CN101732258B - Nano microsphere preparation used for chemotherapy of tumors and preparation method thereof - Google Patents
Nano microsphere preparation used for chemotherapy of tumors and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of the pharmacy of medicine, which relates to a gemcitabine-albumin nano microsphere preparation used for the chemotherapy of the tumors of pancreatic cancer and the like and a preparation method thereof. The invention uses an ethanol precipitation-glutaric dialdehyde crosslinking denaturation method to prepare a slow-release gemcitabine biodegradable albumin nano microsphere. By animal experiments, the result confirms that the invention can obviously enhance the slow-release property and the tissue retention property of the medicine, enhances the concentration of gemcitabine in tumors and other target organs effectively, prolongs the effective acting time of the gemcitabine and reduces the side effect of the medicine. The nano microsphere can be used for the chemotherapy and the interventional chemotherapy of pancreatic cancer and non-small cell lung cancer and is suitable for the venous chemotherapy, the arterial interventional treatment, the local tumor injection interstitial chemotherapy, the celiac chemotherapy and the oral chemotherapy of tumor patients with gemcitabine adaptive diseases.
Description
Technical field
The invention belongs to medical pharmaceutical technology field, relate to tumor chemotherapeutic drug novel form-Nano microsphere, be specifically related to a kind of gemcitabine for chemotherapy of tumors such as cancer of pancreas-albumin nanometer microball preparation and preparation method thereof.
Background technology
Gemcitabine [gemcitabine, GCB; Gemzart mono-hydrochloric salts (beta isomer); DFdC] belong to miazines cell cycle specific antineoplastic agent, molecular weight is 263.1.GCB is the main chemotherapeutics of the tumors such as current clinical cancer of pancreas and nonsmall-cell lung cancer, it is unique first-line drug by FDA approval treatment advanced pancreatic cancer up to now, about research discloses and traditional 5-FU curative effect comparative result is: 23.8%vs 4.8%, P=0.0022, show that the GCB chemotherapy has clear superiority.
The gemcitabine preparation of clinical practice at present is the gemcitabine hydrochloride freeze-dried powder, the clinical practice demonstration, and this dosage form exists three more serious shortcomings: (1) metabolism is fast, and plasma half-life is short, and only, about 17min, slow-releasing is inadequate; (2) molecular weight is little, and hydrophilic is strong, tissue-accumulating and poor for the targeting of the vitals such as tumor, pancreas, liver, spleen, lungs; (3) above-mentioned two characteristics are in conjunction with having caused the gemcitabine dosage large, and clinical efficacy does not reach satisfactory level, and the whole body toxic and side effects also increases thereupon.
Research shows, Nano microsphere can be used as the carrier of targeting drug delivery system, at present as the focus of Chinese scholars research, has goodish potential applicability in clinical practice.
Nano microsphere comprises nanosphere and two continuous concepts of microsphere, and described nanosphere (nanospheres) is a kind of of nanoparticle (nanoparticles, Ne), and its size is between 10～1000nm; Described microsphere (microspheres) refers to that particle diameter is greater than the Nano microsphere of 1 micron.One of key component of Nano microsphere is framework material.Comparatively ideal framework material requires good biocompatibility, biodegradable, safety non-toxic, but medicament slow release, targeting are clear and definite.The disclosed framework material of prior art has: synthetic polylactic acid, poly-hydroxyl ethanol acid copolymer of poly lactic acid, polybutylcyanoacrylate, liposome, polyphosphate ester copolymer, copolymerization or the blend of poly phosphate and PLA, polifeprosan, PLGA etc., polifeprosan, bis-fatty acid and decanedioic acid copolymer, EVAc, etc.Although these materials mostly can biodegradation and the medicine desorption good, be synthetic, the safety of intravascular administration needs to estimate.
Common drug-supplying system manufacturing process, mostly be and utilize gemcitabine precursor, gemcitabine derivant, gemcitabine compound at present, and then its bag is carried particulate delivery system.The method of this change chemical constitution, no doubt can improve drug loading and the stability of gemcitabine microparticulate systems, the drug toxicity that can partly keep gemcitabine simultaneously, but the gemcitabine after change structure, its pharmacodynamics, pharmacokinetics, safety all need to reappraise, clinical practice shows, above-mentioned drug-supplying system still can not replace original gemcitabine.
Summary of the invention
The purpose of this invention is to provide tumor chemotherapeutic drug novel form-Nano microsphere, be specifically related to a kind of gemcitabine for chemotherapy of tumors-albumin nanometer microball preparation and preparation method thereof.
The present invention adopts precipitation-cross-linking method nanoparticle technology of preparing, carry out the reagent selection, prescription is determined and preferably, take albumin as framework material, under the prerequisite that does not change the gemcitabine structure molecular structure, change the dosage form of gemcitabine, the nanometer good by slow-releasing is to micron particles---the albumin nanometer is microsphere supported---, and parcel carries the gemcitabine crude drug, realizes high drug load and good stability.
Described albumin is one of aqueous albumen in human plasma; the albumin of take is made Nano microsphere as framework material and can be overcome hemolytic that prior art exists and the defect of immunogenicity; and there is good biocompatibility, safety non-toxic, biodegradable, can protect the advantages such as medicament slow release, increase targeting, minimizing drug side effect.
It is that framework material is made Nano microsphere that the present invention adopts albumin, and parcel carries the gemcitabine crude drug for the preparation of the gemcitabine of chemotherapy of tumors-albumin nanometer microball preparation.
" gemcitabine-albumin " of the present invention Nano microsphere is comprised of the material for preparing of following weight ratio:
Gemcitabine 0.1-40mg
Albumin 5-200mg
Water for injection or sodium chloride solution 1-20mL
Dehydrant 2-100mL
Cross-linking agent 0.01-0.3mL
Sodium hydroxide is appropriate
Above-mentioned dehydrant is selected from a kind of in ethanol, methanol or acetone;
Described cross-linking agent is selected from a kind of in glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or genipin.
The present invention adopts ethanol precipitation-glutaraldehyde cross-linking degeneration methods to prepare " gemcitabine-albumin " Nano microsphere by following step:
1, dissolve and mix: gemcitabine, albumin are dissolved in respectively in water for injection or sodium chloride solution by described weight proportion, adopt sodium hydroxide solution to regulate pH to 6-11;
2, dehydration: after the two mixes, stir lower constant speed and add dehydrant,
Described dehydrant is selected from ethanol, methanol or acetone;
3, crosslinking curing: blue-opalescent adds appropriate cross-linking agent continuous stirring 10-13 hour after producing, and promotes the crosslinking curing of Nano microsphere,
Described cross-linking agent is selected from glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or genipin;
4, lyophilizing: by the gemcitabine albumin nanometer microsphere colloidal suspension of gained, after 30 ℃-50 ℃ decompressions of temperature control are removed, lyophilization obtains gemcitabine albumin nanometer microsphere.
The Nano microsphere that the present invention makes did not wait because of the gemcitabine, albumin, dehydrant, the ratio of cross-linking agent and the crosslinked time that add, and its particle diameter both can be in the 50-1000nm scope (nanosphere), or was 1000nm above (microsphere).The present invention preferably peak value is 406nm, is distributed in the gemcitabine albumin nanometer microsphere in the 200-1000nm scope.
The present invention adopts animal experiment checking " gemcitabine-albumin " medicine for effect and carries out pharmacodynamic assessment, result shows: described nano microsphere preparations is applied to oncotherapy can increase targeting by the EPR effect (enhancedpermeability and retention effect, infiltration and retention effect) of tumor.Clinical practice shows, the cancer of pancreas regional arterial perfusion is about to ductus arteriosus and inserts tumor blood for tremulous pulse, and inject chemotherapeutics through conduit, arterial perfusion can make gemcitabine in pancreas, tumor by local, liver, even the drug level of the target organ tissue such as regional lymph nodes obviously improves, in body, the holdup time obviously extends, to the toxic and side effects minimizing of whole body other organs.Metabolism than the common gemcitabine injection of current application is fast, plasma half-life is short, slow-releasing is not enough, molecular weight is little, hydrophilic is strong, tissue-accumulating and vitals targeting deficiency, the shortcomings such as dosage is large, toxic and side effects is large, gemcitabine of the present invention-albumin nanometer microsphere is applied to the local intra-arterial infusion chemotherapy, can reach that perfusion administration, first pass effect, circulation delay, wall of micrangium high penetration, tumor cell are highly engulfed, the effect of lymph retention etc. " multistage targeting ".Said preparation not only can be applicable to intravenous chemotherapy, the local intra-arterial infusion chemotherapy of the related neoplasms such as cancer of pancreas, nonsmall-cell lung cancer, can also be applied to other methods of chemotherapies such as chemotherapy of mesenchyma stroma, intraperitoneal chemotherapy of related neoplasms, have a good application prospect aspect chemotherapy of tumors.
