CN102743337A - Nano-particulate medicinal composition and preparation method thereof - Google Patents
Nano-particulate medicinal composition and preparation method thereof Download PDFInfo
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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 a kind of pharmaceutical composition and preparation of drug combination method, particularly, relate to a kind of nanoparticle pharmaceutical composition and nanoparticle preparation of drug combination method.
Background technology
Nanometer medicine-carried system is meant 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 be difficult for being removed rapidly through the minimum blood capillary of human body by phagocyte, and prolonged the RT in blood circulation; (2) arrive target sites such as the concentrated liver of reticuloendothelial system distribution, spleen, lung, bone marrow, lymph; (3) can the penetrate tissue gap and absorbed by cell, help in Transdermal absorption and the cell drug effect and bring into play; (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 the effect of medicine sustained release; (6) improve bioavailability of medicament and reduce toxic and side effects etc.
Nanoparticle is a kind of selection commonly used in the nanometer medicine-carried system, is used as the polymer carrying medicament of pharmaceutical carrier usually, obtains the nanoparticle pharmaceutical composition.But mostly the nanoparticle pharmaceutical composition that present disclosed nanoparticle preparation of drug combination method obtains is the nanoparticle pharmaceutical composition of a kind of medical compounds of load.As for the hydrophilic medicament chemical compound; Through the emulsive mode of hydrophilic medical compounds is loaded on the polymer; Concrete grammar is: amphipathic nature polyalcohol is dissolved in the organic solvent; And with the aqueous solution of hydrophilic medicament chemical compound after under the ultrasound wave condition, carry out the emulsifying first time; For the first time the material after the emulsifying adds surfactant and carries out emulsifying second time, with the emulsion dispersion that obtains for the second time in aqueous surfactant solution also rotary evaporation remove organic solvent, obtain the nanoparticle compositions of load hydrophilic medicament chemical compound after the centrifugalize.As for hydrophobic pharmaceutical compounds; Through the emulsive mode of hydrophobicity medical compounds is loaded on the 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 the aqueous surfactant solution; Ultrasonic emulsification obtains emulsion after stirring certain hour, and the emulsion rotary evaporation that obtains is removed organic solvent, obtains the nanoparticle compositions of load hydrophobic pharmaceutical compounds after the centrifugalize.When the multiple medical compounds of load; If through emulsive mode of hydrophilic or the emulsive mode of hydrophobicity multiple medical compounds is loaded on the polymer respectively; In the nanoparticle pharmaceutical composition that obtains; Content ratio between each medical compounds is difficult to control, has limited the raising of the result of use of nanoparticle pharmaceutical composition.
Summary of the invention
Inventor of the present invention finds; The different drug chemical compound is because hydrophilic and/or hydrophobicity are different; When loading on multiple medical compounds on the amphipathic nature polyalcohol through emulsive mode of hydrophilic or the emulsive mode of hydrophobicity respectively; In the nanoparticle pharmaceutical composition that obtains, the content ratio between each medical compounds can only be for than close limit, and can't adjust according to the medication demand; But; If the multi-emulsion method through having twice emulsifying step is compound loaded to said amphipathic nature polyalcohol with hydrophilic and/or hydrophobicity different drug; Just can adjust in the nanoparticle pharmaceutical composition that obtains according to the medication demand at an easy rate; Content ratio between each medical compounds obtains the present invention thus.
The invention provides a kind of nanoparticle preparation of drug combination method, said nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and this method may further comprise the steps:
(1) under the ultrasound wave radiation condition, first solution is mixed and emulsifying with second solution, obtain first emulsion;
Said first solution contains the said amphipathic nature polyalcohol and first organic solvent, and said second solution contains said hydrophilic medicament and water;
Said first organic solvent be for can dissolve said amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(2) with said first emulsion and first surface activating agent aqueous solution, and the mixed material of gained mixed with the 3rd solution and emulsifying, obtain second emulsion;
Said the 3rd solution contains the said hydrophobic drug and second organic solvent;
Said second organic solvent be for can dissolve said hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(3) with said second emulsion and second surface activating agent aqueous solution, and remove said first organic solvent and said second organic solvent, separate obtaining said nanoparticle pharmaceutical composition.
Inventor of the present invention also finds; If said method is changed into: with the aqueous solution of said amphipathic nature polyalcohol as first solution; The solution that will contain said hydrophobic drug and said second organic solvent is as second solution; And the solution that will contain said hydrophilic medicament and water is as the 3rd solution, with the result of use that reduces said nanoparticle pharmaceutical composition greatly.
Method provided by the invention can be at an easy rate adjusted according to the medication demand and is made in the nanoparticle compositions provided by the invention content ratio between hydrophilic and/or the hydrophobicity different drug chemical compound.Through above-mentioned adjustment; Can utilize the peculiar advantage of nanometer medicine-carried system on administering mode efficiently; Reach best compatibility of drugs result of use; Especially can make that in the regional area that receives the medicine target site for example tumor takes place in the site, hydrophilic and/or hydrophobicity different drug chemical compound reach best compatibility of drugs result of use.
