CN103142482A - Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition - Google Patents
Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition Download PDFInfo
- Publication number
- CN103142482A CN103142482A CN2011104024209A CN201110402420A CN103142482A CN 103142482 A CN103142482 A CN 103142482A CN 2011104024209 A CN2011104024209 A CN 2011104024209A CN 201110402420 A CN201110402420 A CN 201110402420A CN 103142482 A CN103142482 A CN 103142482A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- aqueous solution
- organic solvent
- nanoparticle pharmaceutical
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method for a nanoparticle pharmaceutical composition. The method comprises the following steps of (1) mixing and emulsifying a first solution with an aqueous solution of hydrophilic small molecule drugs to obtain a first emulsion, wherein the first solution comprises an amphiphilic polymer and a first organic solvent; (2) mixing the first emulsion with an aqueous solution of a first surfactant, mixing the mixed materials with a second solution and an aqueous solution of a cationic polymer and emulsifying to obtain a second emulsion, wherein the second solution contains hydrophobic drugs and a second organic solvent; (3) mixing the second emulsion with an aqueous solution of a second surfactant, carrying out centrifugal separation to obtain a precipitate; and (4) dissolving the precipitate in water and mixing the dissolved precipitate with nucleic acid drugs, and separating to obtain the nanoparticle pharmaceutical composition. The invention also provides the nanoparticle pharmaceutical composition prepared by the above method.
Description
Technical field
The present invention relates to the nanoparticle drug world, particularly, the nanoparticle pharmaceutical composition that relates to a kind of preparation method of nanoparticle pharmaceutical composition and prepared by the method.
Background technology
Nanometer medicine-carried system refers to the delivery system of the particle diameter of medicine and nano-carrier formation between 1-1000nm, comprises nanosphere, nanocapsule, nanoparticle and nanometer liposome etc.Nanometer medicine-carried system is compared with the 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 the penetrate tissue gap and by Cell uptake, be conducive to drug effect performance in Transdermal absorption and cell; (4) but medicine embedding or be bonded in inside nanoparticles, also adsorbable or coupling is on its surface; (5) utilize the biodegradability of nano material itself, pH or temperature sensitivity etc., reach medicine and control the effect discharged; (6) improve the bioavailability of medicine and reduce toxic and side effects etc.
Nanoparticle is a kind of selection commonly used in nanometer medicine-carried system, is typically used as the Polymer-supported medicine into pharmaceutical carrier, obtains the 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 the hydrophilic small molecules medical compounds, 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 small molecules medical compounds after carry out emulsifying for the first time under Ultrasonic Conditions, material after emulsifying adds surfactant to carry out emulsifying for the second time for the first time, by the emulsion dispersion that obtains for the second time in aqueous surfactant solution and rotary evaporation remove organic solvent, obtain the nanoparticle compositions of load hydrophilic small molecules medical compounds after centrifugalize.As for hydrophobic pharmaceutical compounds, mode by hydrophobicity emulsifying loads on medical compounds on amphipathic nature polyalcohol, concrete grammar is: the organic solution that will be dissolved with medicine and amphipathic nature polyalcohol slowly splashes into and contains in aqueous surfactant solution, after stirring certain hour, ultrasonic emulsification obtains emulsion, the emulsion rotary evaporation obtained is removed to organic solvent, obtain the nanoparticle compositions of load hydrophobic pharmaceutical compounds after centrifugalize.When load multi-medicament compound, if the mode respectively by hydrophilic emulsifying or the mode of hydrophobicity emulsifying are compound loaded on polymer by multi-medicament, in the nanoparticle pharmaceutical composition obtained, content ratio between each medical compounds is difficult to control, and has limited the raising of the result of use of nanoparticle pharmaceutical composition.
Therefore, there is the unmanageable defect of content ratio between each medical compounds in existing nanoparticle pharmaceutical composition.
Summary of the invention
There is the unmanageable defect of content ratio between each medical compounds in order to overcome existing nanoparticle pharmaceutical composition, the invention provides and can control the preparation method of nanoparticle pharmaceutical composition of the content ratio between each medical compounds and nanoparticle pharmaceutical composition prepared by the method by demand a kind of the preparation.
The present inventor finds, different medical compoundss is due to hydrophilic and/or hydrophobicity difference, in the mode of the mode by hydrophilic emulsifying or hydrophobicity emulsifying respectively, that multi-medicament is compound loaded on amphipathic nature polyalcohol the time, in the nanoparticle pharmaceutical composition obtained, content ratio between each medical compounds can only be for than close limit, and can't be adjusted according to the medication demand; But, if by the multi-emulsion method with twice emulsifying step, hydrophilic and/or the different medical compounds of hydrophobicity are loaded on described amphipathic nature polyalcohol, just can adjust the content ratio between each medical compounds in the nanoparticle pharmaceutical composition obtained according to the medication demand at an easy rate, and due to mixing of cationic polymer, can realize the load of nucleic acid drug, obtain thus the present invention.
