CN102743337B - Nano-particulate medicinal composition and preparation method thereof - Google Patents
Nano-particulate medicinal composition and preparation method thereof Download PDFInfo
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- CN102743337B CN102743337B CN201110099898.9A CN201110099898A CN102743337B CN 102743337 B CN102743337 B CN 102743337B CN 201110099898 A CN201110099898 A CN 201110099898A CN 102743337 B CN102743337 B CN 102743337B
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Abstract
The invention provides a preparation method of a nano-particulate medicinal composition. The nano-particulate medicinal composition contains an amphiphilic polymer, a hydrophobic medicine and a hydrophilic medicine. The method comprises the following steps: 1, mixing and emulsifying a first solution and a second solution under supersonic wave radiation conditions to obtain a first emulsion, wherein the first solution contains the amphiphilic polymer and a first organic solvent, and the second solution contains the hydrophilic medicine and water; and 2, mixing the first emulsion with an aqueous solution of a first surfactant, mixing the resulting mixture with a third solution, and emulsifying to obtain a second emulsion, wherein the third solution contains the hydrophobic medicine and a second organic solvent. The invention also provides the nano-particulate medicinal composition obtained through preparing through the method, wherein the weight ratio of the hydrophobic medicine to the hydrophilic medicine is 1:10000-10000:1.
Description
Technical field
The present invention relates to the preparation method of a kind of pharmaceutical composition and pharmaceutical composition, particularly, relate to the preparation method of a kind of nanoparticle pharmaceutical composition and nanoparticle pharmaceutical composition.
Background technology
Nanometer medicine-carried system refers to that the particle diameter of medicine and nano-carrier formation, between the delivery system of 1-1000nm, comprises nanosphere, nanocapsule, nanoparticle and nanometer liposome etc.Nanometer medicine-carried system, compared with other medicines carrier, has significant advantage: (1) ultra micro small size, can pass through the blood capillary of human body minimum, and be difficult for being removed rapidly by phagocyte, extended the retention time in blood circulation; (2) arrive the reticuloendothelial system target sites such as concentrated liver, spleen, lung, bone marrow, lymph that distribute; (3) can penetrate tissue gap and by Cell uptake, be conducive to drug effect performance in Transdermal absorption and cell; (4) medicine can embedding or is bonded in inside nanoparticles, and also adsorbable or coupling is on its surface; (5) utilize the biodegradability of nano material itself, pH or temperature sensitivity etc., reach the effect that medicine control discharges; (6) improve the bioavailability of medicine and reduce toxic and side effects etc.
Nanoparticle is that one conventional in nanometer medicine-carried system is selected, and is typically used as the Polymer-supported medicine into pharmaceutical carrier, obtains nanoparticle pharmaceutical composition.But the nanoparticle pharmaceutical composition that the preparation method of current disclosed nanoparticle pharmaceutical composition obtains mostly is the nanoparticle pharmaceutical composition of a kind of medical compounds of load.As for hydrophilic medicament compound, mode by hydrophilic emulsifying loads on medical compounds on polymer, concrete grammar is: amphipathic nature polyalcohol is dissolved in organic solvent, and with the aqueous solution of hydrophilic medicament compound after under Ultrasonic Conditions, carry out emulsifying for the first time, material after emulsifying adds surfactant to carry out emulsifying for the second time for the first time, by the emulsion dispersion obtaining for the second time in aqueous surfactant solution and rotary evaporation remove organic solvent, after centrifugalize, obtain the nanoparticle compositions of load hydrophilic medicament compound.As for hydrophobic pharmaceutical compounds, mode by hydrophobicity emulsifying loads on medical compounds on amphipathic nature polyalcohol, concrete grammar is: the organic solution that is dissolved with medicine and amphipathic nature polyalcohol is slowly splashed into and contained in aqueous surfactant solution, after stirring certain hour, ultrasonic emulsification obtains emulsion, the emulsion rotary evaporation obtaining is removed to organic solvent, after centrifugalize, obtain the nanoparticle compositions of load hydrophobic pharmaceutical compounds.When load multi-medicament compound, if respectively by the mode of hydrophilic emulsifying or the mode of hydrophobicity emulsifying by compound loaded multi-medicament on polymer, in the nanoparticle pharmaceutical composition obtaining, content ratio between each medical compounds is difficult to control, and has limited the raising of the result of use of nanoparticle pharmaceutical composition.
Summary of the invention
The present inventor finds, different medical compoundss is due to hydrophilic and/or hydrophobicity difference, respectively by the mode of hydrophilic emulsifying or the mode of hydrophobicity emulsifying by compound loaded multi-medicament on amphipathic nature polyalcohol time, in the nanoparticle pharmaceutical composition obtaining, content ratio between each medical compounds can only be compared with close limit, and cannot adjust according to medication demand; But, if hydrophilic and/or the different medical compounds of hydrophobicity are loaded on described amphipathic nature polyalcohol by the multi-emulsion method with twice emulsifying step, just can according to medication demand, adjust in the nanoparticle pharmaceutical composition obtaining easily, content ratio between each medical compounds, obtains the present invention thus.