Inventor of the present invention also finds; When said hydrophobic drug is a paclitaxel; When said hydrophilic medicament is amycin; When loading on multiple medical compounds on the polymer through the emulsive mode of single, in the nanoparticle pharmaceutical composition that obtains, the weight ratio of said hydrophobic drug and said hydrophilic medicament can only be located less than 1: 100000 or greater than in 100000: 1 the scope.
The present invention also provides a kind of nanoparticle pharmaceutical composition; This nanoparticle pharmaceutical composition is obtained by method for preparing, and wherein, said hydrophobic drug is a paclitaxel; Said hydrophilic medicament is an amycin; Said amphipathic nature polyalcohol is poly glycol monomethyl ether-polylactic-co-glycolic acid, and in the said nanoparticle pharmaceutical composition, the weight ratio of said hydrophobic drug and said hydrophilic medicament is 1: 10000-10000: 1.
The experiment proof; Above-mentioned nanoparticle pharmaceutical composition provided by the invention; Is 1 by paclitaxel with the weight ratio of amycin with inciting somebody to action the only paclitaxel loaded nanoparticle pharmaceutical composition and the nanoparticle pharmaceutical composition of a load amycin: the pharmaceutical composition that 0.9-1.1 obtains after mixing is compared, and has better therapeutic effect for tumors such as melanoma, pulmonary carcinoma and hepatocarcinoma.
Other features and advantages of the present invention will partly specify in the specific embodiment subsequently.
Description of drawings
Fig. 1 is the image of the nanoparticle pharmaceutical composition that observation embodiment 1 obtains under transmission electron microscope, and wherein, what labelling 1 marked is the nuclear of nanoparticle, and what labelling 2 marked is the shell of nanoparticle.
Fig. 2 records the grain-size graph of the nanoparticle pharmaceutical composition that embodiment 1 obtains for laser particle analyzer.
Fig. 3 detects amycin and the collection of illustrative plates of paclitaxel in the nanoparticle pharmaceutical composition that embodiment 1 obtains for HPLC.
The specific embodiment
Be elaborated below in conjunction with the accompanying drawing specific embodiments of the invention.Should be understood that the specific embodiment described herein only is used for explanation and explains the present invention, is not limited to the present invention.
The invention provides a kind of nanoparticle preparation of drug combination method, said nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and this method may further comprise the steps:
(1) under the ultrasound wave radiation condition, first solution is mixed and emulsifying with second solution, obtain first emulsion;
Said first solution contains the said amphipathic nature polyalcohol and first organic solvent, and said second solution contains said hydrophilic medicament and water;
Said first organic solvent be for can dissolve said amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(2) with said first emulsion and first surface activating agent aqueous solution, and the mixed material of gained mixed with the 3rd solution and emulsifying, obtain second emulsion;
Said the 3rd solution contains the said hydrophobic drug and second organic solvent;
Said second organic solvent be for can dissolve said hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(3) with said second emulsion and second surface activating agent aqueous solution, and remove said first organic solvent and second organic solvent, separate obtaining said nanoparticle pharmaceutical composition.
Wherein, In the step (1), the volume ratio of said first solution and said second solution does not have special requirement, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, the volume ratio of said first solution and said second solution is 1: 1-1: 10; Further be preferably 1: 2-1: 6, most preferably be 1: 4.
According to the present invention, in said first solution, with respect to every milliliter first organic solvent; The content of said amphipathic nature polyalcohol does not have special requirement; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in said first solution; With respect to every milliliter first organic solvent, the content of said amphipathic nature polyalcohol is the 5-100 milligram; Further be preferably the 20-40 milligram.
According to the present invention, in said second solution, with respect to every milliliter water; The content of said hydrophilic medicament does not have special requirement; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in said second solution; With respect to every milliliter water, the content of said hydrophilic medicament is the 0.01-100 milligram; Further be preferably the 0.1-50 milligram.
According to the present invention; In the step (1), the selection of said amphipathic nature polyalcohol does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; For example, said amphipathic nature polyalcohol is for contain the polymer of hydrophilic radical and hydrophobic group simultaneously; Said hydrophilic radical can be polyglycol chain section and/or polyisobutylene acid segment, and said hydrophobic group can be in polylactic acid-glycollic acid segment, polystyrene segment and the polycaprolactone segment one or more.Need to prove; The arrangement mode of the repetitive of said amphipathic nature polyalcohol is requirement especially not; Get final product so long as can be used to form the nanoparticle pharmaceutical composition; For example can for alternately, in the block, random or grafting one or more, also can obtain by the monomer homopolymerization that contains hydrophilic radical and hydrophobic group; The molecular weight of said amphipathic nature polyalcohol does not have special requirement, gets final product so long as can be used to form the nanoparticle pharmaceutical composition, and the weight average molecular weight that the method that for example said amphipathic nature polyalcohol is stipulated according to SHT 1759-2007 records can be 10
4-10
5
According to the present invention, can also have more special Targeting Performance and/or imaging performance in order to make said nanoparticle pharmaceutical composition, under the preferable case, in the step (1), said amphipathic nature polyalcohol also contains targeting group and/or imaging group.
