CN101732258A - 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 one Nano microsphere, be specifically related to a kind of gemcitabine-albumin nanometer microball preparation that is used for chemotherapy of tumors such as cancer of pancreas and preparation method thereof.
Background technology
Gemcitabine [gemcitabine, GCB; 2 '-deoxidation-2 ', 2 '-difluoro cytidine 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 tumors such as present clinical cancer of pancreas and nonsmall-cell lung cancer, it is unique up to now a line medicine by FDA approval treatment advanced pancreatic cancer, about research discloses and traditional 5-FU curative effect comparative result is: 23.8%vs 4.8%, P=0.0022 shows that the GCB chemotherapy has clear superiority.
The gemcitabine preparation of clinical practice at present is the gemcitabine hydrochloride freeze-dried powder, and clinical practice shows, this dosage form exists three than important disadvantages: (1) metabolism is fast, and plasma half-life is short, and only about 17min, slow-releasing is not enough; (2) molecular weight is little, and hydrophilic is strong, tissue-accumulating and poor at the targeting of vitals such as tumor, pancreas, liver, spleen, lungs; (3) above-mentioned two characteristics are in conjunction with having caused the gemcitabine dosage big, and clinical efficacy does not reach satisfactory level, and the whole body toxic and side effects also increases thereupon.
Studies show that Nano microsphere can be used as the carrier of targeting drug delivery system,, have goodish potential applicability in clinical practice at present as the focus of Chinese scholars research.
Nano microsphere comprises nanosphere and two successive notions of microsphere, and described nanosphere (nanospheres) is that (its size is between 10～1000nm for nanoparticles, Ne) a kind of for nanoparticle; Described microsphere (microspheres) is meant that particle diameter is greater than 1 micron Nano microsphere.One of key component of Nano microsphere is a 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 awaits to estimate.
Common drug-supplying system manufacturing process mostly is and utilizes gemcitabine precursor, gemcitabine derivant, gemcitabine chemical compound at present, and then its bag is carried particulate delivery system.The method of this change chemical constitution, no doubt can improve the drug loading and the stability of gemcitabine microparticulate systems, the drug toxicity that can partly keep gemcitabine simultaneously, but the gemcitabine after the change structure, its pharmacodynamics, pharmacokinetics, safety all need to reappraise, clinical practice shows that above-mentioned drug-supplying system still can not replace primary 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-albumin nanometer microball preparation that is used for chemotherapy of tumors and preparation method thereof.
The present invention adopts precipitation-cross-linking method nanoparticle technology of preparing, carrying out reagent selects, writes out a prescription and determine to reach preferably, with the albumin is framework material, under the prerequisite that does not change the gemcitabine structure molecular structure, change the dosage form of gemcitabine,---the albumin nanometer is microsphere supported---parcel carries the gemcitabine crude drug to micron particles by the good nanometer of slow-releasing, realizes high drug load and good stable.
Described albumin is one of aqueous albumen in the human plasma; be that framework material is made Nano microsphere and can be overcome the hemolytic that prior art exists and the defective of immunogenicity with the albumin; and have good biocompatibility, safety non-toxic, biodegradable, can protect 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 gemcitabine-albumin nanometer microball preparation that the preparation of gemcitabine crude drug is used for chemotherapy of tumors.
" gemcitabine-albumin " of the present invention Nano microsphere is made up of the preparation material 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 an amount of
Above-mentioned dehydrant is selected from a kind of in ethanol, methanol or the acetone;
Described cross-linking agent is selected from a kind of in glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or the genipin.