The invention provides a kind of preparation method of nanoparticle pharmaceutical composition, described nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and the method comprises the following steps:
(1) under Ultrasonic Radiation condition, the first solution is mixed and emulsifying with the second solution, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent, and described the second solution contains described hydrophilic medicament and water;
Described the first organic solvent be for can dissolve described amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
(2) by described the first emulsion and first surface activating agent aqueous solution, and mixed gained material is mixed with the 3rd solution and emulsifying, obtain the second emulsion;
Described the 3rd solution contains described hydrophobic drug and the second organic solvent;
Described the second organic solvent be for can dissolve described hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
(3) by described the second emulsion and second surface activating agent aqueous solution, and remove described the first organic solvent and described the second organic solvent, separate and obtain described nanoparticle pharmaceutical composition.
The present inventor also finds, if said method is changed into: using the aqueous solution of described amphipathic nature polyalcohol as the first solution, using the solution that contains described hydrophobic drug and described the second organic solvent as the second solution, and using the solution that contains described hydrophilic medicament and water as the 3rd solution, the result of use of described nanoparticle pharmaceutical composition will be reduced greatly.
Method provided by the invention, can adjust and make in nanoparticle compositions provided by the invention according to medication demand easily, the content ratio between the different medical compounds of hydrophilic and/or hydrophobicity.By above-mentioned adjustment, can utilize efficiently the peculiar advantage of nanometer medicine-carried system on administering mode, reach best compatibility of drugs result of use, especially can make being subject in the regional area of medicine target site, for example tumor occurs in site, and the different medical compounds of hydrophilic and/or hydrophobicity reaches best compatibility of drugs result of use.
The present inventor also finds, when described hydrophobic drug is paclitaxel, when described hydrophilic medicament is amycin, in the mode by single emulsifying by compound loaded multi-medicament on polymer time, in the nanoparticle pharmaceutical composition obtaining, the weight ratio of described hydrophobic drug and described hydrophilic medicament can only be located to be less than 1: 100000 or to be greater than in the scope of 100000: 1.
The present invention also provides a kind of nanoparticle pharmaceutical composition, this nanoparticle pharmaceutical composition is prepared by said method, wherein, described hydrophobic drug is paclitaxel, described hydrophilic medicament is amycin, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, and in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic medicament is 1: 10000-10000: 1.
Experimental results show that, above-mentioned nanoparticle pharmaceutical composition provided by the invention, with by the nanoparticle pharmaceutical composition of only paclitaxel loaded nanoparticle pharmaceutical composition and a load amycin, by paclitaxel, be 1 with the weight ratio of amycin: after 0.9-1.1 mixes, compared with the pharmaceutical composition that obtains, for tumors such as melanoma, pulmonary carcinoma and hepatocarcinoma, there is better therapeutic effect.
Other features and advantages of the present invention are described in detail the specific embodiment part subsequently.
Accompanying drawing explanation
Fig. 1 is the image of observing the nanoparticle pharmaceutical composition that embodiment 1 obtains under transmission electron microscope, and wherein, what labelling 1 marked is the core of nanoparticle, and what labelling 2 marked is the shell of nanoparticle.
Fig. 2 is the grain-size graph that laser particle analyzer records the nanoparticle pharmaceutical composition that embodiment 1 obtains.
Fig. 3 is that high performance liquid chromatography detects amycin in the nanoparticle pharmaceutical composition that obtains of embodiment 1 and the collection of illustrative plates of paclitaxel.
The specific embodiment
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is elaborated.Should be understood that, the specific embodiment described herein only, for description and interpretation the present invention, is not limited to the present invention.
The invention provides a kind of preparation method of nanoparticle pharmaceutical composition, described nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and the method comprises the following steps:
(1) under Ultrasonic Radiation condition, the first solution is mixed and emulsifying with the second solution, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent, and described the second solution contains described hydrophilic medicament and water;
Described the first organic solvent be for can dissolve described amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
(2) by described the first emulsion and first surface activating agent aqueous solution, and mixed gained material is mixed with the 3rd solution and emulsifying, obtain the second emulsion;
Described the 3rd solution contains described hydrophobic drug and the second organic solvent;
Described the second organic solvent be for can dissolve described hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
(3) by described the second emulsion and second surface activating agent aqueous solution, and remove described the first organic solvent and the second organic solvent, separate and obtain described nanoparticle pharmaceutical composition.
Wherein, in step (1), the volume ratio of described the first solution and described the second solution does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, the volume ratio of described the first solution and described the second solution is 1: 1-1: 10; More preferably 1: 2-1: 6, most preferably be 1: 4.
According to the present invention, in described the first solution, with respect to first organic solvent of every milliliter, the content of described amphipathic nature polyalcohol does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in described the first solution, with respect to first organic solvent of every milliliter, the content of described amphipathic nature polyalcohol is 5-100 milligram; More preferably 20-40 milligram.
According to the present invention, in described the second solution, with respect to the water of every milliliter, the content of described hydrophilic medicament does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in described the second solution, with respect to the water of every milliliter, the content of described hydrophilic medicament is 0.01-100 milligram; More preferably 0.1-50 milligram.
According to the present invention, in step (1), the selection of described amphipathic nature polyalcohol does not have special requirement, can be the selection of nanoparticle pharmaceutical composition preparation field routine, for example, described amphipathic nature polyalcohol is the polymer that simultaneously contains hydrophilic radical and hydrophobic group; Described hydrophilic radical can be polyglycol chain section and/or polyisobutylene acid segment, and described hydrophobic group can be one or more in polylactic acid-glycollic acid segment, polystyrene segment and polycaprolactone segment.It should be noted that, the arrangement mode of the repetitive of described amphipathic nature polyalcohol is requirement especially not, as long as being used to form nanoparticle pharmaceutical composition, can be for example one or more alternately, in block, random or grafting, also can be obtained by the monomer homopolymerization that contains hydrophilic radical and hydrophobic group; The molecular weight of described amphipathic nature polyalcohol does not have special requirement, and as long as being used to form nanoparticle pharmaceutical composition, the weight average molecular weight that for example described amphipathic nature polyalcohol records according to the method for SHT 1759-2007 regulation can be 10
4-10
5.