Wherein, The selection of said targeting group and/or imaging group does not have special requirement; Can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; In order further to improve the result of use of said nanoparticle pharmaceutical composition, further under the preferable case, said targeting group is one or more in folic acid group, essence-Gan-aspartic acid motif cyclic peptide (RGD) group and the transferrins group etc.; Said imaging group is quantum dot group and/or fluorescent dye group.For example, said quantum dot group can be in the nano materials such as golden quantum dot group, cadmium quantum dot group and palladium quantum dot group one or more; Said fluorescent dye group can be in Fluorescein isothiocyanate group, eosin disodium group and the acid red 87 group one or more.
Wherein, The not requirement especially of content of said targeting group and/or imaging group can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, for example; With respect to every mole hydrophilic radical, the content of said targeting group and/or imaging group can be the 0.2-1 mole.
A preferred embodiment of the invention, in the step (1), said amphipathic nature polyalcohol is one or more in poly glycol monomethyl ether-polylactic acid-glycollic acid, PEO-PPOX, Polyethylene Glycol and the poly (l-lactic acid).
Wherein, The hydrophilic group of said poly glycol monomethyl ether-polylactic acid-glycollic acid is the poly glycol monomethyl ether group; Hydrophobic group is the polylactic acid-glycollic acid group; The arrangement mode of the repetitive of said poly glycol monomethyl ether-polylactic-co-glycolic acid is a block; Wherein, the mol ratio between ethylene glycol unit and the lactic acid-ethanol unit can be 1: 1-8, the weight average molecular weight that the method that said poly glycol monomethyl ether-polylactic-co-glycolic acid is stipulated according to SHT 1759-2007 records can be 10
4-10
5Poly glycol monomethyl ether-the polylactic-co-glycolic acid that meets above-mentioned requirements can be through being purchased acquisition.
According to the present invention; The selection of said hydrophilic medicament does not have special requirement; Can select according to desired drug effect and the dissolubility of medicine in water, for example, can be chosen in dissolubility in the water greater than the medicine of 1g/100g as hydrophilic medicament; Under the preferable case, said hydrophilic medicament is one or more in amycin, mitoxantrone, daunorubicin and the epirubicin.
According to the present invention; The selection of said first organic solvent does not have special requirement; Can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; In order further to improve the result of use of said nanoparticle pharmaceutical composition and to reduce cost, under the preferable case, said first organic solvent is one or more in dichloromethane, dimethyl sulfoxide, oxolane, acetone, espeleton, dichloro-benzenes and the methyl isopropyl ketone.
According to the present invention, in the step (1), said emulsive condition does not have special requirement; Can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in the step (1); Said emulsive condition comprises: the radiating frequency of ultrasound wave is 20-25kHz, further is preferably 22-23kHz; Accept the radiating material of ultrasound wave with respect to every milliliter, power is 10-190W, further is preferably 28.5-57W; Emulsive temperature is 1-99 ℃, further is preferably 20-30 ℃; The emulsive time is 1-30 minute, further is preferably 3-10 minute.
Wherein, In the step (1), said blended mode does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; In order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (1), said blended mode comprises: second solution is joined in first solution mix.
According to the present invention, in the step (2), the consumption of said first surface activating agent aqueous solution and the consumption of said the 3rd solution do not have special requirement; Can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, for the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case; In the step (2); With respect to first emulsion of 1 volume, the consumption of said first surface activating agent aqueous solution is the 0.5-2 volume, further is preferably the 0.8-1 volume; The consumption of said the 3rd solution is the 0.1-1 volume, further is preferably the 0.4-0.6 volume.
Wherein, in the step (2), in the said first surface activating agent aqueous solution; The content of said first surface activating agent does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (2), in the said first surface activating agent aqueous solution; The content of said first surface activating agent is 0.6-6 weight %, further is preferably 2-4 weight %.
Wherein, in the step (2), in said the 3rd solution; With respect to every milliliter second organic solvent, the content of said hydrophobic drug does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in the step (2); In said the 3rd solution; With respect to every milliliter second organic solvent, the content of said hydrophobic drug can be 0.01 milligram in said second organic solvent, the reach capacity content of concentration of said hydrophobic drug, further is preferably the 0.1-10 milligram.
According to the present invention; In the step (2), the selection of said first surface activating agent does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; In order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (2), said first surface activating agent is one or more in polyvinyl alcohol, soil temperature 80, span and the dodecyl sodium sulfate.
Wherein, the selection of said polyvinyl alcohol does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, and for example, said polyvinyl alcohol can be the pharmaceutical grade polyvinyl alcohol; The saponification degree of said polyvinyl alcohol can be 70-95mol%; The viscosity of said polyvinyl alcohol under 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be through being purchased acquisition, and the trade mark that for example can buy from Chemical Reagent Co., Ltd., Sinopharm Group is the product of PVA-124.