The present invention is by basic research and animal experiment, result confirms: the dosage form that changes gemcitabine, the nanometer good by slow-releasing is to micron particles---the albumin nanometer is microsphere supported---, and parcel carries the gemcitabine crude drug, can obviously improve slow-releasing and the tissue-accumulating of this medicine, effectively improve the gemcitabine concentration in tumor and other target organs, extend the effective acting time of gemcitabine, and reduce side effects of pharmaceutical drugs.
The accompanying drawing explanation
Fig. 1 is the general form of gemcitabine albumin nanometer microsphere, wherein A: lyophilized powder, B: aqueous solution.
Fig. 2 is particle size distribution figure and the transmission electron microscope photo (10,000 times of *) of gemcitabine albumin nanometer microsphere.
Fig. 3 is the vitro drug release curve of gemcitabine albumin nanometer microsphere.
Fig. 4 is medicine tissue distribution and the slow release of gemcitabine albumin nanometer microsphere in the rat body.
Fig. 5 is the pharmacodynamics of gemcitabine albumin nanometer microsphere: BXPC-3 cell strain suppression ratio-administration concentration curve.
Fig. 6 is the pharmacodynamics of gemcitabine albumin nanometer microsphere: nude mice Implanted growth curve.
Fig. 7 is the gemcitabine albumin nanometer microsphere Beagle dog chemotherapy drug distribution figure of test organization.
The specific embodiment:
Now in conjunction with the embodiments, the present invention is described in detail
Embodiment 1
The 20mg albumin is dissolved in 1mL water for injection, regulate pH value to 8.5 with 1M NaOH solution, the 1.25mg gemcitabine hydrochloride is dissolved in 100 μ L waters for injection, regulate pH value to 9.0 left and right with 1M NaOH solution, under stirring, drug solution is added in albumin solution, speed with 1.0mL/min under stirring state adds 3.0mL ethanol, to forming blue-opalescent, after stirring 10min, add 2.5 μ L cross-linking agent glutaraldehydes, continuous stirring 12h impels the nanoparticle crosslinking curing, 40 ℃ of lower reduction vaporizations are removed ethanol, lyophilization, obtain gemcitabine albumin nanometer microsphere.
50mg albumin and 10mg gemcitabine hydrochloride are dissolved in the 2mL normal saline, regulate pH value to 9.0 with 1M NaOH solution, speed with 1.0mL/min under stirring state adds the 5.0mL dehydrated alcohol, form the liliquoid suspension, add 15 μ L glutaraldehydes under stirring state, continuous stirring 6h impels the albumin nano granular crosslinking curing, removes ethanol under reduced pressure under 30 ℃, lyophilization, obtain gemcitabine albumin nanometer microsphere.
Embodiment 3
100mg albumin and 10mg gemcitabine hydrochloride are dissolved in the 2mL normal saline, regulate pH value to 9.0 with 1M NaOH solution, speed with 1.0mL/min under stirring state adds the 5mL acetone soln, form the liliquoid suspension, add 30 μ L glutaraldehydes under stirring state, continuous stirring 8h impels the albumin nano granular crosslinking curing, removes acetone under reduced pressure under 30 ℃, lyophilization, obtain gemcitabine albumin nanometer microsphere.
Preparation and the parameter detecting of embodiment 4 gemcitabine albumin nanometer microspheres
The 50mg albumin is dissolved in 2mL water for injection, with 1M NaOH solution, regulates pH value to 10.0, the speed with 1.0mL/min under stirring state adds the 8.0mL dehydrated alcohol, forms the liliquoid suspension.Separately the 5mg gemcitabine hydrochloride is dissolved in 0.5mL water for injection, after regulating pH value to 10.0 with 1M NaOH solution, under stirring state, join in blank liliquoid suspension, after stirring 1h makes gemcitabine be adsorbed to the nanoparticle surface balance, add 5 μ L glutaraldehyde cross-linkings, stir 12h, remove ethanol under reduced pressure under 40 ℃, by the colloid solution lyophilization, obtain albumin nanometer microball preparation.
It is 405.6 ± 3.5nm that particle size analyzer detects mean diameter, is positioned at the 200-1000nm scope.Drug loading is 13.40%, and envelop rate is 92.56%, reaches the higher level of Nano microsphere medicine carrying; Slow-release time reaches 8-12 hour, with gemcitabine freeze dried powder solution, in human body, after administration, after 1 hour, just drops to below effective blood drug concentration and compares, and is significantly improved.After administration, to release rate be 21.77% to 1 hour inwardly projecting, within the acceptable range.
The lyophilized powder of substantially seeing Nano microsphere is white puffy, and aqueous solution is for being suspended shape, Electronic Speculum detection display spheroidal, and the smooth of the edge, medicament region is seen at part Nano microsphere center.The partial parameters that table 1 is gemcitabine albumin nanometer microsphere.
Table 1
Embodiment 5: the safety of gemcitabine albumin nanometer microsphere, slow-releasing and targeting experiment
Gemcitabine albumin nanometer microsphere is arrived to (n in SD rat body by vena femoralis injection
1=10), take the pure medicine injection of gemcitabine crude drug group as contrast (n
2=10), observe the survival condition of animal, different time points is got blood, and the 6th hour taking internal organ adopts high-efficient liquid phase chromatogram technology to detect blood plasma and Tissue, inquires into safety, slow-releasing and the targeting of gemcitabine Nano microsphere.
After injectable drug, each treated animal is all revived within 1-2 hour after anesthesia, and experimental group and control animals survival condition are without significant difference, still more active before extremely dissecting, and prompting novel drugs novel form does not have overt toxicity.The drug plasma elution profiles of two groups in the rat body, take the crude drug group as high, 10min, 30min, 1h be without significant difference (p>0.05), 2 hours and 4 hours significant differences (p<0.05), by 6 hours again without significant difference (p>0.05).Thereby infer that the Nano microsphere fraction is distributed in blood plasma, and major part still retention in tissue.
After administration 6 hours, organize drug distribution for two groups in the rat body, the Nano microsphere group in the distribution of pancreas, liver, three important target organs of spleen apparently higher than matched group (p<0.05), and the concentration of heart, lungs, muscle, kidney is there are no increasing (p>0.05), result has embodied good targeting and slow-releasing.Meaningfully the pancreas distribution of gemcitabine itself is also higher than its hetero-organization, and the distribution of liver and spleen is denier but, and the former is the advantage of this medicine, and the latter is but a very serious deficiency, must cause the inhibition of liver, spleen transfer inadequate.Nano microsphere of the present invention has given significant improvement at this just, has very important realistic meaning.
Embodiment 6: the inhibition test of gemcitabine albumin nanometer microsphere to a plurality of pancreas cancer cell strains
By in vitro tests, mtt assay (tetramethyl azo azoles salt trace enzyme reaction colorimetry) and flow cytometer method, detect gemcitabine albumin nanometer microsphere with respect to gemcitabine crude drug and blank Nano microsphere the difference to the depression effect of tumor cell, and whether the preparation process of gemcitabine albumin nanometer microsphere has drug effect impairment and the Nano microsphere biocompatibility at cellular level.
Select pancreas cancer cell strain PANC-1, BXPC-3, SW-1990, CFPAC-1 and nonsmall-cell lung cancer A549 totally 5 strains, totally 4 groups of gemcitabine Nano microsphere, blank Nano microsphere, gemcitabine crude drug, culture fluid, 0.01,0.1,1,10,50 μ g/ml totally 5 concentration, 48 hours, 72 hours two time points, each group is done 5 multiple holes.
Result shows, administration group, administration concentration, time point, 4 key factors of cell classification all produce the obviously impact (P=0.000) to the suppression ratio of cell strain.Nano microsphere group and crude drug group reach respectively 56.98 ± 12.51% and 55.84 ± 13.11% to the overall suppression ratio of cell, and blank set of balls is 24.76%.The multi-level analysis of multi-angle also points out Nano microsphere group curative effect to be more than or equal to the crude drug group; Blank Nano microsphere biocompatibility is good, there is no cytotoxicity (generally take suppression ratio 30% as boundary).Flow cytometer detects also points out the Nano microsphere group rate of increase relatively to reduce, and apoptosis rate increases relatively.
Embodiment 7: the inhibition test of gemcitabine albumin nanometer microsphere to transplanted tumor in nude mice
Detect gemcitabine albumin nanometer microsphere by nude mice cancer of pancreas Implanted model (PANC-1 cell) in vivo test whether more effective to the inhibition of nude mice Implanted growth with respect to the pure crude drug of gemcitabine and blank microsphere, the biocompatibility of Nano microsphere in nude mouse how; And detect apoptosis, propagation, microvessel density by SABC; Variation by the relevant important gene of a plurality of cancer of pancreas of RT-PCR technology for detection.
4 week age, male nude mouse nude mouse was 30, back plantation 1 * 10
8the PANC-1 cell 0.2ml of/ml sets up uniform and stable cancer of pancreas Implanted model, grow to 0.5 centimetre of left and right (latter 1 week of inoculation) until tumor, be divided at random 4 groups: Nano microsphere group, crude drug group, blank set of balls and normal saline matched group, every group each 6.After inoculation 1 week, by nude mice tail intravenously administrable, every 5 days injectable drugs once, continuous 4 times.According to people-animal dose reduction formula, in conjunction with the microsphere drug loading, carry out dose calculating.Rise after inoculation and survey tumor size 1 time with slide gauge in every 5 days, and claim the nude mice body weight.Press formula volume=(1/6) * ∏ * major diameter * minor axis
2calculate gross tumor volume, draw tumor growth curve.After inoculation, put to death animal the 5th weekend, weighs; Peel off tumor, analytical balance claims the tumor weight; Tumor is cut half cryopreservation, follow-uply carries out the rt-PCR detection; Second half is fixed with dipped into formalin, follow-uply carries out the pathological section detection.
Result shows: in the experimentation of whole 5 weeks, and 30 none death of nude mice.But during the administration of crude drug group nude mice, weight loss is serious, drop to 17.83 grams by 20.67, the weight loss of Nano microsphere group is far away not as good as the crude drug group.The prompting Nano microsphere has the effect that reduces the chemotherapeutic toxic and side effects.Blank set of balls curve is lasting parallel with normal saline suite line, illustrates that microsphere itself has no side effect.
Nano microsphere group tumor growth curve is starkly lower than other each group (p<0.01), and continuous decrease; The crude drug group also has obvious growth curve to descend, but not as good as Nano microsphere group (p<0.05), and after the drug withdrawal of crude drug group, recovery trend is arranged.Blank set of balls and normal saline group tumor continue to increase, and the two difference is remarkable (p>0.05) not.The heavy tumour inhibiting rate of volume calculated tumour inhibiting rate and tumor, the Nano microsphere group has reached 169% and 69%, and the crude drug group is 100% and 40% left and right only.
Cut tumor after 5 weeks, Nano microsphere group body surface is not obviously seen tumor, and 6 nude mices are only deposited 4 unconspicuous little tumors, and tumor tissues is belittled atrophy, without the blood streak, is membrane-like and is attached to subcutaneously, needs scraping to obtain.Little on crude drug group total tumor, but disappear without tumor, form is full, has thin blood vessel to stretch into, and subcutaneously presents granularly, easily dissects.Blank set of balls and normal saline group gross tumor volume obviously are greater than other each groups, and in the end one week, two groups respectively have a tumor generation ulceration suppuration, reduction in bulk, and it is abundant that naked eyes are seen tumor vessel, peels off smoothly.
Crude drug group, blank set of balls and normal saline group are respectively found a nude mice hepatic metastasis, and the order of severity increases progressively successively, in the crude drug group, are several " buphthalmos shape " kitchen range, at blank set of balls, are " Caulis et folium pavettae hongkongensis ", in the normal saline group, are the distortion of liver nodositas.Do not find the transfers such as lymph node, lungs
Use the Ki-67 SABC to detect the Implanted rate of increase, the result demonstration, the Nano microsphere group is starkly lower than other each group (P<0.05); Use tunel method detection limit tumor death rate, the chemotherapy group apoptosis rate is higher than other each group, and the Nano microsphere group is the highest, reaches 39%, but statistical discrepancy P>0.05; The result of using the CD34 SABC to measure Implanted microvessel density (MVD) shows, chemotherapy group MVD is starkly lower than non-chemotherapy group (P<0.05), and wherein micro-group of nanosphere is again numerically lower than the crude drug group.Use RT-PCR technology for detection apoptosis-related genes bcl-2 and bax, Angiogenesis genes VEGF, methylate related gene MBD1 and Multidrug resistance gene MDR1, statistical result all has difference and the meaning on numerical value.