The invention provides a kind of preparation method of nanoparticle pharmaceutical composition, described nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, cationic polymer, hydrophobic drug, hydrophilic small molecules medicine and nucleic acid drug, and the method comprises the following steps:
(1) under the Ultrasonic Radiation condition, make aqueous solution the emulsifying of the first solution and hydrophilic small molecules medicine, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent; Described the first organic solvent is 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, described hydrophilic small molecules medicine and described nucleic acid drug generation chemical reaction;
(2) by described the first emulsion and first surface activating agent aqueous solution, and, by aqueous solution the emulsifying of the mixed material of gained and the second solution and cationic polymer, obtain the second emulsion;
Described the second solution contains described hydrophobic drug and the second organic solvent; Described the second organic solvent is 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, described hydrophilic small molecules medicine and described nucleic acid drug 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, then centrifugal and separation is precipitated thing.
(4) described precipitate is mixed with nucleic acid drug with the aqueous solution dissolving is rear, separate and obtain the nanoparticle pharmaceutical composition.
Method provided by the invention, can adjust and make in nanoparticle compositions provided by the invention according to the medication demand at an easy rate, between the different medical compounds of hydrophilic and/or hydrophobicity and with the content ratio of nucleic acid drug.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 in the regional area that is subject to the medicine target site, for example tumor occurs in site, and hydrophilic small molecules medicine, hydrophobic drug and nucleic acid drug compound reach best compatibility of drugs result of use.
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 small molecules medicine is amycin, described nucleic acid drug is siRNA, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, described cationic polymer is ε-poly-D-lysine, in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic small molecules medicine is 1: 10000-10000: 1.
Experimental results show that, above-mentioned nanoparticle pharmaceutical composition provided by the invention, with inciting somebody to action only paclitaxel loaded nanoparticle pharmaceutical composition and the nanoparticle pharmaceutical composition of a load amycin, by paclitaxel, with the weight ratio of amycin, be 1: the pharmaceutical composition that 0.9-1.1 obtains after mixing is compared, and for tumors such as melanoma, pulmonary carcinoma and hepatocarcinoma, has better therapeutic effect.
Other features and advantages of the present invention will partly be described in detail in the specific embodiment subsequently.
The accompanying drawing explanation
Fig. 1 is the image of the nanoparticle pharmaceutical composition that observation embodiment 1 obtains under transmission electron microscope.
Fig. 2 is the grain-size graph that laser particle analyzer records the nanoparticle pharmaceutical composition that embodiment 1 obtains.
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, cationic polymer, hydrophobic drug, hydrophilic small molecules medicine and nucleic acid drug, and the method comprises the following steps:
(1) under the Ultrasonic Radiation condition, make aqueous solution the emulsifying of the first solution and hydrophilic small molecules medicine, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent; Described the first organic solvent is 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, described hydrophilic small molecules medicine and described nucleic acid drug generation chemical reaction;
(2) by described the first emulsion and first surface activating agent aqueous solution, and, by aqueous solution the emulsifying of the mixed material of gained and the second solution and cationic polymer, obtain the second emulsion;
Described the second solution contains described hydrophobic drug and the second organic solvent; Described the second organic solvent is 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, described hydrophilic small molecules medicine and described nucleic acid drug 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, then centrifugal and separation is precipitated thing.
(4) described precipitate is mixed with nucleic acid drug with the aqueous solution dissolving is rear, separate and obtain the nanoparticle pharmaceutical composition.
Wherein, in step (1), the volume ratio of the aqueous solution of described the first solution and described hydrophilic small molecules medicine 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 the aqueous solution of described the first solution and described hydrophilic small molecules medicine 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, the first organic solvent with respect to 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 the 5-100 milligram; 20-40 milligram more preferably.
According to the present invention, in the aqueous solution of described hydrophilic small molecules medicine, water with respect to every milliliter, the content of described hydrophilic small molecules medicine does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in the aqueous solution of described hydrophilic small molecules medicine, with respect to the water of every milliliter, the content of described hydrophilic small molecules medicine is the 1-100 milligram; 10-50 milligram more preferably.
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, the polymer of described amphipathic nature polyalcohol for contain hydrophilic radical and hydrophobic group simultaneously; Described hydrophilic radical can be one or more in polyethylene group, polyoxyethylene group and polyisobutylene acid groups etc., and described hydrophobic group can be medium one or more of polyoxyethylene group, polylactic acid-glycollic acid group, polystyrene group and polycaprolactone group.It should be noted that, the arrangement mode of the repetitive of described amphipathic nature polyalcohol is requirement especially not, so long as can be used to form the nanoparticle pharmaceutical composition, get final product, for example can for alternately, one or more 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, so long as can be used to form the nanoparticle pharmaceutical composition, gets final product, and the weight average molecular weight that the method that for example described amphipathic nature polyalcohol is stipulated according to SHT 1759-2007 records can be 10
4-10
5.