According to the present invention, in order to make described nanoparticle pharmaceutical composition can also have more special Targeting Performance and/or imaging performance, under preferable case, in step (1), described amphipathic nature polyalcohol also contains targeting group and/or imaging group.
Wherein, the selection of described targeting group and/or imaging group does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, further, under preferable case, described targeting group is one or more in folic acid group, essence-Gan-aspartic acid motif cyclic peptide (RGD) group and transferrins group etc.; Described imaging group is quantum dot group and/or fluorescent dye group.For example, described quantum dot group can be one or more in the nano materials such as golden quantum dot group, cadmium quantum dot group and palladium quantum dot group; Described fluorescent dye group can be one or more in Fluorescein isothiocyanate group, eosin disodium group and acid red 87 group.
Wherein, the not requirement especially of the content of described targeting group and/or imaging group can be the selection of nanoparticle pharmaceutical composition preparation field routine, for example, with respect to the hydrophilic radical of every mole, the content of described targeting group and/or imaging group can be 0.2-1 mole.
A preferred embodiment of the invention, in step (1), described amphipathic nature polyalcohol is one or more in MPEG-PLA-glycolic, poly(ethylene oxide)-poly(propylene oxide), Polyethylene Glycol and poly (l-lactic acid).
Wherein, the hydrophilic group of described MPEG-PLA-glycolic is poly glycol monomethyl ether group, hydrophobic group is polylactic acid-glycollic acid group, the arrangement mode of the repetitive of described MPEG-PLA-ethanol copolymer is block, wherein, mol ratio between ethylene glycol unit and lactic acid-ethanol unit can be 1: 1-8, the weight average molecular weight that described MPEG-PLA-ethanol copolymer records according to the method for SHT 1759-2007 regulation can be 10
4-10
5.MPEG-PLA-the ethanol copolymer that meets above-mentioned requirements can be by commercially available.
According to the present invention, the selection of described hydrophilic medicament does not have special requirement, can select by the dissolubility in water according to desired drug effect and medicine, for example, can be chosen in medicine that the dissolubility in water is greater than 1g/100g as hydrophilic medicament, under preferable case, described hydrophilic medicament is one or more in amycin, mitoxantrone, daunorubicin and epirubicin.
According to the present invention, the selection of described the first organic solvent does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition and to reduce costs, under preferable case, described the first organic solvent is one or more in dichloromethane, dimethyl sulfoxide, oxolane, acetone, espeleton, dichloro-benzenes and methyl isopropyl ketone.
According to the present invention, in step (1), the condition of described emulsifying does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (1), the condition of described emulsifying comprises: the frequency of Ultrasonic Radiation is 20-25kHz, more preferably 22-23kHz; With respect to every milliliter of material of accepting Ultrasonic Radiation, power is 10-190W, more preferably 28.5-57W; The temperature of emulsifying is 1-99 ℃, more preferably 20-30 ℃; The time of emulsifying is 1-30 minute, more preferably 3-10 minute.
Wherein, in step (1), the mode of described mixing does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (1), the mode of described mixing comprises: the second solution is joined in the first solution and mixed.
According to the present invention, in step (2), the consumption of described first surface activating agent aqueous solution and the consumption of described the 3rd solution do not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), with respect to the first emulsion of 1 volume, the consumption of described first surface activating agent aqueous solution is 0.5-2 volume, more preferably 0.8-1 volume; The consumption of described the 3rd solution is 0.1-1 volume, more preferably 0.4-0.6 volume.
Wherein, in step (2), in described first surface activating agent aqueous solution, the content of described first surface activating agent does not have special requirement, can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), in described first surface activating agent aqueous solution, the content of described first surface activating agent is 0.6-6 % by weight, more preferably 2-4 % by weight.
Wherein, in step (2), in described the 3rd solution, with respect to second organic solvent of every milliliter, the content of described hydrophobic drug does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), in described the 3rd solution, with respect to second organic solvent of every milliliter, the content of described hydrophobic drug can be 0.01 milligram to reach capacity in described the second organic solvent content of concentration of described hydrophobic drug, more preferably 0.1-10 milligram.
According to the present invention, in step (2), the selection of described first surface activating agent does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), described first surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate.
Wherein, the selection of described polyvinyl alcohol does not have special requirement, can be the selection of nanoparticle pharmaceutical composition preparation field routine, and for example, described polyvinyl alcohol can be pharmaceutical grade polyvinyl alcohol; The saponification degree of described polyvinyl alcohol can be 70-95mol%; The viscosity of described polyvinyl alcohol at 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be by commercially available, the product that for example can to buy from the trade mark of Chemical Reagent Co., Ltd., Sinopharm Group be PVA-124.
Wherein, the selection of described hydrophobic drug does not have special requirement, can select by the dissolubility in water according to desired drug effect and medicine, for example, can be chosen in medicine that the dissolubility in water is less than 1g/100g as hydrophobic drug, under preferable case, described hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and vinorelbine.