Wherein, The selection of said hydrophobic drug does not have special requirement; Can select according to desired drug effect and the dissolubility of medicine in water, for example, can be chosen in dissolubility in the water less than the medicine of 1g/100g as hydrophobic drug; Under the preferable case, said hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and the vinorelbine.
Wherein, in the step (2), said emulsive condition does not have special requirement; Can select according to desired drug effect and the dissolubility of medicine in water; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in the step (2); Said emulsive condition comprises: the radiating frequency of ultrasound wave is 20-25kHz, further is preferably 22-23kHz; Accept the radiating material of ultrasound wave with respect to every milliliter, power is 10-190W, further is preferably 28.5-57W; Emulsive temperature is 1-99 ℃, further is preferably 20-30 ℃; The emulsive time is 1-30 minute, further is preferably 3-10 minute.
Wherein, In the step (2), in the process with said first emulsion and said first surface activating agent aqueous solution, said blended mode does not have special requirement; Can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; For the further result of use that improves said nanoparticle pharmaceutical composition, under the preferable case, in the step (2); In the process with said first emulsion and said first surface activating agent aqueous solution; Said blended mode comprises: under the stirring condition of 100-1200 commentaries on classics/min, said first emulsion joined in the said first surface activating agent aqueous solution mix, and the speed that said first emulsion adds is 0.1-3ml/min.
Wherein, in the step (2), with the mixed material of gained mix with said the 3rd solution and emulsification in; Said blended mode does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case; In the step (2), with the mixed material of gained mix with said the 3rd solution and emulsification in, said blended mode comprises: under the stirring condition of 1000-1200 commentaries on classics/min; Said the 3rd solution is joined in the mixed material of said gained, and the speed that said the 3rd solution adds is 0.1-1ml/min.
According to the present invention, in the step (3), with respect to said second emulsion of 1 volume; The consumption of said second surface activating agent aqueous solution does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (3), with respect to said second emulsion of 1 volume; The consumption of said second surface activating agent aqueous solution is the 2-20 volume, further is preferably the 10-15 volume.
Wherein, in the step (3), in the said second surface activating agent aqueous solution; The content of said second surface activating agent does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (3), in the said second surface activating agent aqueous solution; The content of said second surface activating agent is 0.3-3 weight %, further is preferably 0.6-1 weight %.
Wherein, In the step (3), said second surface activating agent selects not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field; In order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case, in the step (3), said second surface activating agent is one or more in polyvinyl alcohol, soil temperature 80, span and the dodecyl sodium sulfate.
Wherein, the selection of said polyvinyl alcohol does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, and for example, said polyvinyl alcohol can be the pharmaceutical grade polyvinyl alcohol; The saponification degree of said polyvinyl alcohol can be 70-95mol%; The viscosity of said polyvinyl alcohol under 25 ℃ can be 500-900mPas.The polyvinyl alcohol that meets above-mentioned requirements can be through being purchased acquisition, and the trade mark that for example can buy from Chemical Reagent Co., Ltd., Sinopharm Group is the product of PVA-124.
Wherein, in step (3), in the process with said second emulsion and second surface activating agent aqueous solution; Said blended mode does not have special requirement, can be the conventional selection in nanoparticle preparation of pharmaceutical compositions field, in order further to improve the result of use of said nanoparticle pharmaceutical composition; Under the preferable case; In step (3), in the process with said second emulsion and second surface activating agent aqueous solution, said blended mode comprises: under the stirring condition of 100-1200 commentaries on classics/min; Said second emulsion is joined in the said second surface activating agent aqueous solution, and the speed that said second emulsion adds is 0.1-3ml/min; After adding said second emulsion, can change/keep 5-100min under the stirring condition of min at 100-1200.
Wherein, In step (3); Remove in the process of said first organic solvent and second organic solvent; Said method of removing said first organic solvent and second organic solvent does not have special requirement, for example, can remove said first organic solvent and second organic solvent through the mode of rotary evaporation.
Wherein, In step (3), separate obtaining in the process of said nanoparticle pharmaceutical composition, said isolating method does not have special requirement; For example, method that can be through centrifugal and collecting precipitation (resulting be precipitated as said nanoparticle pharmaceutical composition) is separated.Wherein, centrifugal speed can be 5000-15000g.
The present invention also provides a kind of nanoparticle pharmaceutical composition; This nanoparticle pharmaceutical composition is obtained by method for preparing, and wherein, said hydrophobic drug is a paclitaxel; Said amphipathic nature polyalcohol is poly glycol monomethyl ether-polylactic-co-glycolic acid; Said hydrophilic medicament is an amycin, and in the said nanoparticle pharmaceutical composition, the weight ratio of said hydrophobic drug and said hydrophilic medicament is 1: 10000-10000: 1.