According to the present invention, can also there is more special Targeting Performance and/or imaging performance in order to make described nanoparticle pharmaceutical composition, 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 the poly glycol monomethyl ether group, hydrophobic group is the 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: 1-1: 8, and the weight average molecular weight that the method that described MPEG-PLA-ethanol copolymer is stipulated according to SHT 1759-2007 records 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 small molecules medicine does not have special requirement, can be selected by the dissolubility in water according to desired drug effect and medicine, the molecular weight of described hydrophilic small molecules medicine can be for below 1000Da, for example, can be chosen in medicine that the dissolubility in water is greater than 1g/100g as the hydrophilic small molecules medicine, under preferable case, described hydrophilic small molecules medicine 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 19-190W, 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 aqueous solution of described hydrophilic small molecules medicine is joined in the first solution and mixes.
According to the present invention, in step (2), the consumption of the aqueous solution of the consumption of described first surface activating agent aqueous solution, described the second solution and cationic polymer does not have special requirement, 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 the 0.5-2 volume, more preferably the 0.8-1 volume; The consumption of described the second solution is the 0.1-1 volume, more preferably the 0.4-0.6 volume; The consumption of the aqueous solution of described cationic polymer is the 0.1-1 volume, more preferably the 0.4-0.6 volume.
Wherein, in step (2), in described first surface activating agent aqueous solution, water with respect to every milliliter, the content 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), in described first surface activating agent aqueous solution, the content of described first surface activating agent is the 0.6-6 % by weight, more preferably the 2-4 % by weight.
Wherein, in step (2), in described the second solution, the second organic solvent with respect to every milliliter, the content of described hydrophobic drug does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), in described the second solution, with respect to second organic solvent of every milliliter, the content of described hydrophobic drug can be 0.1 milligram to described hydrophobic drug reach capacity in described the second organic solvent content of concentration, more preferably 1-10 milligram.
Wherein, in step (2), in the aqueous solution of described cationic polymer, the content of described cationic polymer does not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (2), in described the 4th solution, the content of described cationic polymer can be 1 milligram to described cationic polymer reach capacity in institute's aqueous solution content of concentration, more preferably 20-40 milligram.
According to the present invention, in step (2), the effect of described first surface activating agent is the stability that improves the second emulsion, thereby can improve the stability of nanoparticle pharmaceutical composition, its selection 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 the pharmaceutical grade polyvinyl alcohol; The saponification degree of described polyvinyl alcohol can be 70-95mol%; The viscosity of described polyvinyl alcohol under 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be by commercially available, for example can buy the product that the trade mark from Chemical Reagent Co., Ltd., Sinopharm Group is PVA-124.
Wherein, the selection of described hydrophobic drug does not have special requirement, can be selected by the dissolubility in water according to desired drug effect and medicine, for example, the dissolubility that can be chosen in water is less than the medicine of 1g/100g as hydrophobic drug, under preferable case, described hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and vinorelbine.
Wherein, the selection of described cationic polymer does not have special requirement, can be selected according to desired nanoparticle surface electromotive force, for example, can be chosen in water is the cationic polymer of positive potential, under preferable case, described cationic polymer is one or more in poly-D-lysine, chitosan and Polyetherimide-amine type dendrimer.Described poly-D-lysine is preferably ε-poly-D-lysine.
Wherein, in step (2), the condition of described emulsifying does not have special requirement, can be selected 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 19-190W, 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 mixes, and the speed that described the first emulsion adds is 0.1-3ml/min.
Wherein, in step (2), to as above mix in the aqueous solution emulsification of the mixed material of gained and described the second solution and described cationic polymer, 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 aqueous solution emulsification of the mixed material of gained and described the second solution and described cationic polymer, the mode of described mixing comprises: under the stirring condition of turn at 1000-1200/min, the aqueous solution of described the second solution and described cationic polymer is joined and as above mixes in the mixed material of gained, and the speed that described the second solution adds is 0.1-1ml/min.
According to the present invention, in step (3), described the second emulsion with respect to 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), described the second emulsion with respect to 1 volume, the consumption of described second surface activating agent aqueous solution is the 2-20 volume, more preferably the 10-15 volume.
Wherein, in step (3), in described second surface activating agent aqueous solution, water with respect to every milliliter, 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 the 0.3-3 % by weight, more preferably the 0.6-1 % by weight.
Wherein, in step (3), the effect of described second surface activating agent is to improve described sedimentary stability, thereby can improve the stability of nanoparticle pharmaceutical composition, its selection 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), 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 the pharmaceutical grade polyvinyl alcohol; The saponification degree of described polyvinyl alcohol can be 70-95mol%; The viscosity of described polyvinyl alcohol under 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be by commercially available, for example can buy the product that the trade mark from Chemical Reagent Co., Ltd., Sinopharm Group is 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, after adding 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), it can be 5000-15000g that centrifugal and separation is precipitated speed centrifugal in the process of thing.