The present invention adopts ethanol precipitation-glutaraldehyde cross-linking degeneration methods to prepare " gemcitabine-albumin " Nano microsphere by following step:
1, dissolving is mixed: gemcitabine, albumin are dissolved in respectively in water for injection or the sodium chloride solution by described weight proportion, adopt sodium hydroxide solution to regulate pH to 6-11;
2, dehydration: after the two mixes, stir constant speed adding dehydrant down,
Described dehydrant is selected from ethanol, methanol or acetone;
3, crosslinking curing: blue opalescence added an amount of cross-linking agent continuous stirring 10-13 hour after producing, and promoted the crosslinking curing of Nano microsphere,
Described cross-linking agent is selected from glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or genipin;
4, lyophilizing: with the gemcitabine albumin nanometer microsphere colloidal suspension of gained, after 30 ℃-50 ℃ decompressions of temperature control were removed, lyophilization promptly obtained 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 with carry out pharmacodynamic assessment, the 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 regional arterial perfusion of cancer of pancreas is about to ductus arteriosus and inserts tumor blood for tremulous pulse, and through conduit injection chemotherapeutics, arterial perfusion can make gemcitabine in pancreas, tumor by local, liver, even the drug level of target organ tissue such as regional lymph nodes obviously improves, the holdup time obviously prolongs in the body, to the toxic and side effects minimizing of other internal organs of whole body.Metabolism than the common gemcitabine injection of present 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, shortcomings such as dosage is big, toxic and side effects is big, gemcitabine of the present invention-albumin nanometer microsphere is applied to local intra-arterial infusion and gets involved chemotherapy, can reach that perfusion administration, first pass effect, circulation delay, wall of micrangium high penetration, tumor cell height are engulfed, the effect of lymph retention etc. " multistage targeting ".Intravenous chemotherapy, local intra-arterial infusion that said preparation not only can be applicable to related neoplasms such as cancer of pancreas, nonsmall-cell lung cancer get involved chemotherapy, can also be applied to other chemotherapy modes such as chemotherapy of mesenchyma stroma, intraperitoneal chemotherapy of related neoplasms, aspect chemotherapy of tumors, have a good application prospect.
The present invention is by basic research and animal experiment, the result confirms: the dosage form that changes gemcitabine,---the albumin nanometer is microsphere supported---parcel carries the gemcitabine crude drug to micron particles by the good nanometer of slow-releasing, can obviously improve the slow-releasing and the tissue-accumulating of this medicine, effectively improve the gemcitabine concentration in tumor and other target organs, prolong the effective acting time of gemcitabine, and reduce side effects of pharmaceutical drugs.
Description of drawings
Fig. 1 is the general form of gemcitabine albumin nanometer microsphere, wherein A: lyophilized powder, B: aqueous solution.
Fig. 2 is the 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 that gemcitabine albumin nanometer microsphere is at intravital medicine tissue distribution of rat and slow release.
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 plantation tumor growth curve.
Fig. 7 is that gemcitabine albumin nanometer microsphere Beagle dog is got involved the 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 the 1mL water for injection, regulate pH value to 8.5 with 1M NaOH solution, the 1.25mg gemcitabine hydrochloride is dissolved in the 100 μ L waters for injection, regulate about pH value to 9.0 with 1M NaOH solution, stir down drug solution is added in the albumin solution, speed with 1.0mL/min under the stirring state adds 3.0mL ethanol, to forming blue opalescence, after stirring 10min, add 2.5 μ L cross-linking agent glutaraldehydes, continuous stirring 12h impels the nanoparticle crosslinking curing, and 40 ℃ of following reduction vaporizations are removed ethanol, lyophilization promptly gets 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 the stirring state adds the 5.0mL dehydrated alcohol, form the liliquoid suspension, stirring state adds down 15 μ L glutaraldehydes, and continuous stirring 6h impels the albumin nano granular crosslinking curing, removes ethanol under reduced pressure under 30 ℃, lyophilization promptly gets 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 the stirring state adds the 5mL acetone soln, form the liliquoid suspension, stirring state adds down 30 μ L glutaraldehydes, and continuous stirring 8h impels the albumin nano granular crosslinking curing, removes acetone under reduced pressure under 30 ℃, lyophilization promptly gets gemcitabine albumin nanometer microsphere.