Experiment showed, when said nanoparticle pharmaceutical composition is used for mice, calculate with the amount of amycin, is the 0.1-10mg/kg body weight through the effective dose of intravenously administrable.
Among the present invention, the volume of gas and liquid is under 20 ℃, the numerical value that standard atmosphere is depressed.
Below, through embodiment further explain the present invention, but scope of the present invention is not limited in following examples.
Embodiment 1
Present embodiment prepares the nanoparticle pharmaceutical composition according to following steps.
(1) with amphipathic nature polyalcohol (poly glycol monomethyl ether-polylactic acid-glycollic acid of 20mg; PLGA-PEG; Available from Mount Tai, Jinan handle of the Big Dipper bio tech ltd, the hydrophilic group of this poly glycol monomethyl ether-polylactic-co-glycolic acid is the poly glycol monomethyl ether group, and hydrophobic group is the polylactic acid-glycollic acid group; The arrangement mode of the repetitive of said poly glycol monomethyl ether-polylactic-co-glycolic acid is a block; Wherein, the mol ratio between ethylene glycol unit and the lactic acid-ethanol unit is 1: 4, and the weight average molecular weight that the method for stipulating according to SHT 1759-2007 records is 1 * 10
5) be dissolved in 1ml first organic solvent (dichloromethane), obtain first solution.The hydrophilic medicament (amycin, available from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) of 0.6mg is dissolved in the 1ml water, obtains second solution.Second solution of 250 μ l is added in first solution of 1ml, obtain mixed material.Under 25 ℃, the frequency of the above-mentioned mixed material that obtains of 1ml being used 28.5W after 3 minutes, obtains first emulsion as the ultrasound wave radiation of 23kHz.
(2) with the first surface activating agent (polyvinyl alcohol, available 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%, obtain first surface activating agent aqueous solution.Under the stirring condition of 1000 commentaries on classics/min, first emulsion that 1ml step (1) is obtained joins in the 1ml first surface activating agent aqueous solution with the speed of 1ml/min, obtains mixed material.0.125mg hydrophobic drug (paclitaxel, available from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml second organic solvent (dichloromethane), obtains the 3rd solution.Under the stirring condition of 1000 commentaries on classics/min, in the above-mentioned mixed material that obtains of speed adding of above-mentioned the 3rd solution that obtains with 0.25ml, obtain being used for ultransonic material with 1ml/min.Under 25 ℃, the above-mentioned frequency that ultransonic material uses 57W of being used for that obtains of 1ml after 5 minutes, is obtained second emulsion as the ultrasound wave radiation of 23kHz.
(3) with the second surface activating agent (polyvinyl alcohol, available 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 800 commentaries on classics/min, 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 600-800 commentaries on classics/min, keeps 10min then.Under room temperature ℃, rotary evaporation is removed first organic solvent (dichloromethane) and second organic solvent (dichloromethane), obtains revolving the product after the steaming.To revolve product after the steaming after under the centrifugal speed of 13000g centrifugal 10 minutes, collecting precipitation obtains the nanoparticle pharmaceutical composition.
(Ashlynn L.Z.Lee is etc. biomaterial (Biomaterials) 2009,30 according to document; Method 919-927) is observed the nanoparticle pharmaceutical composition that present embodiment obtains under transmission electron microscope, the result is as shown in Figure 1; Wherein, What labelling 1 marked is the nuclear of nanoparticle, and what labelling 2 marked is the shell of nanoparticle, explains that the size of the nanoparticle pharmaceutical composition that obtains is about 200nm.
According to document (Ashlynn L.Z.Lee; Deng. biomaterial (Biomaterials) 2009,30, the method described in 919-927); The particle diameter that utilizes laser particle analyzer to record the nanoparticle pharmaceutical composition that present embodiment obtains is 243.63 ± 12.36nm (Fig. 2); Dispersion is 0.131, and the zeta current potential is-21.6 ± 0.14, shows this nanoparticle pharmaceutical composition stability better.
According to document (Ashlynn L.Z.Lee; Deng. biomaterial (Biomaterials) 2009,30, the method described in 919-927); Dissolve with acetonitrile after the nanoparticle pharmaceutical composition lyophilization that present embodiment is obtained; Utilize HPLC to detect (standard substance available from Agilent Technologies, trade mark Agilent1200series), can find out that nanoparticle pharmaceutical composition that present embodiment obtains has the characteristic peak (Fig. 3) of amycin and paclitaxel simultaneously.Explain that amycin and paclitaxel exist simultaneously in the nanoparticle pharmaceutical composition that present embodiment obtains, and the content of amycin is 0.15g in the nanoparticle pharmaceutical composition that obtains of the present embodiment of every gram, the content of paclitaxel is 0.075g.
Comparative Examples 1
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with embodiment 1 identical method; Different is: with amphipathic nature polyalcohol (poly glycol monomethyl ether-polylactic-co-glycolic acid of 20mg; PLGA-PEG; Available from Mount Tai, Jinan handle of the Big Dipper bio tech ltd) be dissolved in the 1ml water, the solution that obtains is as first solution; 0.125mg hydrophobic drug (paclitaxel, available from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml second organic solvent (dichloromethane), and the solution that obtains is as second solution; The hydrophilic medicament (amycin, available from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) of 0.6mg is dissolved in the 1ml water, and the solution that obtains 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 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.
Comparative Examples 2
Prepare the nanoparticle pharmaceutical composition according to following steps.
(1) with amphipathic nature polyalcohol poly glycol monomethyl ether-polylactic-co-glycolic acid of 20mg, PLGA-PEG is available from Mount Tai, Jinan handle of the Big Dipper bio tech ltd) be dissolved in 1ml first organic solvent (dichloromethane), obtain first solution.The hydrophilic medicament (amycin, available from Beijing Hua Feng Science and Technology Ltd., the trade mark is HF090516) of 0.6mg is dissolved in the 1ml water, obtains second solution.First surface activating agent (polyvinyl alcohol, available from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124) is formulated as the aqueous solution of concentration 2 weight %, obtains first surface activating agent aqueous solution.0.125mg hydrophobic drug (paclitaxel, available from Beijing Nuorui Medical Tech. Co., Ltd., the trade mark is 090328) is dissolved in 1ml second organic solvent (dichloromethane), obtains the 3rd solution.
Under the stirring condition of 1000 commentaries on classics/min,, obtain being used for ultransonic material with above-mentioned first solution that obtains, above-mentioned second solution that obtains, above-mentioned the 3rd solution that obtains, the above-mentioned first surface activating agent aqueous solution that obtains.Under 25 ℃, with 1ml above-mentioned obtain be used for frequency that ultransonic material uses earlier 28.5W as the ultrasound wave radiation of 23kHz after 3 minutes, the frequency of reuse 57W is the ultrasound wave radiation 3 minutes of 23kHz, obtains second emulsion.
(2) second surface activating agent (polyvinyl alcohol, available from Chemical Reagent Co., Ltd., Sinopharm Group, the trade mark is PVA-124) is formulated as the aqueous solution of concentration 0.6 weight %, obtains second surface activating agent aqueous solution.Under the stirring condition of 1000 commentaries on classics/min, 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 600-800 commentaries on classics/min, keeps 10min then.At room temperature, rotary evaporation 10min removes first organic solvent (dichloromethane) and second organic solvent (dichloromethane), obtains revolving the product after the steaming.To revolve product after the steaming after under the centrifugal speed of 13000g centrifugal 10 minutes, collecting precipitation obtains 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.
Present embodiment is according to preparing the nanoparticle pharmaceutical composition with embodiment 1 identical method, and different is, the concentration of amycin is 0.4mg/ml in said second solution, and the concentration of paclitaxel is 10mg/ml in said 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 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 Examples 3
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with Comparative Examples 2 identical methods, and different is, the concentration of amycin is 0.4mg/ml in said second solution, and the concentration of paclitaxel is 10mg/ml in said 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 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.
Embodiment 3
Present embodiment is according to preparing the nanoparticle pharmaceutical composition with embodiment 1 identical method, and different is, the concentration of amycin is 10mg/ml in said second solution, and the concentration of paclitaxel is 0.4mg/ml in said 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 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 Examples 4
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with Comparative Examples 2 identical methods, and different is, the concentration of amycin is 10mg/ml in said second solution, and the concentration of paclitaxel is 0.4mg/ml in said 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 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 0.0002g.
Comparative Examples 5
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with Comparative Examples 2 identical methods, and different is do not use the 3rd solution, and the use amount of amycin to be 3.5mg in second 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 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.
Comparative Examples 6
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with Comparative Examples 2 identical methods, and different is not use second solution; And said paclitaxel is replaced by the link coupled paclitaxel of Fluorescein isothiocyanate (FITC-paclitaxel; Seek Bioisystech Co., Ltd available from Nanjing; And in the weight of paclitaxel part, the use amount of FITC-paclitaxel is 1.5mg in the 3rd solution trade mark TQSJ010).
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 in the weight of paclitaxel part, the content of FITC-paclitaxel is 0.15g.
Embodiment 4
According to preparing the nanoparticle pharmaceutical composition with identical method that embodiment 1 makes; Different is; Said paclitaxel is replaced by the link coupled paclitaxel of Fluorescein isothiocyanate (FITC seeks Bioisystech Co., Ltd available from Nanjing, trade mark TQSJ010); And in the weight of paclitaxel part, the use amount of FITC-paclitaxel is 0.125mg in 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 Examples 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 in the weight of paclitaxel part, the content of FITC-paclitaxel is 0.075g.The nanoparticle pharmaceutical composition that present embodiment is obtained is as the experiment medicine.
The weight such as nanoparticle pharmaceutical composition that nanoparticle pharmaceutical composition that Comparative Examples 5 is obtained and Comparative Examples 6 obtain are mixed, and the content that obtains amycin is that the content of 15 weight % and FITC-paclitaxel is the nanoparticle pharmaceutical composition mixture of 7.5 weight %.With this nanoparticle pharmaceutical composition mixture as control drug.