Wherein, in step (2), the condition of described emulsifying does not have special requirement, can select by the dissolubility in water according to desired drug effect and medicine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), the condition of described emulsifying comprises: the frequency of Ultrasonic Radiation is 20-25kHz, more preferably 22-23kHz; With respect to every milliliter of material of accepting Ultrasonic Radiation, power is 10-190W, more preferably 28.5-57W; The temperature of emulsifying is 1-99 ℃, more preferably 20-30 ℃; The time of emulsifying is 1-30 minute, more preferably 3-10 minute.
Wherein, in step (2), by in the process of described the first emulsion and described first surface activating agent aqueous solution, the mode of described mixing does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), by in the process of described the first emulsion and described first surface activating agent aqueous solution, the mode of described mixing comprises: under the stirring condition of turn at 100-1200/min, described the first emulsion is joined in described first surface activating agent aqueous solution and mixed, and the speed that described the first emulsion adds is 0.1-3ml/min.
Wherein, in step (2), mixed gained material is mixed with described the 3rd solution and emulsification in, the mode of described mixing does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), mixed gained material is mixed with described the 3rd solution and emulsification in, the mode of described mixing comprises: under the stirring condition of turn at 1000-1200/min, described the 3rd solution is joined in the mixed material of described gained, and the speed that described the 3rd solution adds is 0.1-1ml/min.
According to the present invention, in step (3), with respect to described second emulsion of 1 volume, the consumption of described second surface activating agent aqueous solution does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (3), with respect to described second emulsion of 1 volume, the consumption of described second surface activating agent aqueous solution is 2-20 volume, more preferably 10-15 volume.
Wherein, in step (3), in described second surface activating agent aqueous solution, the content of described second surface activating agent does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (3), in described second surface activating agent aqueous solution, the content of described second surface activating agent is 0.3-3 % by weight, more preferably 0.6-1 % by weight.
Wherein, in step (3), described second surface activating agent selects not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (3), described second surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate.
Wherein, the selection of described polyvinyl alcohol does not have special requirement, can be the selection of nanoparticle pharmaceutical composition preparation field routine, and for example, described polyvinyl alcohol can be pharmaceutical grade polyvinyl alcohol; The saponification degree of described polyvinyl alcohol can be 70-95mol%; The viscosity of described polyvinyl alcohol at 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be by commercially available, the product that for example can to buy from the trade mark of Chemical Reagent Co., Ltd., Sinopharm Group be PVA-124.
Wherein, in step (3), by in the process of described the second emulsion and second surface activating agent aqueous solution, the mode of described mixing does not have special requirement, it can be the selection of nanoparticle pharmaceutical composition preparation field routine, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (3), by in the process of described the second emulsion and second surface activating agent aqueous solution, the mode of described mixing comprises: under the stirring condition of turn at 100-1200/min, described the second emulsion is joined in described second surface activating agent aqueous solution, and the speed that described the second emulsion adds is 0.1-3ml/min, add after described the second emulsion, can under the stirring condition of turn at 100-1200/min, maintain 5-100min.
Wherein, in step (3), remove in the process of described the first organic solvent and the second organic solvent, described method of removing described the first organic solvent and the second organic solvent does not have special requirement, for example, can remove described the first organic solvent and the second organic solvent by the mode of rotary evaporation.
Wherein, in step (3), separation obtains in the process of described nanoparticle pharmaceutical composition, the method of described separation does not have special requirement, for example, can separate by the method for centrifugal and collecting precipitation (obtain be precipitated as described nanoparticle pharmaceutical composition).Wherein, centrifugal speed can be 5000-15000g.
The present invention also provides a kind of nanoparticle pharmaceutical composition, this nanoparticle pharmaceutical composition is prepared by said method, wherein, described hydrophobic drug is paclitaxel, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, described hydrophilic medicament is amycin, and in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic medicament is 1: 10000-10000: 1.
While experiment showed, described nanoparticle pharmaceutical composition for mice, with the amount of amycin, calculating, is 0.1-10mg/kg body weight through the effective dose of intravenously administrable.
In the present invention, the volume of gas and liquid is at 20 ℃, the numerical value that standard atmosphere is depressed.
Below, by embodiment, further describe the present invention, but scope of the present invention is not limited in following examples.
Embodiment 1
The present embodiment is prepared nanoparticle pharmaceutical composition according to following steps.
(1) by amphipathic nature polyalcohol (MPEG-PLA-glycolic of 20mg, PLGA-PEG, purchased from Dai Gang bio tech ltd, Jinan, the hydrophilic group of this MPEG-PLA-ethanol copolymer is poly glycol monomethyl ether group, hydrophobic group is polylactic acid-glycollic acid group, the arrangement mode of the repetitive of described MPEG-PLA-ethanol copolymer is block, wherein, mol ratio between ethylene glycol unit and lactic acid-ethanol unit is 1: 4, the weight average molecular weight recording according to the method for SHT 1759-2007 regulation is 1 × 10
5) be dissolved in 1ml the first organic solvent (dichloromethane), obtain the first solution.The hydrophilic medicament of 0.6mg (amycin, purchased from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) is dissolved in 1ml water, obtains the second solution.The second solution of 250 μ l is added in the first solution of 1ml, obtain mixed material.At 25 ℃, the Ultrasonic Radiation that is 23kHz by the frequency of 28.5W by the obtained above mixed material of 1ml, after 3 minutes, obtains the first emulsion.
