CN102302441A - Method for preparing medicament-carrying polymer micro and nano fibers by using quick freezing technology - Google Patents
Method for preparing medicament-carrying polymer micro and nano fibers by using quick freezing technology Download PDFInfo
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- CN102302441A CN102302441A CN 201110256146 CN201110256146A CN102302441A CN 102302441 A CN102302441 A CN 102302441A CN 201110256146 CN201110256146 CN 201110256146 CN 201110256146 A CN201110256146 A CN 201110256146A CN 102302441 A CN102302441 A CN 102302441A
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Abstract
The invention discloses a method for preparing medicament-carrying polymer micro and nano fibers by using a quick freezing technology. The method comprises the following steps of: preparing medicament solution and polymer solution, preparing the medicament solution and the polymer solution into mixed solution in a certain ratio, fully dissolving medicaments in a polymer to obtain transparent homogeneous phase solution, putting the mixed solution into a proper container, quickly freezing the solution into solid by using liquid nitrogen, putting the frozen solid into a vacuum freeze dryer, performing continuous freeze drying to directly sublimate ice in the solid into water vapor, and thus obtaining the medicament-carrying polymer micro and nano fibers. According to the micro and nano fibers prepared by the method, the medicaments are mainly carried in the fibers or adsorbed on the surfaces of the fibers. The method is simple, quick, low in cost, and high in yield of the fibers with uniform shape; and the diameters of the fibers are of micro and nano scales, and the fibers have broad application prospect in medicament release.
Description
Technical field
Invention belongs to biological medicine and material technology field, is specifically related to the method that a kind of quick freezing technology prepares drug-carrying polymer micro-nano fiber.
Background technology
According to the common recognition of pathology educational circles, the capsule size of medicine and entrapped drug is more little, and medicine just is absorbed by the body more easily, and the surface area of pharmaceutical carrier is big more, and the rate of dispersion of drug particles is fast more.The diameter of axle ratio and the surface area of micro-nano fiber are bigger, utilize it as carrier material, and the drug slow ground that can make some be difficult to originally be absorbed by the body decomposes release, reaches therapeutic effect.Through uploading different pharmaceutical, polymer fiber can be widely used in the reconstruction of multiple treatment of diseases and body tissue.As above the fiber of carrying anti-tumor medicine can make the direct positioning action of chemotherapeutics in tumor cell; A lot of chemotherapeutics can not see through the shortcoming of some biological barrier when avoiding systemic chemotherapy; And when improving local drug concentration, increasing therapeutic effect, reduce toxic and side effects, be very suitable for the treatment of solid tumor; Iatric fiber is used for wound when treatment, because its absorbability and pliability preferably, thereby can absorb the transudate of wound, reduces the probability of superinfection.In a word, polymer fiber can be used for uploading multiple medicine and genes such as antineoplastic agent, depressor, antibiotic, analgesic, vaccine, thereby has the research and development prospect of treating and preventing multiple disease.
The present method for preparing the micro-nano fiber has many, and Chinese patent (CN101347403A) discloses a kind of method with the preparing organic metal compound anti-cancer medicine with electrostatic spinning technique fiber; Flat its of China Medicine University can be taught (the J.Controlled Release of seminar; 2007; 118,325-332.) utilization wet spinning technical research a kind of long-acting fluorouracil medicine carrier fibrous framework that supplies the body heeling-in, the result shows that drug loading and medicine carrying efficient are all higher.
But all there is certain defective in said method, requires medicine and polymer to have the specific molecule structure like self-assembling technique; Electrostatic spinning technique prepares the special instrument and equipment of fiber needs; There is bigger influence or the like in the size of wet spinning technology Chinese medicine to the diameter and the length of fiber.In view of the shortcoming that above method exists, the present invention intends and adopts the new method-quick freezing technology of preparation polymer nanofiber in the material science in recent years to prepare biocompatibility and biological degradability drug-carrying polymer micro-nano fiber.The method is simple, quick, need not special technology and equipment, obtains the fiber production height, uniform form, and fiber width is in micro-nano rank, in drug release, has broad application prospects.
Summary of the invention
The objective of the invention is for overcoming the deficiency of above-mentioned prior art, provide a kind of quick freezing technology to prepare the method for drug-carrying polymer micro-nano fiber, the purpose that it can reach sustained and controlled release medicament, improve drug bioavailability and reduce its toxic and side effects.