Embodiment 8: his shore albumin nanometer microsphere of west is finished the test of lattice dog chemotherapy
Carry out the cancer of pancreas chemotherapy with complete lattice dog, observe gemcitabine albumin nanometer microsphere and be used for chemotherapy with respect to the pure medicine (n of gemcitabine crude drug
1=6, n
2=6) in the advantage of slow-releasing and targeting.After chemotherapy, 0-12 hour a plurality of time points are got blood, 4th, 8,12 hours taking internal organs, adopt high-efficient liquid phase chromatogram technology to detect blood plasma and Tissue, observe gemcitabine albumin nanometer microsphere and apply to distribution, the slow release characteristics of interventional therapy in animal blood slurry and organs and tissues.The impact of detection of drugs on hepatic and renal function, organizational structure simultaneously, etc.
Result shows: after injectable drug after each treated animal continuous narcosis 12 hours, vital sign was steady, within the 4th, 8 hours, opens the abdomen taking internal organ, within the 12nd hour, put to death and taking internal organ, and zero accident death, experimental group and control animals survival condition are without significant difference.
The initial blood drug level of crude drug group is higher, but drop to very soon low concentration and continue, descends; Although nanometer set of balls initial concentration is lower, descend slowly, maintain concentration higher, the time is longer.Nanometer set of balls portal vein continues higher than the crude drug group, the high blood drug level of prompting portal vein area target organ.
Internal organs gemcitabine (GCB) concentration during to each group 4,8,12h is added up, and can see more pancreas, spleen, the liver of being distributed in of Nano microsphere group, and gemcitabine concentration wherein continues apparently higher than other two groups (p<0.05); The more muscle that is distributed in of crude drug group.Prompting Nano microsphere group is good to the targeting of pancreas, liver, spleen.
In liver, the gemcitabine Nano microsphere shows rise phenomenon, can support the above microsphere of 200nm easily to be engulfed by monokaryon-phagocyte, takes back the theory of liver by circulation.To showing except platelet has obvious decline with the statistics of the intervention routine blood test of latter 12 hours, hepatic and renal function before each group chemotherapy, other indexs are without significant change, and the prompting medicine, without newly-increased toxic and side effects, has the safety of blood system and hepatic and renal function.HE stained to important organ different time points such as each group pancreas, liver, spleens is carried out Microscopic observation, and having no experimental group has notable difference in tissue morphology configuration aspects and matched group.
Claims (2)
1. the preparation method for the nano microsphere preparations of chemotherapy of tumors is characterized in that by following step:
By gemcitabine, albumin is dissolved in respectively in water for injection or sodium chloride solution by weight ratio, regulate pH to 6-11 with sodium hydroxide solution, after the two mixes, stir lower constant speed and add dehydrant, after blue-opalescent produces, add cross-linking agent, within continuous stirring 10-13 hour, make the crosslinking curing of Nano microsphere, gemcitabine albumin nanometer microsphere colloidal suspension by gained, after 30 ℃-50 ℃ decompressions of temperature control are removed, lyophilization obtains gemcitabine albumin nanometer microball preparation, the mean diameter of described nano microsphere preparations is 405.6 ± 3.5nm, drug loading is 13.40%, described preparation is comprised of the material of following weight ratio:
Wherein, described albumin is that framework material is made Nano microsphere, and parcel carries the gemcitabine crude drug.
2. by the preparation method of the nano microsphere preparations for chemotherapy of tumors claimed in claim 1, it is characterized in that described dehydrant is selected from a kind of in ethanol, methanol or acetone; Described cross-linking agent is selected from a kind of in glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or genipin.
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| EP3142647A4 (en) * | 2014-05-16 | 2017-12-20 | Dana-Farber Cancer Institute, Inc. | Protein-based particles for drug delivery |
| EP3272335A1 (en) * | 2016-07-20 | 2018-01-24 | Richard C.K. Yen | Albumin nanosphere preparations to control bleeding from surgical operations |
| EP3758490A4 (en) * | 2018-03-02 | 2021-12-22 | January Therapeutics, Inc. | Nanoparticle compositions |
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| CN103356492A (en) * | 2012-04-10 | 2013-10-23 | 山东靶点药物研究有限公司 | Tripterine pharmaceutical composition using albumin as pharmaceutical carrier |
| CN104337769A (en) * | 2013-08-06 | 2015-02-11 | 于湛 | Improved preparation technology of alhumin nanosphere and inner ear transmembrane administration sustained release microsphere drug carrier |
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| CN104710630A (en) * | 2013-12-17 | 2015-06-17 | 南京理工大学 | Bovine serum albumin nano microsphere preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3758490A4 (en) * | 2018-03-02 | 2021-12-22 | January Therapeutics, Inc. | Nanoparticle compositions |
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