(2) by first surface activating agent (polyvinyl alcohol, purchased from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124, saponification degree is 85mol%; Viscosity at 25 ℃ is 700mPas) be formulated as the aqueous solution of concentration 2%, obtain first surface activating agent aqueous solution.Under the stirring condition of turn 1000/min, the first emulsion that 1ml step (1) is obtained joins in 1ml first surface activating agent aqueous solution with the speed of 1ml/min, obtains mixed material.0.125mg hydrophobic drug (paclitaxel, purchased from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml the second organic solvent (dichloromethane), obtains the 3rd solution.Under the stirring condition of turn 1000/min, the 3rd solution obtained above of 0.25ml is added in mixed material obtained above with the speed of 1ml/min, obtain for ultrasonic material.At 25 ℃, the Ultrasonic Radiation that is 23kHz by the frequency of 57W for ultrasonic material obtained above 1ml, after 5 minutes, is obtained to the second emulsion.
(3) by second surface activating agent (polyvinyl alcohol, purchased from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124, saponification degree is 85mol%; Viscosity at 25 ℃ is 700mPas) be formulated as the aqueous solution of concentration 0.6%, obtain second surface activating agent aqueous solution.Under the stirring condition of turn 800/min, the second emulsion that 1ml step (2) is obtained joins in the above-mentioned second surface activating agent aqueous solution of 10ml with the speed of 2ml/min, under the stirring condition of then turn at 600-800/min, maintains 10min.At room temperature ℃, rotary evaporation is removed the first organic solvent (dichloromethane) and the second organic solvent (dichloromethane), obtains revolving the product after steaming.To revolve product after steaming under the centrifugal speed of 13000g after centrifugal 10 minutes, collecting precipitation, obtains nanoparticle pharmaceutical composition.
According to document (Ashlynn L.Z.Lee, Deng. biomaterial (Biomaterials) 2009,30, method 919-927) is observed the nanoparticle pharmaceutical composition that the present embodiment obtains under transmission electron microscope, and result as shown in Figure 1, wherein, what labelling 1 marked is the core of nanoparticle, and what labelling 2 marked is the shell of nanoparticle, illustrates that the size of the nanoparticle pharmaceutical composition obtaining is about 200nm.
According to document (Ashlynn L.Z.Lee, Deng. biomaterial (Biomaterials) 2009,30, method 919-927), the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that the present embodiment obtains is 243.63 ± 12.36nm (Fig. 2), dispersion is that 0.131, zeta current potential is-21.6 ± 0.14, shows that this nanoparticle pharmaceutical composition stability is better.
According to document (Ashlynn L.Z.Lee, Deng. biomaterial (Biomaterials) 2009,30, method 919-927), after the nanoparticle pharmaceutical composition lyophilization that the present embodiment is obtained, with acetonitrile, dissolve, (standard substance are purchased from Agilent Technologies to utilize high performance liquid chromatography detection, trade mark Agilent1200series), can find out that nanoparticle pharmaceutical composition that the present embodiment obtains has the characteristic peak (Fig. 3) of amycin and paclitaxel simultaneously.Illustrate in the nanoparticle pharmaceutical composition that amycin and paclitaxel obtain at the present embodiment and exist simultaneously, and in the nanoparticle pharmaceutical composition that obtains of the present embodiment of every gram, the content of amycin is 0.15g, the content of paclitaxel is 0.075g.
Comparative example 1
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with embodiment 1, difference is: by amphipathic nature polyalcohol (MPEG-PLA-ethanol copolymer of 20mg, PLGA-PEG, purchased from Dai Gang bio tech ltd, Jinan) be dissolved in 1ml water, the solution obtaining is as the first solution; 0.125mg hydrophobic drug (paclitaxel, purchased from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml the second organic solvent (dichloromethane), and the solution obtaining is as the second solution; The hydrophilic medicament of 0.6mg (amycin, purchased from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) is dissolved in 1ml water, and the solution obtaining is as the 3rd solution.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0.05g, and the content of paclitaxel is 0g.
Comparative example 2
According to following steps, prepare nanoparticle pharmaceutical composition.
(1) by amphipathic nature polyalcohol MPEG-PLA-ethanol copolymer of 20mg, PLGA-PEG, purchased from Dai Gang bio tech ltd, Jinan) be dissolved in 1ml the first organic solvent (dichloromethane), obtain the first solution.The hydrophilic medicament of 0.6mg (amycin, purchased from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) is dissolved in 1ml water, obtains the second solution.The aqueous solution that first surface activating agent (polyvinyl alcohol, purchased from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124) is formulated as to concentration 2 % by weight, obtains first surface activating agent aqueous solution.0.125mg hydrophobic drug (paclitaxel, purchased from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml the second organic solvent (dichloromethane), obtains the 3rd solution.
Under the stirring condition of turn 1000/min, by the first solution obtained above, the second solution obtained above, the 3rd solution obtained above, first surface activating agent aqueous solution obtained above, obtain for ultrasonic material.At 25 ℃, by the Ultrasonic Radiation that is first 23kHz by the frequency of 28.5W for ultrasonic material obtained above 1ml after 3 minutes, then the Ultrasonic Radiation that is 23kHz by the frequency of 57W 3 minutes, obtain the second emulsion.