According to the present invention, wherein, in step (4), with respect to the described precipitate of 1 weight portion, the consumption of water can be the 1-1000 weight portion, is preferably the 10-100 weight portion.
Wherein, in step (4), with respect to the described precipitate of 1 weight portion, the consumption of described nucleic acid drug can be the 0.001-1 weight portion, is preferably the 0.1-0.2 weight portion.
Wherein, described nucleic acid drug comprises the various medicines that nucleic acid is effective ingredient of take, and for example DNA medicine and RNA medicine, be preferably the siRNA medicine.
Wherein, in step (4), in the process that described precipitate is dissolved with aqueous solution and the process of mixing with nucleic acid drug subsequently, the mode of dissolving and the mode of mixing do not have special requirement, in order further to improve the result of use of described nanoparticle pharmaceutical composition, under preferable case, in step (4), the mode that just described precipitate mixes with nucleic acid drug after dissolving with aqueous solution comprises: under the stirring condition of turn at 100-1200/min, described precipitate and described nucleic acid drug are added to the water, then, can under the stirring condition of turn at 100-1200/min, maintain 5-100min.
Wherein, in step (4), separate and obtain in the process of described nanoparticle pharmaceutical composition, the method of described separation does not have special requirement, for example, method that can be by centrifugal and collecting precipitation (resulting be precipitated as described nanoparticle pharmaceutical composition) is separated, and 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 hydrophilic small molecules medicine is amycin, described nucleic acid drug is siRNA, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, described cationic polymer is ε-poly-D-lysine, in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic small molecules medicine is 1: 10000-10000: 1.
Wherein, under preferable case, the weight ratio of described hydrophobic drug and described hydrophilic small molecules medicine is 1: 1000-1000: 1.
Wherein, described nucleic acid drug can be in required ratio and nanoparticle mixed phase the described precipitate for 1 weight portion, the consumption of described nucleic acid drug can be the 0.001-1 weight portion, is preferably the 0.01-0.2 weight portion.
While experiment showed, described nanoparticle pharmaceutical composition for mice, with the amount of amycin, calculating, is the 0.1-10mg/kg body weight through the effective dose of intravenously administrable.
In the present invention, the volume of gas and liquid is under 20 ℃, the numerical value that standard atmosphere is depressed.
Below, further describe the present invention by embodiment, but scope of the present invention is not limited in following examples.
Embodiment 1
The present embodiment prepares the nanoparticle pharmaceutical composition according to following steps.
(1) by amphipathic nature polyalcohol (MPEG-PLA-glycolic of 20mg, PLGA-PEG, purchased from Mount Tai, Jinan handle of the Big Dipper bio tech ltd, the hydrophilic group of this MPEG-PLA-ethanol copolymer is the poly glycol monomethyl ether group, hydrophobic group is the 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: 1-1: 8, the weight average molecular weight that the method for stipulating according to SHT 1759-2007 records is 10
4-1.5 * 10
5) be dissolved in 1ml the first organic solvent (dichloromethane), obtain the first solution.The hydrophilic small molecules medicine 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 aqueous solution of hydrophilic small molecules medicine.The aqueous solution of the hydrophilic small molecules medicine of 250 μ l is added in the first solution of 1ml, obtain mixed material.Under 25 ℃, by the obtained above mixed material of 1ml, with power, be 28.5W and the frequency Ultrasonic Radiation that is 23kHz after 3 minutes, obtain the first emulsion.
(2) by the 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 under 25 ℃ is 700mPas) be formulated as the aqueous solution of concentration 2 % by weight, 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 second solution.The cationic polymer of 20mg (ε-poly-D-lysine, purchased from Yinxiang Biological Engineering Co., Ltd., Zhejiang Prov) is dissolved in the 0.1ml aqueous solution, obtains the aqueous solution of cationic polymer.Under the stirring condition of turn 1000/min, the aqueous solution of the cationic polymer obtained above of the second solution obtained above of 0.25ml and 0.1ml is added in mixed material obtained above with the speed of 1ml/min respectively, obtain for ultrasonic material.Under 25 ℃, by 1ml obtained above for ultrasonic material, with power, be 57W and the frequency Ultrasonic Radiation that is 23kHz after 5 minutes, obtain the second emulsion.
(3) by the 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 under 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.Under room temperature ℃, rotary evaporation is removed the first organic solvent (dichloromethane) and the second organic solvent (dichloromethane), obtains revolving the product after steaming.The product that will revolve after steaming after centrifugal 10 minutes, is collected and is precipitated thing under the centrifugal speed of 13000g.