The preparation and the parameter detecting of embodiment 4 gemcitabine albumin nanometer microspheres
The 50mg albumin is dissolved in the 2mL water for injection, regulates pH value to 10.0 with 1M NaOH solution, the speed with 1.0mL/min under the stirring state adds the 8.0mL dehydrated alcohol, forms the liliquoid suspension.In addition the 5mg gemcitabine hydrochloride is dissolved in the 0.5mL water for injection, regulating pH value to 10.0 back with 1M NaOH solution joins under stirring state in the barren 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 ℃,, promptly get albumin nanometer microball preparation the colloid solution lyophilization.
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, just drops to below the effective blood drug concentration after 1 hour after the administration in human body with gemcitabine freeze dried powder solution and compares, and is significantly improved.Dashing forward in 1 hour after the administration and releasing rate is 21.77%, within the acceptable range.
The lyophilized powder of seeing Nano microsphere substantially is white puffy, and aqueous solution detects and shows spheroidal for outstanding turbid shape, Electronic Speculum, and the edge is smooth, and medicament region is seen at part Nano microsphere center.Table 1 is the partial parameters of gemcitabine albumin nanometer microsphere.
Table 1
Embodiment 5: safety, slow-releasing and the targeting experiment of gemcitabine albumin nanometer microsphere
Gemcitabine albumin nanometer microsphere is arrived (n in the SD rat body by vena femoralis injection
1=10) be contrast (n, with the pure medicine injection of gemcitabine crude drug group
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 remedy,tissue's substrate concentration, inquires into safety, slow-releasing and the targeting of gemcitabine Nano microsphere.
Each treated animal is all revived within 1-2 hour in the anesthesia back behind the injectable drug, and experimental group and control animals survival condition do not have significant difference, and is still more active before extremely dissecting, and prompting novel drugs novel form does not have overt toxicity.Two groups were height in the intravital drug plasma elution profiles of rat with the crude drug group, and 10min, 30min, 1h do not have significant difference (p＞0.05), and 2 hours and 4 hours significant differences (p＜0.05) did not have significant difference (p＞0.05) once more by 6 hours.Thereby infer that the Nano microsphere fraction is distributed in blood plasma, and major part still retention in tissue.
After the administration 6 hours, two groups in the intravital drug distribution of organizing of rat, 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 does not see increase there is (p＞0.05), and the result has embodied good targeting and slow-releasing.Meaningfully the pancreas of gemcitabine itself distributes and also is 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 but is a very serious deficiency, must cause the inhibition of liver, spleen transfer not enough.Nano microsphere of the present invention has given significant improvement at this just, has very important realistic meaning.
Embodiment 6: gemcitabine albumin nanometer microsphere is to the inhibition test of 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 difference, and whether the preparation process of gemcitabine albumin nanometer microsphere there is drug effect impairment and the Nano microsphere biocompatibility at cellular level to the depression effect of tumor cell.
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 are done 5 multiple holes.
The result shows, administration group, administration concentration, time point, 4 key factors of cell classification, and all the suppression ratio of pair cell strain produces obviously influence (P=0.000).The overall suppression ratio of Nano microsphere group and crude drug group pair cell reaches 56.98 ± 12.51% and 55.84 ± 13.11% respectively, and blank set of balls is 24.76%.The multi-level analysis of multi-angle also points out Nano microsphere group curative effect more than or equal to the crude drug group; Blank Nano microsphere biocompatibility is good, does not have cytotoxicity (being the boundary with suppression ratio 30% generally).Flow cytometer detects also points out the Nano microsphere group rate of increase to reduce relatively, and apoptosis rate increases relatively.
Embodiment 7: gemcitabine albumin nanometer microsphere is to the inhibition test of transplanted tumor in nude mice
Whether with respect to gemcitabine pure crude drug and blank microsphere to the inhibition of nude mice plantation tumor growth more effective, at the intravital biocompatibility of nude mice how Nano microsphere by the in vivo test of nude mice cancer of pancreas plantation tumor model (PANC-1 cell) if detecting gemcitabine albumin nanometer microsphere; And by SABC detection apoptosis, propagation, microvessel density; Variation by the relevant important gene of a plurality of cancer of pancreas of RT-PCR technology for detection.