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
A kind of quick freezing technology prepares the method for drug-carrying polymer micro-nano fiber, and concrete steps are following:
(1) preparation of polymer solution: with water is that solvent preparation mass fraction is the polymer solution of 0.1-0.5%, after heated and stirred to polymer dissolves fully, places certain hour and makes its abundant swelling; Said polymer is selected from one or more the mixture in the following material: natural starch based, cellulose, plant gum, animal glue and alginate; Or semisynthetic carboxymethyl starch, hydroxy methocel, sodium carboxymethyl cellulose, or synthetic polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone;
(2) preparation of medicine and polymer mixed solution: with the polymer solution is solvent, and adding mass fraction is the water soluble drug of 1-50%, is stirred to medicine and is dissolved in the polymer solution fully; The ratio of polymer and medicine is 1: 1-9: 1;
(3) quick freezing: with behind the mixed solution mixing of step (2) gained in liquid nitrogen quick freezing;
(4) lyophilization: the continuous lyophilization of solid with step (3) after freezing is complete, obtains the polymer micro-nano fiber.
Among the present invention, the polymer solution described in the step (1), the effect the when mass ratio of polymer is 0.1-0.5% when water is solvent after the lyophilization is better, obtains uniform form easily, and diameter is in the fiber of micro/nano level.
The temperature of heating is 50-100 ℃ when stirring in described (1) step.
Mixing speed in described (1) step is 50-200 rev/min, and mixing time is 0.5-2.5h.
Placing after polymer in described (1) step dissolves fully and making its abundant swollen time is 12-48h.
In described (1) step, when polymer was two kinds, its mass ratio was 1: 9-9: 1.
Water soluble drug in described (2) step is one or more the mixture in 5-fluorouracil (5-Fu), metformin hydrochloride (MH), daunorubicin, doxorubicin, the gentamycin sulfate.The freezing efficiency of sample was better when the interface of liquid nitrogen will be higher than the interface of sample.
Low temperature in described (3) step is-196 ℃, and used medium is a liquid nitrogen; The time of solution in liquid nitrogen is 5-20 minute, and the interface of liquid nitrogen will be higher than the interface of sample, and guarantees that sample freezes fully, in low temperature, is frozen into solid.
The time that freeze solid is put into vacuum freeze drier in described (4) step is 24-72 hour, and the ice in the solid is directly sublimed into steam, guarantees the sample bone dry.
Among the present invention, products obtained therefrom can characterize its pattern and structure through means such as SEM, XRD, DSC, FTIR.The medicine release in vitro situation of products obtained therefrom can be measured through methods such as uv-visible absorption spectra method, HPLC.
The present invention starts with from the cross point of polymer science, material science and pharmaceutics; New method-quick freezing the technology of preparation polymer nanofiber in the polymer science is used for pharmaceutical preparation; Prepare biocompatibility and Biodegradable polymer drug-loading fibre with the method; And study its release in vitro result, polymer science and pharmaceutical preparation are combined closely; Measure through polymer supported drug fiber being carried out physicochemical properties, the formation mechanism of probing polymer drug-loading fibre is for polymer fiber provides theoretical foundation as pharmaceutical carrier.
The present invention can be through controlling polymers conditions such as concentration, drug level just can obtain other polymer fiber of micro/nano level, for the slow controlled release of realizing medicine provides a kind of new carrier.
The inventive method has simply, fast; Need not special technology and equipment; Production cost is lower; Obtain the fiber production height, uniform form, fiber width is in the micro-/ nano rank; The medicine response rate is high; Product is easy to advantages such as preservation, for commercial production provides reference value, in drug release, has broad application prospects.
Description of drawings
Fig. 1 is the SEM picture of 0.1%MH-PVA fiber;
Fig. 2 is the XRD figure sheet of 0.1%MH-PVA fiber; Wherein, a:MH, b:PVA, c:MH-PVA fiber;
Fig. 3 is the release profiles of 0.1%5-Fu-NaCMC fiber in the PBS of pH7.4 buffer;
Fig. 4 is the SEM picture of 25% NaCMC fiber for drug loading;
Fig. 5 is the SEM picture of 33% NaCMC fiber for drug loading;
Fig. 6 is the release behavior of fiber in the PBS of pH 7.4 buffer of different N aCMC/PVA ratio
The specific embodiment
Through the specific embodiment content of the present invention is further described below, but these embodiment do not limit protection scope of the present invention.
Embodiment 1:
(1) accurately measure PVA and water (mass ratio of PVA and water is 0.1%) with analytical balance after, place clean beaker, under 90 ℃, magnetic stirring apparatus effect, stir 2h; Mixing speed is 100 rev/mins; Dissolve fully to PVA, place 48h and make its abundant swelling, obtain PVA solution;
(2) accurately measure MH (mass ratio of MH and PVA is 25%) with analytical balance, be added in a certain amount of PVA solution, magnetic agitation 0.5h at room temperature, mixing speed is 100 rev/mins, dissolves fully to MH, obtains MH and PVA mixed solution;
(3) get MH and PVA mixed solution 10ml behind the mixing, inject the 100ml beaker, preservative film seals and is dazzling on preservative film, and sample was put into liquid nitrogen freezing 10 minutes, and the interface of liquid nitrogen will be higher than the interface of sample, and guarantees that sample freezes fully;
(4) solid after freezing is put into vacuum freeze drier; Continuous lyophilization 24h (thickness per sample, volume determine the cryodesiccated time); Ice in the solid is directly sublimed into steam, guarantees that the sample finish-drying is complete, take out and promptly get MH-PVA and tie up and receive fiber.
(5) products obtained therefrom characterizes its pattern and structure with means such as SEM, XRD, DSC, FTIR.The medicine release in vitro situation of products obtained therefrom can be measured through the uv-visible absorption spectra method.
(6) diameter of prepared MH-PVA fiber be 500nm to 1000nm, the SEM picture is shown in accompanying drawing 1, XRD result is shown in accompanying drawing 2.
Embodiment 2:
Replace " mass ratio of PVA and water is 0.1% " among the embodiment 1 (1) with " mass ratio of PVA and water is 0.5% ", all the other repeat (1)～(5) step among the embodiment 1, obtain medicine carrying PVA fibre diameter with quadrat method and arrive 1000nm at 600nm.
Embodiment 3:
(1) accurately measure NaCMC and water (mass ratio of NaCMC and water is 0.1%) with analytical balance after; Place clean beaker under magnetic agitation 60 ℃ stir 2h, mixing speed is 100 rev/mins, dissolves fully to NaCMC; Place 48h and make its abundant swelling, obtain NaCMC solution;
(2) accurately measure 5-Fu (mass ratio of 5-Fu is 14%) with analytical balance, join in a certain amount of NaCMC solution, room temperature magnetic agitation 0.5h, mixing speed is 100 rev/mins, dissolves fully to 5-Fu, obtains 5-Fu and NaCMC mixed solution; All the other repeat (3)～(5) step among embodiment 1, the diameter of prepared 5-Fu-NaCMC fiber be 500nm to 1200nm, the release behavior of prepared fiber in the PBS of pH 7.4 buffer is shown in accompanying drawing 3.Visible by figure, the polymer fiber of medicine carrying is slowly release in 12 hours, the low more drug release of drug loading slow more, and drug loading is that the cumulative percentage medicine realeasing rate of 14% fiber is about 40%.Medicine relies on the degraded and the corrosion of polymeric material in the regular hour, medicine is discharged lentamente.So, this fiber preparation can prolong drug action time, reduce administration number of times, thereby improve bioavailability of medicament, reduce the toxic and side effects of medicine.
Embodiment 4:
Replace " mass ratio of 5-Fu is 14% " among the embodiment 3 (1) with " mass ratio of 5-Fu is 25% "; All the other repeat (1)～(5) step among the embodiment 3; Obtain the 5-Fu-NaCMC fibre diameter with quadrat method and arrive 1200nm at 500nm, the SEM picture is shown in accompanying drawing 4.
Embodiment 5:
Replace " mass ratio of 5-Fu is 14% " among the embodiment 3 (1) with " mass ratio of 5-Fu is 33% "; All the other repeat (1)～(5) step among the embodiment 3; Obtain the 5-Fu-NaCMC fibre diameter with quadrat method and arrive 1200nm at 500nm; The release behavior of prepared fiber in the PBS of pH 7.4 buffer is shown in accompanying drawing 3, and the SEM picture is shown in accompanying drawing 5.
Embodiment 6:
Replace " mass ratio of NaCMC and water is 0.1% " among the embodiment 3 (1) with " mass ratio of NaCMC and water is 0.5% ",
All the other repeat (1)～(5) step among the embodiment 3, obtain the 5-Fu-NaCMC fibre diameter with quadrat method and arrive 1200nm at 600nm.
Embodiment 7:
Replace " NaCMC " among the embodiment 3 (1) with " sodium alginate ", all the other repeat (1)～(5) step among the embodiment 3, obtain 5-Fu-sodium alginate fibre diameter with quadrat method and arrive 1200nm at 500nm.
Embodiment 8:
(1) (total mass ratio of NaCMC/PVA and water is 0.1% accurately to measure NaCMC and PVA and water with analytical balance; The ratio of NaCMC/PVA is 1: 9) after; Place clean beaker to stir 2h down at 90 ℃; Mixing speed is 100 rev/mins; Dissolve fully to NaCMC and PVA; Place 48h and make its abundant swelling, obtain the NaCMC/PVA mixed solution;
(2) accurately measure 5-Fu (mass ratio of 5-Fu and total polymer is 25%) with analytical balance; Join in a certain amount of NaCMC/PVA solution, room temperature magnetic agitation 0.5h, mixing speed is 100 rev/mins; Dissolve fully to 5-Fu, obtain 5-Fu and NaCMC/PVA mixed solution; All the other repeat (3)～(5) step among the embodiment 1, and the diameter of prepared 5-Fu-NaCMC/PVA fiber is that 500nm is to 1000nm.
Embodiment 9:
Replace " ratio of NaCMC/PVA is 1: 9 " among the embodiment 8 (1) with " ratio of NaCMC/PVA is 3: 7 ", all the other repeat (1)～(5) step among the embodiment 8, obtain the 5-Fu-NaCMC/PVA fibre diameter with quadrat method and arrive 1000nm at 600nm.
Embodiment 10:
Replace " ratio of NaCMC/PVA is 1: 9 " among the embodiment 8 (1) with " ratio of NaCMC/PVA is 5: 5 "; All the other repeat (1)～(5) step among the embodiment 8; Obtain the 5-Fu-NaCMC/PVA fibre diameter with quadrat method and arrive 1200nm at 600nm, the release behavior of the fiber of different N aCMC/PVA ratio in the PBS of pH 7.4 buffer is shown in accompanying drawing 6.
Claims (8)
1. a quick freezing technology prepares the method for drug-carrying polymer micro-nano fiber, and concrete steps are following:
(1) preparation of polymer solution: with water is that solvent preparation mass fraction is the polymer solution of 0.1-0.5%, after heated and stirred to polymer dissolves fully, places and makes its abundant swelling; Said polymer is selected from one or more the mixture in the following material: natural starch based, cellulose, plant gum, animal glue and alginate; Or semisynthetic carboxymethyl starch, hydroxy methocel, sodium carboxymethyl cellulose, or synthetic polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone;
(2) preparation of medicine and polymer mixed solution: with the polymer solution is solvent, and adding mass fraction is the water soluble drug of 1-50%, is stirred to medicine and is dissolved in the polymer solution fully; The ratio of polymer and medicine is 1: 1-9: 1;
(3) quick freezing: with behind the mixed solution mixing of step (2) gained in liquid nitrogen quick freezing;
(4) lyophilization: the continuous lyophilization of solid with step (3) after freezing is complete, obtains the polymer micro-nano fiber.
2. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: the temperature of heating is 50-100 ℃ when stirring in described (1) step.
3. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: the mixing speed in described (1) step is 50-200 rev/min, and mixing time is 0.5-2.5h.
4. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: placing after the polymer in described (1) step dissolves fully and making its abundant swollen time is 12-48h.
5. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: in described (1) step, when polymer was two kinds, its mass ratio was 1: 9-9: 1.
6. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: the water soluble drug in described (2) step is one or more the mixture in 5-fluorouracil, metformin hydrochloride, daunorubicin, doxorubicin, the gentamycin sulfate.
7. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: the low temperature in described (3) step is-196 ℃, and used medium is a liquid nitrogen; The time of solution in liquid nitrogen is 5-20 minute, and the interface of liquid nitrogen will be higher than the interface of sample, and guarantees that sample freezes fully.
8. quick freezing technology as claimed in claim 1 prepares the method for drug-carrying polymer micro-nano fiber, it is characterized in that: the time that freeze solid is put into vacuum freeze drier in described (4) step is 24-72 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102943318A (en) * | 2012-11-28 | 2013-02-27 | 苏州大学 | polyvinyl alcohol (PVA)/sodium carboxy methylated cellulose (Na-CMC) nanofiber, preparation method and application |
| WO2014101743A1 (en) * | 2012-12-26 | 2014-07-03 | Li Hewei | Freeze-dried excipient and preparation method thereof |
-
2011
- 2011-09-01 CN CN 201110256146 patent/CN102302441A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 《International Journal of Pharmaceutics》 20110718 Xiaoqing Cai 《Sustained release of 5-fluorouracil by incorporation into sodium carboxymethylcellulose sub-micron fibers》 第2.2-2.3 1-8 第419卷, 第1-2期 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102943318A (en) * | 2012-11-28 | 2013-02-27 | 苏州大学 | polyvinyl alcohol (PVA)/sodium carboxy methylated cellulose (Na-CMC) nanofiber, preparation method and application |
| WO2014101743A1 (en) * | 2012-12-26 | 2014-07-03 | Li Hewei | Freeze-dried excipient and preparation method thereof |
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Application publication date: 20120104 |