(4) after the precipitate (10mg left and right) obtained is used to the water dissolution of 2ml, nucleic acid drug (the siRNA that adds 0.05mg, the positive-sense strand sequence is 5 '-GAAUUAACCCUUGGUGAAUTT-3 ' (SEQ ID NO:1), the antisense strand sequence is 5 '-AUUCACCAAGGGUUAAUUCTT-3 ' (SEQ ID NO:2), purchased from the English Weihe River prompt base (Shanghai) trade Co., Ltd, this siRNA can reticent anti-apoptotic proteins survivin gene expression, thereby the growth of inhibition tumor cell), vibration mixes rear room temperature and places 30 minutes, under the centrifugal speed of 13000g after centrifugal 10 minutes, collecting precipitation, obtain the nanoparticle pharmaceutical composition.
According to document (Ashlynn L.Z.Lee, Deng. biomaterial (Biomaterials) 2009,30, method 919-927), observe the nanoparticle pharmaceutical composition that the present embodiment obtains under transmission electron microscope, result as shown in Figure 1, illustrates that the size of the nanoparticle pharmaceutical composition obtained is about 200nm.
According to document (Ashlynn L.Z.Lee, Deng. biomaterial (Biomaterials) 2009,30, method 919-927), the mean diameter of utilizing laser particle analyzer to record the nanoparticle pharmaceutical composition that the present embodiment obtains is 200.63 ± 12.36nm (Fig. 2), dispersion is that 0.131, zeta current potential is 29.6 ± 0.14, shows that the stability of this nanoparticle pharmaceutical composition 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, utilize high performance liquid chromatography to detect (standard substance purchased from Agilent Technologies, trade mark Agilent 1200 series), can find out that nanoparticle pharmaceutical composition that the present embodiment obtains has the characteristic peak of amycin and paclitaxel simultaneously.And record in the nanoparticle pharmaceutical composition that the present embodiment obtains and contain siRNA by the ultraviolet spectrophotometer method, 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 the present embodiment of every gram obtains, the content of amycin is 0.15mg, the content of paclitaxel is 0.075mg, and the content of siRNA is 0.045mg.
Comparative Examples 1
This Comparative Examples prepares the nanoparticle pharmaceutical composition according to the method for embodiment 1, difference is: by amphipathic nature polyalcohol (MPEG-PLA-ethanol copolymer of 20mg, PLGA-PEG, purchased from Mount Tai, Jinan handle of the Big Dipper bio tech ltd) be dissolved in 1ml water, the solution obtained is as the first solution, and water is replaced the first organic solvent (dichloromethane).
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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0.05g, and the content of paclitaxel is 0g, and the content of siRNA is 0g.
Comparative Examples 2
Prepare the nanoparticle pharmaceutical composition according to following steps.
(1), by amphipathic nature polyalcohol MPEG-PLA-ethanol copolymer of 20mg, PLGA-PEG, purchased from Mount Tai, Jinan handle of the Big Dipper bio tech ltd) be dissolved in 1ml the first organic solvent (dichloromethane), obtain the first solution.The hydrophilic small molecules medicine 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 obtained is as the aqueous solution of hydrophilic small molecules medicine.First 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 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 second solution.
Under the stirring condition of turn 1000/min, by the aqueous solution of the first solution obtained above, the second solution obtained above, hydrophilic small molecules medicine obtained above, first surface activating agent aqueous solution obtained above, obtain for ultrasonic material.Under 25 ℃, by the 1ml Ultrasonic Radiation that is first 23kHz by the frequency of 28.5W for ultrasonic material obtained above 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, remove the first organic solvent (dichloromethane) and the second organic solvent (dichloromethane), obtains revolving the product after steaming.The product that will revolve after steaming after centrifugal 10 minutes, is collected and is precipitated thing under the centrifugal speed of 13000g.
(4) after the precipitate (10mg left and right) obtained is used to the water dissolution of 2ml, nucleic acid drug (the siRNA that adds 0.05mg, in the same manner as in Example 1), vibration mixes rear room temperature and places 30 minutes, under the centrifugal speed of 13000g after centrifugal 10 minutes, collecting precipitation, obtain the 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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0g, and the content of paclitaxel is 0.02g, and the content of siRNA is 0g.
Embodiment 2
The present embodiment prepares the nanoparticle pharmaceutical composition according to the method for embodiment 1, difference is, in the aqueous solution of described hydrophilic small molecules medicine, the concentration of amycin is 0.4mg/ml, and in described the second solution, the concentration of paclitaxel is 10mg/ml, and the consumption of described nucleic acid drug is 0.05mg.
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 about 200nm; 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, and the content of siRNA is 0.000045g.
Comparative Examples 3
This Comparative Examples prepares the nanoparticle pharmaceutical composition according to the method for Comparative Examples 2, difference is, in the aqueous solution of described hydrophilic small molecules medicine, the concentration of amycin is 0.4mg/ml, and in described the second solution, the concentration of paclitaxel is 10mg/ml, and the consumption of described nucleic acid drug is 0.05mg.
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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0g, and the content of paclitaxel is 0.1g, and the content of siRNA is 0g.
