.After lotion is continuously stirred 4 hours after being added dropwise to complete, the membrane filtration for being 1 micron with aperture takes the microballoon on filter membrane
It can be obtained the PLGA biodegradable microspheres of load disulfiram drug after freeze-drying.
Comparative example 2
The PLGA biodegradable microspheres of load disulfiram drug are prepared using traditional precipitation method:
By the PLGA Biodegradable high molecular (LA and GA molar ratio are 2:1) and disulfiram medicine that intrinsic viscosity is 0.15dL/g
Object is dissolved in tetrahydrofuran according to the mass ratio of 15:1, disulfiram/PLGA mixed solution is added drop-wise in distilled water dropwise, tetrahydro
The volume ratio of furans and water is 1:45.After solution is continuously stirred 4 hours after being added dropwise to complete, the filter membrane mistake for being 1 micron with aperture
Filter can be obtained the PLGA biodegradable microspheres of load disulfiram drug after taking the microballoon on filter membrane to be freeze-dried.
The solvent on the PLGA biodegradable microspheres surface of measurement Examples 1 to 5 load disulfiram drug obtained is residual respectively
Allowance and the carrying drug ratio for being adsorbed on microsphere surface load disulfiram with made from 1~2 conventional emulsification method of comparative example and the precipitation method
The PLGA biodegradable microspheres of drug are compared, as a result such as the following table 1.
1 conventional emulsification method of table and the precipitation method with it is disclosed by the invention prepare micro-sphere method result compared with
Claims (8)
1. a kind of preparation method for the PLGA biodegradable microspheres for loading disulfiram drug, which comprises the steps of:
(1) poly lactide-glycolide acid and disulfiram drug are dissolved in methylene chloride, and acquired solution is transferred to injection
In device；
(2) syringe needle of syringe is submerged in the water being vigorously stirred, water temperature is higher than methylene chloride boiling point, then by disulfiram/poly-
The mixed solution of poly lactic coglycolic acid is added drop-wise in water dropwise；
(3) stirring gained lotion, obtains the microballoon of different-grain diameter after being added dropwise to complete, and to thus obtained microsphere classification, takes micron order microballoon
It is freeze-dried to get the PLGA biodegradable microspheres of load disulfiram drug.
2. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (1), the intrinsic viscosity of the poly lactide-glycolide acid is 0.1~0.5dL/g, and polylactic acid-glycolic base
In acetate multipolymer, the molar ratio of lactic acid and hydroxyacetic acid is 10:1~1:1.
3. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (1), the poly lactide-glycolide acid is dissolved in disulfiram drug according to the mass ratio of 50:1~10:1
Methylene chloride.
4. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (2), the water temperature is 40~70 DEG C.
5. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (2), described be vigorously stirred is more than or equal to 1000r/min for stirring rate.
6. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (2), the volume ratio of the methylene chloride and water is 1:100~1:10.
7. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In in step (3), gained lotion is continuously stirred 1~5 hour after being added dropwise to complete.
8. the preparation method of the PLGA biodegradable microspheres of load disulfiram drug according to claim 1, feature exist
In, in step (3), the method to thus obtained microsphere classification are as follows: membrane filtration thus obtained microsphere is used, nanoscale microballoon is filtered off,
Micron order microballoon is obtained on filter membrane.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516564A (en) * | 2011-12-16 | 2012-06-27 | 华中科技大学 | Soap-free preparation method of biodegradable polymer nanoparticles |
| EP2572708A1 (en) * | 2011-09-21 | 2013-03-27 | National Cheng Kung University | Method of preparation of biocompatible polymer nanocapsules for drug encapsulation |
| CN103690491A (en) * | 2013-10-14 | 2014-04-02 | 皖南医学院 | Preparation method of PEG-PLA/PLA composite drug loaded nanometer microballoon |
| CN107137350A (en) * | 2017-05-02 | 2017-09-08 | 辽宁大学 | A kind of taxol polymer micelle and preparation method thereof |
| CN108513543A (en) * | 2015-11-06 | 2018-09-07 | 胡弗汉顿大学 | disulfiram preparation |
-
2019
- 2019-05-13 CN CN201910392712.5A patent/CN110101680A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2572708A1 (en) * | 2011-09-21 | 2013-03-27 | National Cheng Kung University | Method of preparation of biocompatible polymer nanocapsules for drug encapsulation |
| CN102516564A (en) * | 2011-12-16 | 2012-06-27 | 华中科技大学 | Soap-free preparation method of biodegradable polymer nanoparticles |
| CN103690491A (en) * | 2013-10-14 | 2014-04-02 | 皖南医学院 | Preparation method of PEG-PLA/PLA composite drug loaded nanometer microballoon |
| CN108513543A (en) * | 2015-11-06 | 2018-09-07 | 胡弗汉顿大学 | disulfiram preparation |
| CN107137350A (en) * | 2017-05-02 | 2017-09-08 | 辽宁大学 | A kind of taxol polymer micelle and preparation method thereof |
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Application publication date: 20190809 |