(2) second surface activating agent (polyvinyl alcohol, purchased from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124) is formulated as to the aqueous solution of concentration 0.6 % by weight, obtains second surface activating agent aqueous solution.Under the stirring condition of turn 1000/min, the second emulsion that 1ml step (1) is obtained joins in the above-mentioned second surface activating agent aqueous solution of 10ml with the speed of 1ml/min, under the stirring condition of then turn at 600-800/min, maintains 10min.At room temperature, rotary evaporation 10min, removes the first organic solvent (dichloromethane) and the second organic solvent (dichloromethane), obtains revolving the product after steaming.To revolve product after steaming under the centrifugal speed of 13000g after centrifugal 10 minutes, collecting precipitation, obtains nanoparticle pharmaceutical composition.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0g, and the content of paclitaxel is 0.02g.
The present embodiment is prepared nanoparticle pharmaceutical composition according to the method identical with embodiment 1, and difference is, in described the second solution, the concentration of amycin is 0.4mg/ml, and in described the 3rd solution, the concentration of paclitaxel is 10mg/ml.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that the present embodiment obtains is 243nm; The content that records amycin in the nanoparticle pharmaceutical composition that the present embodiment of every gram obtains is 0.0005g, and the content of paclitaxel is 0.5g.
Comparative example 3
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with comparative example 2, and difference is, in described the second solution, the concentration of amycin is 0.4mg/ml, and in described the 3rd solution, the concentration of paclitaxel is 10mg/ml.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0g, and the content of paclitaxel is 0.1g.
Embodiment 3
The present embodiment is prepared nanoparticle pharmaceutical composition according to the method identical with embodiment 1, and difference is, in described the second solution, the concentration of amycin is 10mg/ml, and in described the 3rd solution, the concentration of paclitaxel is 0.4mg/ml.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that the present embodiment obtains is 260nm; The content that records amycin in the nanoparticle pharmaceutical composition that the present embodiment of every gram obtains is 0.47g, and the content of paclitaxel is 0.00047g.
Comparative example 4
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with comparative example 2, and difference is, in described the second solution, the concentration of amycin is 10mg/ml, and in described the 3rd solution, the concentration of paclitaxel is 0.4mg/ml.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0g, and the content of paclitaxel is 0.0002g.
Comparative example 5
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with comparative example 2, and difference is do not use the 3rd solution, and in the second solution, the use amount of amycin to be 3.5mg.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0.3g, and the content of paclitaxel is 0g.
Comparative example 6
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with comparative example 2, and difference is not use the second solution; And described paclitaxel is replaced by paclitaxel (the FITC-paclitaxel of Fluorescein isothiocyanate coupling, purchased from Nanjing, seek Bioisystech Co., Ltd, trade mark TQSJ010), and with the weighing scale of paclitaxel part, in the 3rd solution, the use amount of FITC-paclitaxel is 1.5mg.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0g, and with the weighing scale of paclitaxel part, the content of FITC-paclitaxel is 0.15g.
According to the identical method making with embodiment 1, prepare nanoparticle pharmaceutical composition, difference is, described paclitaxel is replaced by the paclitaxel (FITC of Fluorescein isothiocyanate coupling, purchased from Nanjing, seek Bioisystech Co., Ltd, trade mark TQSJ010), and with the weighing scale of paclitaxel part, in the 3rd solution, the use amount of FITC-paclitaxel is 0.125mg.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 243nm; The content that records amycin in the nanoparticle pharmaceutical composition that the present embodiment of every gram obtains is 0.15g, and with the weighing scale of paclitaxel part, the content of FITC-paclitaxel is 0.075g.The nanoparticle pharmaceutical composition that the present embodiment is obtained is as Experimental agents.
The weight such as the nanoparticle pharmaceutical composition that the nanoparticle pharmaceutical composition that comparative example 5 is obtained and comparative example 6 obtain are mixed, and the content that obtains amycin is that the content of 15 % by weight and FITC-paclitaxel is the nanoparticle pharmaceutical composition mixture of 7.5 % by weight.By this nanoparticle pharmaceutical composition mixture medicine in contrast.
Culture dish 10 by lung carcinoma cell (A549 cell line, purchased from ATCC, is numbered CCL-185) with every 35mm internal diameter
3individual density is inoculated in respectively the DMEM culture medium (purchased from Gibco, trade mark sh30022.01B) that contains 2ml, and containing the hyclone of 10 volume %) two culture dishs in, at the CO of 37 ℃ and 5 volume %
2under concentration, cultivate after 24 hours, sucking-off culture medium, the culture medium that 2ml is dissolved with to Experimental agents is (in amycin, drug level is 0.17 μ mol/ml) add wherein in a culture dish, the culture medium that 2ml is dissolved with to control drug is (in amycin, drug level is 0.17 μ mol/ml) add in another culture dish the CO by above-mentioned 2 culture dishs at 37 ℃ and 5 volume %
2under concentration, hatch after 2 hours, sucking-off culture medium, with phosphate buffer (purchased from Gibco, trade mark P1020-500) washing 3 times (each 5ml), and use fluorescence microscope imaging, can find, use in the culture dish of Experimental agents, in nucleus, presenting and in redness and Cytoplasm, presenting in the shared visual field of green cell all ratios of cells is 100%, and in the culture dish of use control drug, this ratio is only 48%, and use in the culture dish of Experimental agents, in nucleus, present and in redness and Cytoplasm, present the ratio homogeneous more between red fluorescence intensity and green fluorescence intensity in green cell.
Itself carries fluorescence amycin, under green glow excites, can show HONGGUANG.FITC-paclitaxel can show green glow under blue-light excited.Therefore, the above results illustrative experiment medicine can make cell absorb amycin and paclitaxel simultaneously, and the ratio homogeneous more of picked-up, thereby has better compatibility of drugs result of use.
Comparative example 7
This comparative example is prepared nanoparticle pharmaceutical composition according to the method identical with comparative example 2, and difference is do not use the second solution, and in the 3rd solution, the use amount of paclitaxel to be 2mg.
According to the measuring method identical with embodiment 1, the particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that this comparative example obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this comparative example of every gram obtains is 0g, and the content of paclitaxel is 0.15g.
In the present embodiment, embodiment 1 is made to nanoparticle pharmaceutical composition as Experimental agents; The nanoparticle medicine mixed in equal amounts that the nanoparticle pharmaceutical composition that comparative example 5 is obtained and comparative example 7 obtain, the content that obtains amycin is 15 % by weight, the content of paclitaxel is the nanoparticle pharmaceutical composition mixture of 7.5 % by weight.By this nanoparticle pharmaceutical composition mixture medicine in contrast.
Culture dish 10 by lung carcinoma cell (A549 cell line, purchased from ATCC, is numbered CCL-185) with every 35mm internal diameter
3individual density is inoculated in respectively in two culture dishs of the DMEM culture medium that contains 2ml (purchased from Gibco, trade mark sh30022.01B, and containing the hyclone of 10 volume %), at the CO of 37 ℃ and 5 volume %
2under concentration, cultivate after 24 hours, sucking-off culture medium, the culture medium that 2ml is dissolved with to Experimental agents is (in amycin, drug level is 0.17 μ mol/ml) add wherein in a culture dish, the culture medium that 2ml is dissolved with to control drug is (in amycin, drug level is 0.17 μ mol/ml) add in another culture dish, by above-mentioned 2 culture dishs at 37 ℃ and 5% CO
2under concentration, hatch after 24 hours, according to the CCK-8 method described in document (Qinghua Miao, etc., biomaterial (Biomaterials), 2010,31 (28): 7364-75), detect Level of Apoptosis.Can find, use in the culture dish of Experimental agents, cytoactive is 32.88 ± 3%, uses in the culture dish of control drug, and cytoactive is 64.95 ± 3.4%.The above results illustrative experiment medicine has stronger short apoptosis effect to lung carcinoma cell.
Use hepatoma carcinoma cell (HepG2 cell line, purchased from ATCC, is numbered HB-8065) to carry out above-mentioned identical experiment, can find, use in the culture dish of Experimental agents, cytoactive is 17.7 ± 4.7%, use in the culture dish of control drug, cytoactive is 68.6 ± 15.3%.The above results explanation illustrative experiment medicine has stronger short apoptosis effect to hepatoma carcinoma cell.
Use melanoma cell (B16 cell line, purchased from ATCC, is numbered B16-F10) to carry out above-mentioned identical experiment, can find, use in the culture dish of Experimental agents, cytoactive is 34.68 ± 1.2%, use in the culture dish of control drug, cytoactive is 76.23 ± 2.7%.The above results explanation illustrative experiment medicine has stronger short apoptosis effect to melanoma cell.
Use melanoma cell (B16 cell line, purchased from ATCC, numbering B16-F10) and nude mice (BALB/c-nu system, purchased from Beijing dimension tonneau China company), according to document, (Fariyal Ahmed, learns (Molecular Pharmaceutics) etc. molecular medicine, 3, method 340-350) is prepared tumor bearing nude mice, treats that tumor grows to 0.5cm
2during size, tumor bearing nude mice is divided into experimental group tumor bearing nude mice and matched group tumor bearing nude mice at random, according to the method in document (the same), through tail vein, the phosphate buffer (in amycin, dosage is 3mg/kg body weight) that is dissolved with Experimental agents is administered to experimental group tumor bearing nude mice; The phosphate buffer (in amycin, dosage is 3mg/kg body weight) that is dissolved with control drug is administered to matched group tumor bearing nude mice.After one week, according to document, (Fariyal Ahmed, learns (Molecular Pharmaceutics) etc. molecular medicine, 3, method 340-350) is measured the size of tumor, wherein, and the tumor size average out to 0.34cm of experimental group tumor bearing nude mice
2, the tumor size average out to 0.76cm of matched group tumor bearing nude mice
2.The above results explanation illustrative experiment medicine has stronger inhibition to melanoma.
Use hepatoma carcinoma cell (HepG2 cell line, purchased from ATCC, is numbered HB-8065) to carry out above-mentioned identical experiment, the tumor size average out to 0.22cm of experimental group tumor bearing nude mice
2, the tumor size average out to 0.65cm of matched group tumor bearing nude mice
2.The above results explanation illustrative experiment medicine has stronger inhibition to hepatocarcinoma.
Use lung carcinoma cell (A549 cell line, purchased from ATCC, is numbered CCL-185) to carry out above-mentioned identical experiment, the tumor size average out to 0.42cm of experimental group tumor bearing nude mice
2, the tumor size average out to 1.02cm of matched group tumor bearing nude mice
2.The above results explanation illustrative experiment medicine has stronger inhibition to hepatocarcinoma.
Claims (6)
1. a preparation method for nanoparticle pharmaceutical composition, described nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and the method comprises the following steps:
(1) under Ultrasonic Radiation condition, the first solution is mixed and emulsifying with the second solution, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent, and described the second solution contains described hydrophilic medicament and water;
Described amphipathic nature polyalcohol is one or more in MPEG-PLA-glycolic, poly(ethylene oxide)-poly(propylene oxide), Polyethylene Glycol and poly (l-lactic acid);
Described the first organic solvent be for can dissolve described amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
Described hydrophilic medicament is one or more in amycin, mitoxantrone, daunorubicin and epirubicin;
The volume ratio of described the first solution and described the second solution is 1:1-1:10; In described the first solution, with respect to first organic solvent of every milliliter, the content of described amphipathic nature polyalcohol is 5-100 milligram; In described the second solution, with respect to the water of every milliliter, the content of described hydrophilic medicament is 0.01-100 milligram;
(2) by described the first emulsion and first surface activating agent aqueous solution, and mixed gained material is mixed with the 3rd solution and emulsifying, obtain the second emulsion;
Described first surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate;
Described the 3rd solution contains described hydrophobic drug and the second organic solvent;
Described hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and vinorelbine;
Described the second organic solvent be for can dissolve described hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of described amphipathic nature polyalcohol, described hydrophobic drug and described hydrophilic medicament generation chemical reaction;
With respect to described first emulsion of 1 volume, the consumption of described first surface activating agent aqueous solution is 0.5-2 volume, and the consumption of described the 3rd solution is 0.1-1 volume; In described first surface activating agent aqueous solution, the content of described first surface activating agent is 0.6-6 % by weight; In described the 3rd solution, with respect to second organic solvent of every milliliter, the content of described hydrophobic drug be 0.01 milligram to reach capacity in described the second organic solvent content of concentration of described hydrophobic drug;
(3) by described the second emulsion and second surface activating agent aqueous solution, and remove described the first organic solvent and described the second organic solvent, separate and obtain described nanoparticle pharmaceutical composition;
Described second surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate;
With respect to described second emulsion of 1 volume, the consumption of described second surface activating agent aqueous solution is 2-20 volume; In described second surface activating agent aqueous solution, the content of described second surface activating agent is 0.3-3 % by weight.
2. method according to claim 1 and 2, wherein, in step (1), described amphipathic nature polyalcohol also contains targeting group and/or imaging group; Described targeting group is one or more in essence-Gan-aspartic acid motif cyclic peptide group, folic acid group and transferrins group; Described imaging group is quantum dot group and/or fluorescent dye group.
3. method according to claim 1, wherein, in step (1), described the first organic solvent is one or more in dichloromethane, dimethyl sulfoxide, oxolane, acetone, espeleton, dichloro-benzenes and methyl isopropyl ketone.
4. method according to claim 1, wherein, in step (1), the condition of described emulsifying comprises: the frequency of Ultrasonic Radiation is 20-25kHz, with respect to every milliliter of material of accepting Ultrasonic Radiation, power is 10-190W; The temperature of emulsifying is 1-99 ℃, and the time of emulsifying is 1-30 minute.
5. method according to claim 1, wherein, in step (2), the condition of described emulsifying comprises: the frequency of Ultrasonic Radiation is 20-25kHz, with respect to every milliliter of material of accepting Ultrasonic Radiation, power is 10-190W; The temperature of emulsifying is 1-99 ℃, and the time of emulsifying is 1-30 minute.
6. a nanoparticle pharmaceutical composition, this nanoparticle pharmaceutical composition is prepared by the method described in any one in claim 1-5, wherein, described hydrophobic drug is paclitaxel, described hydrophilic medicament is amycin, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, and in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic medicament is 1:10000-10000:1.
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| CN103142482B (en) * | 2011-12-06 | 2014-09-24 | 国家纳米科学中心 | Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition |
| CN103766351B (en) * | 2014-02-14 | 2015-11-04 | 国家纳米科学中心 | A kind of nano pesticide composition and method of making the same |
| CN103861112B (en) * | 2014-03-25 | 2015-12-30 | 国家纳米科学中心 | Based on the pharmaceutical composition and preparation method thereof of polymer nano-particle carrier |
| CN103893123B (en) * | 2014-04-21 | 2016-04-06 | 国家纳米科学中心 | A kind of lipid-polymer hybridized nanometer particle and its preparation method and application |
| CN104225614B (en) * | 2014-09-22 | 2016-11-30 | 北京航空航天大学 | With chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule and preparation method thereof |
| CN104856960B (en) * | 2015-04-27 | 2018-01-05 | 国家纳米科学中心 | A kind of amphipathic nature polyalcohol contains nano-particle of iron chelating agent and its preparation method and application |
| CN107308458B (en) * | 2017-06-20 | 2020-12-29 | 国家纳米科学中心 | Targeted hybrid nano system and preparation method and application thereof |
| CN108245484B (en) * | 2017-12-27 | 2020-02-21 | 国家纳米科学中心 | Nano-medicine composition and preparation method and application thereof |
| CN110170057A (en) * | 2019-04-08 | 2019-08-27 | 嘉兴市第二医院 | A kind of nanometer grain preparation method of the double medicines of the load of Tf modification and its application |
| CN113082219B (en) * | 2021-04-07 | 2023-02-17 | 中国科学院大学温州研究院(温州生物材料与工程研究所) | Solubilization method of hydrophobic drug based on pi-pi effect |
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