Embodiment 3
The present embodiment prepares the nanoparticle pharmaceutical composition according to the method for embodiment 1, difference is, in the aqueous solution of described hydrophilic small molecules medicine, the concentration of amycin is 10mg/ml, and in described the second solution, the concentration of paclitaxel is 0.4mg/ml, and the consumption of described nucleic acid drug is 0.05mg.
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, and the content of siRNA is 0.000045g.
Comparative Examples 4
This Comparative Examples prepares the nanoparticle pharmaceutical composition according to the method for Comparative Examples 2, difference is, in the aqueous solution of described hydrophilic small molecules medicine, the concentration of amycin is 10mg/ml, and in described the second solution, the concentration of paclitaxel is 0.4mg/ml, and the consumption of described nucleic acid drug is 0.05mg.
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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0g, and the content of paclitaxel is 0.1g, and the content of siRNA is 0g.
Comparative Examples 5
This Comparative Examples prepares the nanoparticle pharmaceutical composition according to the method identical with Comparative Examples 2, difference is, do not use the second solution, and in the aqueous solution of hydrophilic small molecules medicine, the use amount of amycin is 3.5mg, the use amount of nucleic acid drug (siRNA, in the same manner as in Example 1) is 0.1mg.
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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0.3g, and the content of paclitaxel is 0g, and the content of siRNA is 0.09mg.
Comparative Examples 6
This Comparative Examples prepares the nanoparticle pharmaceutical composition according to the method identical with Comparative Examples 2, and difference is do not use the aqueous solution of hydrophilic small molecules medicine, and in the second 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 Examples obtains is 300nm; The content that records amycin in the nanoparticle pharmaceutical composition that this Comparative Examples of every gram obtains is 0g, and the content of paclitaxel is 0.15g.
Test implementation example 1
In this test implementation example, using embodiment 1 make be loaded with multi-medicament nanoparticle compositions as Experimental agents; The nanoparticle medicine mixed in equal amounts that the nanoparticle pharmaceutical composition that Comparative Examples 5 is obtained and Comparative Examples 6 obtain, the content that obtains amycin is 15 % by weight, the nanoparticle pharmaceutical composition mixture that the content of paclitaxel is 7.5 % by weight.By this nanoparticle pharmaceutical composition mixture medicine in contrast.
Culture dish 10 by melanoma cell (B16 cell line, purchased from ATCC, is numbered B16-F10) 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, the sucking-off culture medium, 2ml is dissolved with to the culture medium of Experimental agents (in amycin, drug level is 0.17 μ mol/ml) add wherein in a culture dish, 2ml is dissolved with to the culture medium of control drug (in amycin, drug level is 0.17 μ mol/ml) add in the another culture dish, by above-mentioned 2 culture dishs at 37 ℃ and 5% CO
2after hatching 24 hours under concentration, according to document, (Qinghua Miao, etc., biomaterial (Biomaterials), 2010,31 (28): the CCK-8 method 7364-75) detects the different time sections Level of Apoptosis.Can find, use in the culture dish of Experimental agents, cytoactive is 90.2 ± 1.2 (4h), 31.88 ± 2% (8h), 16.3 ± 3.2% (12h), 6.1 ± 0.05% (24h); Use in the culture dish of control drug, cytoactive is 96.2 ± 2.1% (4h), 53.63 ± 1.3% (8h), 42.5 ± 3.4% (12h), 34.43 ± 1.5 (24h).The above results illustrative experiment medicine has stronger short apoptosis effect to melanoma cell.
Use melanoma cell (B16 cell line, purchased from ATCC, number B16-F10) and C57 mice (C57 system, purchased from Beijing dimension tonneau China company), according to document, (Fariyal Ahmed, learn (Molecular Pharmaceutics) etc. molecular medicine, 3, method 340-350) prepares tumor bearing nude mice, treats that tumor grows to 0.5cm
2during size, tumor bearing nude mice is divided into to experimental group tumor bearing nude mice and matched group tumor bearing nude mice at random, according to the method in document (the same), through the tail vein, the phosphate buffer (in amycin, dosage is the 3mg/kg body weight) that is dissolved with Experimental agents is administered to the experimental group tumor bearing nude mice; The phosphate buffer (in amycin, dosage is the 3mg/kg body weight) that is dissolved with control drug is administered to the matched group tumor bearing nude mice.After one week, according to document (Fariyal Ahmed, learn (Molecular Pharmaceutics) etc. molecular medicine, 3, the method in 340-350) is measured the size of tumor, wherein, the tumor size average out to 452mm of experimental group tumor bearing nude mice
3, the tumor size average out to 8462mm of matched group tumor bearing nude mice
3.The above results explanation illustrative experiment medicine has stronger inhibition to melanoma.