4 ages in week, 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 plantation tumor model, treats that tumor grows to (inoculation 1 week of back) about 0.5 centimetre, is divided into 4 groups at random: Nano microsphere group, crude drug group, blank set of balls and normal saline matched group, every group each 6.1 week of inoculation back rises, by nude mice tail intravenously administrable, per 5 days injectable drugs once, continuous 4 times.According to people-animal dose reduction formula, carry out dose in conjunction with the microsphere drug loading and calculate.Inoculation back is risen and was surveyed the tumor size 1 time with slide gauge in per 5 days, and claims the nude mice body weight.Volume=(1/6) * ∏ * major diameter * minor axis by formula
2Calculate gross tumor volume, draw tumor growth curve.Animal is put to death the 5th weekend in the inoculation back, weighs; Peel off tumor, analytical balance claims tumor heavy; Tumor is cut half cryopreservation, and the follow-up rt-PCR that carries out detects; Second half is fixed with dipped into formalin, and the follow-up pathological section that carries out detects.
The result shows: in the experimentation in whole 5 weeks, and 30 none death of nude mice.But weight loss is serious during the administration of crude drug group nude mice, drops to 17.83 grams, the too late crude drug group of the weight loss of Nano microsphere group far away by 20.67.The prompting Nano microsphere has the effect that reduces the chemotherapeutic toxic and side effects.Blank set of balls curve is lasting parallel with the normal saline sets of curves, 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 continues to descend; The crude drug group also has the 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%, crude drug group only about 100% and 40%.
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, and the no blood streak is membrane-like and is attached to subcutaneously, need scrape and obtain.Little on the crude drug group total tumor, disappear but there is 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 are obviously greater than other each groups, and two groups respectively have a tumor generation ulceration suppuration, reduction in bulk in the week in the end, 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 find that respectively nude mice liver shifts, and the order of severity increases progressively successively, be several " buphthalmos shape " kitchen ranges in the crude drug group, are " Caulis et folium pavettae hongkongensis " at blank set of balls, are that the liver nodositas is out of shape in the normal saline group.Do not find transfers such as lymph node, lungs
Utilization Ki-67 SABC detects the plantation tumor rate of increase, and the result shows that the Nano microsphere group is starkly lower than other each group (P＜0.05); Utilization 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 that utilization CD34 SABC is measured plantation tumor microvessel density (MVD) shows that chemotherapy group MVD is starkly lower than non-chemotherapy group (P＜0.05), and wherein nanosphere numerically is lower than the crude drug group again for little group.Utilization RT-PCR technology for detection apoptosis-related genes bcl-2 and bax, angiogenesis related gene VEGF, methylate related gene MBD1 and multidrug resistance gene MDR1's, statistical result all has difference and the meaning on the numerical value.
Embodiment 8: his shore albumin nanometer microsphere of west is finished the lattice dog and is got involved the chemotherapy test
Carry out cancer of pancreas with complete lattice dog and get involved chemotherapy, observe gemcitabine albumin nanometer microsphere and be used to get involved 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.0-12 hour a plurality of time points are got blood after getting involved chemotherapy, 4th, 8,12 hours taking internal organs, adopt high-efficient liquid phase chromatogram technology to detect blood plasma and remedy,tissue's substrate concentration, observe gemcitabine albumin nanometer microsphere and apply to distribution, the slow release characteristics of interventional therapy in animal blood slurry and organs and tissues.Simultaneously detection of drugs is to the influence of hepatic and renal function, organizational structure, etc.
The result shows: behind the injectable drug behind each treated animal continuous narcosis 12 hours, vital sign was steady, opens the abdomen taking internal organ on the 4th, 8 hour, put to death and taking internal organ in the 12nd hour, and zero accident death, experimental group and control animals survival condition do not have significant difference.
The initial blood drug level of crude drug group is higher, descends but drop to low concentration very soon and continue; Though nanometer set of balls initial concentration is lower, descend slowly, it is higher to keep concentration, and the time is longer.Nanometer set of balls portal vein continues to be 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 the rising phenomenon, can support the above microsphere of 200nm to be engulfed by monokaryon-phagocyte easily, takes back the theory of liver by circulation.To showing that with the statistics that gets involved back 12 hours routine blood test, hepatic and renal function other indexs do not have significant change except that platelet has obvious decline before each group intervention chemotherapy, the prompting medicine does not have 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 carries out observing under the mirror, does not see that experimental group has notable difference in tissue morphology configuration aspects and matched group.
Claims (8)
1. a nano microsphere preparations that is used for chemotherapy of tumors is characterized in that, is made up of the preparation material 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 an amount of;
Wherein, described albumin is that framework material is made Nano microsphere, and parcel carries the gemcitabine crude drug.
2. by the described nano microsphere preparations that is used for chemotherapy of tumors of claim 1, it is characterized in that its particle size range of described Nano microsphere is 0-1000nm or more than the 1000nm.
3. preparation method that is used for the nano microsphere preparations of chemotherapy of tumors is characterized in that by following step:
Gemcitabine, albumin are dissolved in respectively in water for injection or the sodium chloride solution by weight ratio, regulate pH to 6-11 with sodium hydroxide solution, after the two mixes, stir constant speed adding dehydrant down, after blue opalescence produces, add cross-linking agent, made the crosslinking curing of Nano microsphere in continuous stirring 10-13 hour, with the gemcitabine albumin nanometer microsphere colloidal suspension of gained, after 30 ℃-50 ℃ decompressions of temperature control were removed, lyophilization promptly got gemcitabine albumin nanometer microsphere.
4. by the described preparation method that is used for the nano microsphere preparations of chemotherapy of tumors of claim 3, it is characterized in that described dehydrant is selected from a kind of in ethanol, methanol or the acetone; Described cross-linking agent is selected from a kind of in glutaraldehyde, methyl polyethylene-dextran, dialdehyde starch, formaldehyde or the genipin.
5. the described nano microsphere preparations of claim 1 is preparing the purposes for the treatment of in cancer of pancreas or the nonsmall-cell lung cancer preparation.
6. by the described purposes of claim 5, wherein said therapeutic modality is an intravenous chemotherapy.
7. by the described purposes of claim 5, wherein said therapeutic modality is the local intra-arterial infusion interventional therapy.
8. by the described purposes of claim 5, wherein said therapeutic modality is intraperitoneal chemotherapy, inside tumor injection chemotherapy of mesenchyma stroma or oral chemotherapy.
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| CN103356485B (en) * | 2012-04-10 | 2019-06-07 | 青岛大学附属医院 | Hirudin albumin nano granular and preparation method thereof |
| 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 |
| CN104337772A (en) * | 2013-08-09 | 2015-02-11 | 于湛 | Porous albumin micro nanosphere preparation process and inner ear trans-round window membrane administration slow-released medicine carrier |
| CN104710630A (en) * | 2013-12-17 | 2015-06-17 | 南京理工大学 | Bovine serum albumin nano microsphere preparation method |
| RU2624323C2 (en) * | 2015-12-24 | 2017-07-03 | Евгений Рафаилович Хайрутдинов | Method for selective chemoembolization of pancreatic malignant tumors |
| US11306111B2 (en) | 2017-07-31 | 2022-04-19 | January Therapeutics, Inc. | Organophosphate derivatives |
| CN110237049A (en) * | 2019-05-15 | 2019-09-17 | 齐齐哈尔医学院 | A method of preparing drug albumin nano granular |
| US11306399B2 (en) | 2019-08-13 | 2022-04-19 | January Therapeutics, Inc. | Nanoparticle compositions |
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