With the culture dish 10 of lung carcinoma cell (A549 cell line available from ATCC, is numbered CCL-185) with every 35mm internal diameter
3Individual density is inoculated in the DMEM culture medium (available from Gibco, trade mark sh30022.01B) that contains 2ml respectively, and contains the hyclone of 10 volume %) two culture dishs in, at the CO of 37 ℃ and 5 volume %
2Cultivate after 24 hours under the concentration; The sucking-off culture medium; The culture medium (in amycin, drug level is 0.17 μ mol/ml) that 2ml is dissolved with the experiment medicine adds wherein in the culture dish, and the culture medium that 2ml is dissolved with control drug is (in amycin; Drug level is 0.17 μ mol/ml) add in the another culture dish, with the CO of above-mentioned 2 culture dishs at 37 ℃ and 5 volume %
2After hatching 2 hours under the concentration, the sucking-off culture medium, with phosphate buffer (available from Gibco; Trade mark P1020-500) washing 3 times (each 5ml), and use the fluorescence microscope imaging, can find; Use in the culture dish of experiment medicine; Presenting the ratio that presents whole cells in the green shared visual field of cell in redness and the Cytoplasm in the nucleus is 100%, and in the culture dish that uses control drug, this ratio is merely 48%; And use in the culture dish of experiment medicine, appear in the nucleus and present in the green cell homogeneous more of the ratio between the red fluorescence intensity and green fluorescence intensity in redness and the Cytoplasm.
Itself carries fluorescence amycin, and green glow excites down and can show HONGGUANG.The 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 medicament compatibility result of use.
Comparative Examples 7
This Comparative Examples is according to preparing the nanoparticle pharmaceutical composition with Comparative Examples 2 identical methods, and different is do not use second solution, and the use amount of paclitaxel to be 2mg in 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 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.
In the present embodiment, embodiment 1 is made the nanoparticle pharmaceutical composition as the experiment medicine; The nanoparticle medicine mixed in equal amounts that nanoparticle pharmaceutical composition that Comparative Examples 5 is obtained and Comparative Examples 7 obtain, the content that obtains amycin is 15 weight %, the content of paclitaxel is the nanoparticle pharmaceutical composition mixture of 7.5 weight %.With this nanoparticle pharmaceutical composition mixture as control drug.
With the culture dish 10 of lung carcinoma cell (A549 cell line available 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 (available from Gibco, trade mark sh30022.01B, and contain the hyclone of 10 volume %), at the CO of 37 ℃ and 5 volume %
2Cultivate after 24 hours under the concentration; The sucking-off culture medium; The culture medium (in amycin, drug level is 0.17 μ mol/ml) that 2ml is dissolved with the experiment medicine adds wherein in the culture dish, and the culture medium that 2ml is dissolved with control drug is (in amycin; Drug level is 0.17 μ mol/ml) add in the another culture dish, with above-mentioned 2 culture dishs at 37 ℃ and 5% CO
2After hatching 24 hours under the concentration, (Qinghua Miao, etc., biomaterial (Biomaterials), 2010,31 (28): the CCK-8 method 7364-75) detects the apoptosis level according to document.Can find that use in the culture dish of experiment medicine, cytoactive is 32.88 ± 3%, uses in the culture dish of control drug, cytoactive is 64.95 ± 3.4%.The above results illustrative experiment medicine has stronger short apoptosis effect to lung carcinoma cell.
Use HCC (HepG2 cell line available from ATCC, is numbered HB-8065) to carry out above-mentioned identical experiment; Can find that use in the culture dish of experiment medicine, 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 HCC.
Use MC (B16 cell line available from ATCC, is numbered B16-F10) to carry out above-mentioned identical experiment; Can find that use in the culture dish of experiment medicine, 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 MC.
Use MC (B16 cell line available from ATCC, is numbered B16-F10) and nude mice (BALB/c-nu system; Available from Beijing dimension tonneau China company); (Fariyal Ahmed learns (Molecular Pharmaceutics) etc. molecular medicine, 3 according to document; Method 340-350) prepares 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 the document (the same), through the tail vein; The phosphate buffer (in amycin, dosage is the 3mg/kg body weight) that is dissolved with the experiment medicine is administered to the experimental group tumor bearing nude mice; The phosphate buffer that is dissolved with control drug (in amycin, dosage is the 3mg/kg body weight) is administered to the matched group tumor bearing nude mice.After one week, according to document (Fariyal Ahmed learns (Molecular Pharmaceutics) etc. molecular medicine, 3, the method in 340-350) is measured the size of tumor, wherein, the tumor of experimental group tumor bearing nude mice size average out to 0.34cm
2, the tumor size average out to 0.76cm of matched group tumor bearing nude mice
2The above results explanation illustrative experiment medicine has stronger inhibition effect to melanoma.
Use HCC (HepG2 cell line available 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
2The above results explanation illustrative experiment medicine has stronger inhibition effect to hepatocarcinoma.
Use lung carcinoma cell (A549 cell line available 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
2The above results explanation illustrative experiment medicine has stronger inhibition effect to hepatocarcinoma.
Claims (10)
1. nanoparticle preparation of drug combination method, said nanoparticle pharmaceutical composition contains amphipathic nature polyalcohol, hydrophobic drug and hydrophilic medicament, and this method may further comprise the steps:
(1) under the ultrasound wave radiation condition, first solution is mixed and emulsifying with second solution, obtain first emulsion;
Said first solution contains the said amphipathic nature polyalcohol and first organic solvent, and said second solution contains said hydrophilic medicament and water;
Said first organic solvent be for can dissolve said amphipathic nature polyalcohol, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(2) with said first emulsion and first surface activating agent aqueous solution, and the mixed material of gained mixed with the 3rd solution and emulsifying, obtain second emulsion;
Said the 3rd solution contains the said hydrophobic drug and second organic solvent;
Said second organic solvent be for can dissolve said hydrophobic drug, but water insoluble, and under emulsification condition not with the organic solvent of said amphipathic nature polyalcohol, said hydrophobic drug and said hydrophilic medicament generation chemical reaction;
(3) with said second emulsion and second surface activating agent aqueous solution, and remove said first organic solvent and said second organic solvent, separate obtaining said nanoparticle pharmaceutical composition.
2. method according to claim 1, wherein, in the step (1), the volume ratio of said first solution and said second solution is 1: 1-1: 10; In said first solution, with respect to every milliliter first organic solvent, the content of said amphipathic nature polyalcohol is the 5-100 milligram; In said second solution, with respect to every milliliter water, the content of said hydrophilic medicament is the 0.01-100 milligram.
3. method according to claim 1 and 2, wherein, in the step (1), said amphipathic nature polyalcohol also contains targeting group and/or imaging group; Said targeting group is one or more in essence-Gan-aspartic acid motif cyclic peptide group, folic acid group and the transferrins group; Said imaging group is quantum dot group and/or fluorescent dye group.
4. method according to claim 1 and 2, wherein, in the step (1), said amphipathic nature polyalcohol is one or more in poly glycol monomethyl ether-polylactic acid-glycollic acid, PEO-PPOX, Polyethylene Glycol and the poly (l-lactic acid); Said hydrophilic medicament is one or more in amycin, mitoxantrone, daunorubicin and the epirubicin; Said first organic solvent is one or more in dichloromethane, dimethyl sulfoxide, oxolane, acetone, espeleton, dichloro-benzenes and the methyl isopropyl ketone.
5. method according to claim 1, wherein, in the step (1), said emulsive condition comprises: the radiating frequency of ultrasound wave is 20-25kHz, accepts the radiating material of ultrasound wave with respect to every milliliter, power is 10-190W; Emulsive temperature is 1-99 ℃, and the emulsive time is 1-30 minute.
6. method according to claim 1, wherein, in the step (2), with respect to first emulsion of 1 volume, the consumption of said first surface activating agent aqueous solution is the 0.5-2 volume, the consumption of said the 3rd solution is the 0.1-1 volume; In the said first surface activating agent aqueous solution, the content of said first surface activating agent is 0.6-6 weight %; In said the 3rd solution, with respect to every milliliter second organic solvent, the content of said hydrophobic drug be 0.01 milligram in said second organic solvent, the reach capacity content of concentration of said hydrophobic drug.
7. according to claim 1 or 6 described methods, wherein, in the step (2), said first surface activating agent is one or more in polyvinyl alcohol, soil temperature 80, span and the dodecyl sodium sulfate; Said hydrophobic drug is one or more in paclitaxel, camptothecine, harringtonine and the vinorelbine.
8. according to claim 1 or 6 described methods, wherein, in the step (2), said emulsive condition comprises: the radiating frequency of ultrasound wave is 20-25kHz, accepts the radiating material of ultrasound wave with respect to every milliliter, and power is 10-190W; Emulsive temperature is 1-99 ℃, and the emulsive time is 1-30 minute.
9. method according to claim 1, wherein, in the step (3), with respect to said second emulsion of 1 volume, the consumption of said second surface activating agent aqueous solution is the 2-20 volume; In the said second surface activating agent aqueous solution, the content of said second surface activating agent is 0.3-3 weight %;
Said second surface activating agent is one or more in polyvinyl alcohol, soil temperature 80, span and the dodecyl sodium sulfate.
10. nanoparticle pharmaceutical composition; This nanoparticle pharmaceutical composition is prepared by any described method among the claim 1-9, and wherein, said hydrophobic drug is a paclitaxel; Said hydrophilic medicament is an amycin; Said amphipathic nature polyalcohol is poly glycol monomethyl ether-polylactic-co-glycolic acid, and in the said nanoparticle pharmaceutical composition, the weight ratio of said hydrophobic drug and said hydrophilic medicament is 1: 10000-10000: 1.
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