Below describe by reference to the accompanying drawings the preferred embodiment of the present invention in detail; but; the present invention is not limited to the detail in above-mentioned embodiment; in technical conceive scope of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
Claims (10)
1. the preparation method of a nanoparticle pharmaceutical composition, described nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, cationic polymer, hydrophobic drug, hydrophilic small molecules medicine and nucleic acid drug, and the method comprises the following steps:
(1) under the Ultrasonic Radiation condition, make aqueous solution the emulsifying of the first solution and hydrophilic small molecules medicine, obtain the first emulsion;
Described the first solution contains described amphipathic nature polyalcohol and the first organic solvent; Described the first organic solvent is for can dissolve described amphipathic nature polyalcohol, but water-fast organic solvent;
(2) by described the first emulsion and first surface activating agent aqueous solution, and, by aqueous solution the emulsifying of the mixed material of gained and the second solution and cationic polymer, obtain the second emulsion;
Described the second solution contains described hydrophobic drug and the second organic solvent; Described the second organic solvent is for can dissolve described hydrophobic drug, but water-fast organic solvent;
(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, then centrifugal and separation is precipitated thing;
(4) described precipitate is mixed with nucleic acid drug with the aqueous solution dissolving is rear, centrifugalize obtains the nanoparticle pharmaceutical composition.
2. method according to claim 1, wherein, in step (1), the volume ratio of the aqueous solution of described the first solution and described hydrophilic small molecules medicine 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 the 5-100 milligram; In the aqueous solution of described hydrophilic small molecules medicine, with respect to the water of every milliliter, the content of described hydrophilic small molecules medicine is the 1-100 milligram.
3. method according to claim 1 and 2, wherein, in step (1), described amphipathic nature polyalcohol is one or more in MPEG-PLA-glycolic, poly(ethylene oxide)-poly(propylene oxide) and Polyethylene Glycol and poly (l-lactic acid); Described hydrophilic small molecules medicine is one or more in amycin, mitoxantrone, daunorubicin and epirubicin; 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 first emulsion with respect to 1 volume, the consumption of described first surface activating agent aqueous solution is the 0.5-2 volume, the consumption of described the second solution is the 0.1-1 volume, and the consumption of the aqueous solution of described cationic polymer is the 0.1-1 volume; In described first surface activating agent aqueous solution, the content of described first surface activating agent is the 0.6-6 % by weight; In described the second solution, with respect to second organic solvent of every milliliter, the content of described hydrophobic drug be 0.1 milligram to reach capacity in described the second organic solvent content of concentration of described hydrophobic drug; In the aqueous solution of described cationic polymer, with respect to the water of every milliliter, the content of described cationic polymer be 1 milligram to reach capacity in the institute's aqueous solution content of concentration of described cationic polymer.
6. method according to claim 1 or 5, wherein, in step (2), described first surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate; Described hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and vinorelbine; Described cationic polymer be in poly-D-lysine, chitosan, Polyetherimide and polyamide-amide type dendrimer one or more.
7. method according to claim 1 or 5, 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.
8. method according to claim 1, wherein, in step (3), with respect to described second emulsion of 1 volume, the consumption of described second surface activating agent aqueous solution is the 2-20 volume; In described second surface activating agent aqueous solution, the content of described second surface activating agent is the 0.3-3 % by weight;
Described second surface activating agent is one or more in polyvinyl alcohol, POLYSORBATE 80, span and dodecyl sodium sulfate.
9. method according to claim 1, wherein, in step (4), with respect to the described precipitate of 1 weight portion, the consumption of water is the 1-1000 weight portion, the consumption of described nucleic acid drug is the 0.001-1 weight portion.
10. a nanoparticle pharmaceutical composition, this nanoparticle pharmaceutical composition described method of any one in claim 1-9 prepares, wherein, described hydrophobic drug is paclitaxel, described hydrophilic small molecules medicine is amycin, described nucleic acid drug is siRNA, described amphipathic nature polyalcohol is MPEG-PLA-ethanol copolymer, described cationic polymer is ε-poly-D-lysine, in described nanoparticle pharmaceutical composition, the weight ratio of described hydrophobic drug and described hydrophilic small molecules medicine is 1: 10000-10000: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110402420.9A CN103142482B (en) | 2011-12-06 | 2011-12-06 | Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110402420.9A CN103142482B (en) | 2011-12-06 | 2011-12-06 | Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103142482A true CN103142482A (en) | 2013-06-12 |
| CN103142482B CN103142482B (en) | 2014-09-24 |
Family
ID=48540999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110402420.9A Expired - Fee Related CN103142482B (en) | 2011-12-06 | 2011-12-06 | Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103142482B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103695449A (en) * | 2013-12-17 | 2014-04-02 | 吉林大学 | Non-viral cationic gene carrier with tumor targeting and preparation method thereof |
| CN103861112A (en) * | 2014-03-25 | 2014-06-18 | 国家纳米科学中心 | Pharmaceutical composition based on polymer nanoparticle carrier and preparation method thereof |
| CN110124091A (en) * | 2019-05-27 | 2019-08-16 | 南通大学附属医院 | Suture and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100041744A1 (en) * | 2001-09-13 | 2010-02-18 | Daehwa Pharm. Co., Ltd. | Oily paclitaxel composition and formulation for chemoembolization and preparation method thereof |
| CN102743337A (en) * | 2011-04-20 | 2012-10-24 | 国家纳米科学中心 | Nano-particulate medicinal composition and preparation method thereof |
-
2011
- 2011-12-06 CN CN201110402420.9A patent/CN103142482B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100041744A1 (en) * | 2001-09-13 | 2010-02-18 | Daehwa Pharm. Co., Ltd. | Oily paclitaxel composition and formulation for chemoembolization and preparation method thereof |
| CN102743337A (en) * | 2011-04-20 | 2012-10-24 | 国家纳米科学中心 | Nano-particulate medicinal composition and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103695449A (en) * | 2013-12-17 | 2014-04-02 | 吉林大学 | Non-viral cationic gene carrier with tumor targeting and preparation method thereof |
| CN103695449B (en) * | 2013-12-17 | 2015-07-08 | 吉林大学 | Non-viral cationic gene carrier with tumor targeting and preparation method thereof |
| CN103861112A (en) * | 2014-03-25 | 2014-06-18 | 国家纳米科学中心 | Pharmaceutical composition based on polymer nanoparticle carrier and preparation method thereof |
| 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 |
| CN110124091A (en) * | 2019-05-27 | 2019-08-16 | 南通大学附属医院 | Suture and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103142482B (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102743337B (en) | Nano-particulate medicinal composition and preparation method thereof | |
| He et al. | Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer | |
| Lee et al. | The use of cholesterol-containing biodegradable block copolymers to exploit hydrophobic interactions for the delivery of anticancer drugs | |
| Liu et al. | Poly (ω-pentadecalactone-co-butylene-co-succinate) nanoparticles as biodegradable carriers for camptothecin delivery | |
| Ding et al. | Efficacious hepatoma-targeted nanomedicine self-assembled from galactopeptide and doxorubicin driven by two-stage physical interactions | |
| Zhang et al. | Hydrophobic pharmaceuticals mediated self-assembly of β-cyclodextrin containing hydrophilic copolymers: Novel chemical responsive nano-vehicles for drug delivery | |
| Zeng et al. | Chitosan-modified poly (D, L-lactide-co-glycolide) nanospheres for plasmid DNA delivery and HBV gene-silencing | |
| Mu et al. | Hyperbranched polyglycerol-modified graphene oxide as an efficient drug carrier with good biocompatibility | |
| Guo et al. | Pep-1&borneol–bifunctionalized carmustine-loaded micelles enhance anti-glioma efficacy through tumor-targeting and BBB-penetrating | |
| Pan et al. | Synthesis and characterization of biodegradable polyurethanes with folate side chains conjugated to hard segments | |
| Li et al. | Dual pH-responsive micelles with both charge-conversional property and hydrophobic–hydrophilic transition for effective cellular uptake and intracellular drug release | |
| Li et al. | Sorafenib-loaded nanoparticles based on biodegradable dendritic polymers for enhanced therapy of hepatocellular carcinoma | |
| CN111481673B (en) | Preparation method of multi-active-component preparation | |
| Wang et al. | Targeted delivery of tanshinone IIA-conjugated mPEG-PLGA-PLL-cRGD nanoparticles to hepatocellular carcinoma | |
| Chen et al. | Enhanced uptake and cytotoxity of folate-conjugated mitoxantrone-loaded micelles via receptor up-regulation by dexamethasone | |
| Xu et al. | Supramolecular hydrogel from nanoparticles and cyclodextrins for local and sustained nanoparticle delivery | |
| Ma et al. | Iminoboronate-based dual-responsive micelles via subcomponent self-assembly for hydrophilic 1, 2-diol-containing drug delivery | |
| CN103861112B (en) | Based on the pharmaceutical composition and preparation method thereof of polymer nano-particle carrier | |
| Wang et al. | Stereocomplex micelle from nonlinear enantiomeric copolymers efficiently transports antineoplastic drug | |
| CN103142482B (en) | Preparation method for nanoparticle pharmaceutical composition, and nanoparticle pharmaceutical composition | |
| Das et al. | Preparation of a size selective nanocomposite through temperature assisted co-assembly of gelatin and pluronic F127 for passive targeting of doxorubicin | |
| Yuan et al. | Micelle controlled release of 5-fluorouracil: Follow the guideline for good polymer–drug compatibility | |
| Gong et al. | Co-delivery of doxorubicin and afatinib with pH-responsive polymeric nanovesicle for enhanced lung cancer therapy | |
| Gao et al. | Polyethyleneimine functionalized polymer microsphere: a novel delivery vector for cells | |
| Wang et al. | Polymer hydrophobicity regulates paclitaxel distribution in microspheres, release profile and cytotoxicity in vitro |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140924 Termination date: 20201206 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |