CN104548116A - Preparation method of stable protein drug-loaded microparticle system - Google Patents
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Abstract
The invention provides a preparation method of a stable protein drug-loaded microparticle system. The system can be used in a protein microparticle system to deliver a drug into body in order to perform the curative effect. The preparation method comprises the following steps: 1, mixing an organic phase containing the drug with a water phase containing proteins by using a bridging agent to form a homogeneous solution; and 2, directly freeze-drying the homogeneous solution at 0-80DEG C to form a freeze-dried powder injection preparation, carrying out compatibility dilution by using 5% glucose or normal saline or other diluents in clinic use to form the stable protein drug loaded particle; or rapidly diluting the homogeneous solution to reduce the concentration of the bridging agent in order to make the drug rapidly embedded by the proteins and assembled to form the microparticle system. The stable protein drug loaded microparticle system can be used to deliver the drug into body in order to perform the curative effect. The method for preparing the stable protein drug-loaded microparticle system by using the bridging agent has the advantages of mild and simple conditions, suitableness for industrialization, and good application prospect.
Description
Technical field
The present invention discloses a kind of stable protein medicine carrying microgranule system preparation method, can be used for delivering drugs in body and plays drug effect to lesions position, belong to biological pharmacy technical field.
Background technology
It is study large focus at present that protein medicine carrying microgranule system is used for delivering drugs, by the good protein delivery medicine of body internal contact compatibility to lesions position, targeting to focus slow releasing, can the prolong drug half-life and reduce drug toxicity, thus can curative effect be improved, reduce drug toxicity.
Protein microbeads, as study hotspot, has numerous report protein microbeads preparation method, comprises heat cross-linking, chemical crosslinking, emulsion process etc.In these preparation methoies, Typical Representative is emulsifying high pressure homogenization method, and paclitaxel albumin nano granular (abraxane) that goes on the market for 2005 is successful representative, starts the beginning of protein microbeads system clinical treatment.Abraxane adopts emulsifying high pressure homogenize law technology (US Patent No. 6749868, US5560933), the alcoholic solution of albumin solution, paclitaxel and chloroform are mixed to form emulsion, then high pressure homogenizer is used to granulate, then rehydration after high temperature removal organic solvent, can prepare paclitaxel albumin nano granular.This preparation method is complicated, and use the condition such as high pressure homogenize and high temperature, easily cause protein denaturation, lose biological activity, also increase cost, next uses the large solvent of the toxicity such as chloroform, and this has influence on Product Safety undoubtedly.
CN201010247885.7 discloses a kind of method of protein nano grain for the preparation of sending pharmacological active substance in body, utilize protein to open protein hydrophobic region at about 55-75 DEG C, and utilize protein disulfide to open refolding self-assembling method medicine is embedded in protein nano grain.But the method needs about high temperature 55-75 DEG C reaction, cause a lot of pharmacological active substance cannot withstand high temperatures, such as at high temperature its 7-Epitaxol impurity can linearly increase for paclitaxel, thus affects the quality of product.
In existing preparation method, be substantially all according to protein denaturation principle, adopt high temperature, high pressure, chemical modification material solidification albumen, realize the preparation of protein microbeads system.But be high pressure, high temperature, chemical denaturant all make product quality there is unknown unsafe factor.There is loss to protein active, or affect medicine and product quality, all there is certain defect.
Summary of the invention
The invention provides a kind of stable protein medicine carrying microgranule system preparation method, solve the defect such as high temperature, high pressure or chemical denaturant time prepared by above-mentioned protein microbeads, can low temperature, normal pressure and without the condition of chemical denaturant under utilize bridge agent solution method to be prepared into protein medicine carrying microgranule system, ensure further the product quality of protein active and protein medicine carrying microgranule system.Apply in this formulation system delivering drugs to body simultaneously and play drug effect.Preparation technology of the present invention is simple, is applicable to industrialization.
The invention provides a kind of stable protein medicine carrying microgranule system preparation method, it utilizes bridge agent that the organic facies of drug containing and proteinaceous aqueous phase solution are mixed into homogeneous phase solution; Realize the preparation of protein medicine carrying microgranule system, its concrete steps are as follows:
1) use organic solvent dissolution medicine, form pastille organic facies;
2) aqueous phase solution of the protein of 10 ~ 500mg/ml is prepared in protein is water-soluble or buffer system;
3) in step 1), add 1% ~ saturated bridge agent solution mixing, then by 2) in protein aqueous phase solution add, be mixed into homogeneous phase solution;
4) under 0 ~ 80 DEG C of condition, being prepared into freeze-dried powder by forming the direct lyophilization of homogeneous phase solution in step 3), adopting the compatibility dilutions such as 5% glucose or normal saline, namely forming stable protein medicine carrying microgranule system;
Or directly to be used by homogeneous phase solution in step 3) water or 5% glucose, normal saline, buffer salt system to dilute, form stable protein medicine carrying microgranule system;
Described bridge agent is hydrochlorate, sulfate, phosphate, in carbonate any one.
The preferred sodium chloride of bridge agent of the present invention, ammonium sulfate, potassium chloride, sodium sulfate, magnesium sulfate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, sodium carbonate.
Core technology of the present invention prepares protein medicine carrying microgranule system for drug containing organic facies and protein aqueous phase solution being mixed into homogeneous phase solution by bridge agent, and the bridge agent described in it is hydrochlorate, sulfate, phosphate, carbonate.Preferred sodium chloride, ammonium sulfate, potassium chloride, sodium sulfate, magnesium sulfate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, sodium carbonate.More preferably sodium chloride.
In preparation method of the present invention, organic solvent described in step 1) is alcohols, ketone, amide-type or sulfoxide type, preferred alcohol, the tert-butyl alcohol, acetone, N,N-dimethylacetamide, dimethyl sulfoxine.
Step 2 in the technical program preparation method) described protein is albumin, hemoglobin, Myoglobin, lysozyme, immunoglobulin, transferrins, globulin, collagen protein.Be preferably human albumin.
Be described in the technical program that the multiple diluted described in step 4) is 1 ~ 500 times, be preferably 10-50 doubly.
The invention provides a kind of stable protein medicine carrying microgranule system preparation method, it is characterized in that: described bag medicine carrying thing is antitumor drug, preferred paclitaxel, Docetaxel, Cabazitaxel, amycin, CCI-779, sirolimus, mitomycin, romidepsin, SN38, cisplatin and derivant thereof, irinotecan, topotecan, Epothilones, Yi Sha dragon, bortezomib.Be more preferably paclitaxel.
The mean diameter of protein stabilization microparticulate systems of the present invention is 10nm ~ 10 μm, is preferably 50nm ~ 500nm, most preferably is 50nm ~ 250nm.
The present invention discloses a kind of stable human albumin further and carries decitabine microparticulate systems preparation method, comprise the following steps: first dissolve decitabine with dimethyl sulfoxine, then in organic facies, 1 ~ 15% sodium chloride solution is added, after mix homogeneously, add 10 ~ 500mg/ml pH 7 ~ 8 human albumin buffer, mix as after homogeneous phase solution, subpackage, lyophilizing, adopts the diluent compatibilities such as 5% glucose or normal saline to be diluted to stable protein and carries decitabine microparticulate systems during Clinical practice.
The invention also discloses a kind of stable human albumin and carry paclitaxel microparticulate systems preparation method, comprise the following steps: first use anhydrous alcohol solution paclitaxel, then in organic facies, 1% ~ saturated nacl aqueous solution is added, after mix homogeneously, add 10 ~ 500mg/ml albumin aqueous solution, mixing, for after homogeneous phase solution, is diluted in 0 ~ 70 DEG C of water for injection of 10 ~ 50 times, and human albumin's Rapid embedding paclitaxel forms human albumin and carries paclitaxel microparticulate systems.
Direct injection or intravenous drip administration stable protein medicine carrying microgranule system of the present invention can adopt the compatibility such as normal saline, glucose sugar juice to dilute when Clinical practice after.
good effect of the present invention is:preparation method technique is simple, mild condition, is applicable to industrialization, overcomes in existing preparation method and use the shortcomings such as high temperature, high pressure or chemical cross-linking agent, can in a mild condition, utilize bridge agent solution that the organic facies of drug containing and proteinaceous aqueous phase solution are mixed into homogeneous phase solution; Prepare stable protein medicine carrying microgranule system.
The present invention prepares stable protein medicine carrying microgranule system can also use ultrafiltration washing concentrating device, cause microparticulate systems industrialization preferably, be prepared into pharmaceutical preparation by water removal phase simultaneously, the stability of further increase protein stabilization microparticulate systems and practicality, easy to use, store and transport.
Accompanying drawing explanation
The particle size distribution result of Fig. 1, human albumin's carrying mitomycin microparticulate systems.
Fig. 2, human albumin carry the particle size distribution result of paclitaxel microparticulate systems.
Fig. 3, human albumin carry the rear solution thereon of paclitaxel microgranule redissolution.
Fig. 4, bridge agent act on checking in pastille organic facies and human albumin's aqueous phase.
Detailed description of the invention
Further illustrate the present invention by the following examples, mandatory declaration, embodiments of the invention are for illustration of the present invention, and should not be construed as limitation of the present invention.
embodiment 1
10mg mitomycin is dissolved in 1ml N,N-dimethylacetamide, then adds 5% sodium chloride solution 1ml mix homogeneously, finally add and be dissolved into 20% human serum albumin solution 2ml with pH 7.8 phosphate buffer, form homogeneous phase solution.At 0 DEG C, this homogeneous phase solution is directly lyophilized into powder injection formulation, final powder pin finished product adopts normal saline dilution, adopts Malvern Particle Size Analyzer ZS90 to measure particle diameter and HPLC mensuration drug loading.Result display human albumin carrying mitomycin microparticulate systems mean diameter is 290.9nm, and particle diameter and grain size distribution thereof are shown in Fig. 1.Particle drug-loaded amount reaches 2.1%.
embodiment 2
1mg bortezomib is dissolved in the 1ml tert-butyl alcohol, then adds 2% sodium chloride solution 0.5ml mix homogeneously, finally add 2% bovine serum albumin solution 0.5ml, form homogeneous phase solution.At room temperature, this homogeneous phase solution is directly lyophilized into powder injection formulation, and final powder pin finished product adopts normal saline dilution, adopts Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, result shows that preparing microparticulate systems mean diameter is 164nm, and particle drug-loaded amount reaches 7.8%.
embodiment 3
10mg decitabine is dissolved in 1ml dimethyl sulfoxine, then adds 1% sodium radio-phosphate,P-32 solution 1ml mix homogeneously, finally add and be dissolved into 50% bovine serum albumin solution 0.4ml with pH 7.0 phosphate buffer, form homogeneous phase solution.At room temperature, this homogeneous phase solution is directly lyophilized into powder injection formulation, and final powder pin finished product adopts normal saline dilution, adopts Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, result shows that preparing microparticulate systems mean diameter is 264nm, and particle drug-loaded amount reaches 4.1%.
embodiment 4
40mg paclitaxel is dissolved in 4ml ethanol, then adds 12.5% sodium chloride solution 2ml mix homogeneously, finally add 10% human albumin's solution 1.0ml, form homogeneous phase solution.At 40 DEG C, used by this homogeneous phase solution water for injection to dilute 100 times, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 102nm, and Fig. 2 is shown in by grain distribution footpath collection of illustrative plates, and particle drug-loaded amount reaches 18.4%.Simultaneously by after this solution ultrafiltration and concentration, subpackage, lyophilizing, the solution dilution variable concentrations picture that redissolves after lyophilizing see Fig. 3: a. for human albumin carry paclitaxel microgranule redissolve after concentration 0.2mg/ml solution thereon; B. for human albumin carries the rear concentration 0.5mg/ml solution thereon of paclitaxel microgranule redissolution; C. for human albumin carries the rear concentration 2mg/ml solution thereon of paclitaxel microgranule redissolution.
embodiment 5
6mg paclitaxel is dissolved in 2ml methanol, then adds 10% Klorvess Liquid 0.5ml mix homogeneously, finally add 4% bovine serum albumin solution 1ml, be mixed to form homogeneous phase solution.At 80 DEG C, use physiological water to dilute this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 154nm, and drug loading reaches 10.5%.
embodiment 6
20mg paclitaxel is dissolved in 2ml ethanol, then adds 8% sodium chloride solution 1ml mix homogeneously, finally add 10% hemoglobin solutions 1ml, form homogeneous phase solution.This homogeneous phase solution is at room temperature used 5% glucose solution dilution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 185nm, and particle drug-loaded amount also reaches 15.2%.
embodiment 7
10mg paclitaxel is dissolved in 2ml ethanol, then adds 5% sodium dihydrogen phosphate 1ml mix homogeneously, finally add 10% myoglobin solution 1ml, form homogeneous phase solution.At room temperature use water for injection to dilute 20 times this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 173nm, and particle drug-loaded amount reaches 8.3%.
embodiment 8
10mg paclitaxel is dissolved in the 4ml tert-butyl alcohol, then adds 10% ammonium sulfate 1ml mix homogeneously, finally add 5% collagen solution 3ml, form homogeneous phase solution.At room temperature use water for injection to dilute this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 193nm, and particle drug-loaded amount reaches 5.5%.
embodiment 9
10mg paclitaxel is dissolved in the 5ml tert-butyl alcohol, then adds 10% metabisulfite solution 1ml mix homogeneously, finally add 10% globulin solution 1ml, form homogeneous phase solution.At room temperature use water for injection to dilute this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 159nm, and particle drug-loaded amount reaches 8.2%.
embodiment 10
20mg paclitaxel is dissolved in 5ml acetone, then adds 5% sodium radio-phosphate,P-32 solution 1ml mix homogeneously, finally add 10% immunoglobulin solution 2ml, form homogeneous phase solution.At room temperature use water for injection to dilute this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 230nm, and particle drug-loaded amount reaches 7.6%.
embodiment 11
20mg Docetaxel is dissolved in 4ml ethanol, then adds 10% Adlerika 1ml mix homogeneously, finally add 5% Transferrin solution 5ml, form homogeneous phase solution.At 30 DEG C, used by this homogeneous phase solution water for injection to dilute 50 times, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 158nm, and particle drug-loaded amount reaches 5.8%.
embodiment 12
10mg Cabazitaxel is dissolved in 2ml ethanol, then adds 10% sodium carbonate liquor 1ml mix homogeneously, finally add 10% bovine albumin solution 2ml, form homogeneous phase solution.At 40 DEG C, used by this homogeneous phase solution water for injection to dilute 50 times, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 148nm, and particle drug-loaded amount reaches 3.9%.
embodiment 13
2mg Epothilones is dissolved in 5ml methanol, then adds 10% Klorvess Liquid 2ml mix homogeneously, finally add 2% lysozyme soln 3ml, form homogeneous phase solution.At room temperature use water for injection to dilute 50 times this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 156nm, and particle drug-loaded amount reaches 2.8%.
embodiment 14
2mg topotecan is dissolved in 2ml DMSO, then adds 10% sodium chloride potassium solution 0.5ml mix homogeneously, finally add 4% bovine serum albumin solution 1ml, form homogeneous phase solution.At room temperature use water for injection to dilute 10 times this homogeneous phase solution, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 402nm, and drug loading reaches 4.1%.
embodiment 15
100mg paclitaxel is dissolved in 10ml ethanol, then adds 10% sodium chloride potassium solution 5ml mix homogeneously, finally add 20% human albumin's solution 5ml, form homogeneous phase solution.At 35 DEG C, used by this homogeneous phase solution water for injection to dilute 500 times, obtain light blue settled solution.Adopt Malvern Particle Size Analyzer ZS90 mensuration particle diameter and HPLC to measure particle drug-loaded amount, experimental result shows that preparing microparticulate systems mean diameter is 155nm, and drug loading reaches 8.3%.
In order to verify bridge agent effect of the present invention, design is verified as follows respectively:
test example 1
10mg paclitaxel is dissolved in 1ml ethanol, does not add bridge agent, directly add 20% human albumin's solution 1ml; Observe and whether can form homogeneous phase solution.
test example 2
10mg paclitaxel is dissolved in 1ml ethanol, does not add bridge agent, replace adding 1ml water with water, more directly add 20% human albumin's solution 1ml; Observe and whether can form homogeneous phase solution.
test example 3
10mg paclitaxel is dissolved in 1ml ethanol, then adds bridge agent 10% sodium chloride solution 1ml mix homogeneously, finally add 20% human albumin's solution 1ml.Observe and whether can form homogeneous phase solution.
Gather as follows to above-mentioned three test example result of the tests:
| Test example | Phenomenon | Whether homogeneous phase solution can be formed |
| Test example 1 | Muddy immediately, albumen is separated out; | No |
| Test example 2 | Muddy immediately, albumen is separated out; | No |
| Test example 3 | Clarification, forms homogeneous phase solution | Be |
The phenomenon figure of its experimental example is shown in Fig. 4: test example 1 is not for add bridge agent, and muddy immediately after both mixing, albumen is separated out; Test example 2, for not add bridge agent, replaces with water, and also muddy immediately after three's mixing, albumen is separated out; Test example 3, for adding bridge agent 10% sodium chloride solution, forms homogeneous phase solution clarification after mixing.Show in figure, bridge agent plays function served as bridge in organic facies and aqueous phase solution.
The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should limit with claims is as the criterion.
Claims (10)
1. a stable protein medicine carrying microgranule system preparation method, comprises the following steps:
1) use organic solvent dissolution medicine, form pastille organic facies;
2) aqueous phase solution of the protein of 1 ~ 1000mg/ml is prepared in protein is water-soluble or buffer system;
3) in step 1), add 1% ~ saturated bridge agent solution mixing, then by 2) in protein aqueous phase solution add and be mixed into homogeneous phase solution;
4) being prepared into freeze-dried powder by forming homogeneous phase solution lyophilization in step 3), adopting the compatibility dilutions such as 5% glucose or normal saline, namely forming stable protein medicine carrying microgranule system;
5) or at 0 ~ 80 DEG C, homogeneous phase solution in step 3) is used water or 5% glucose or normal saline or buffer salt system rapid dilution, form albumen medicine carrying microgranule system;
Described bridge agent is hydrochlorate, sulfate, phosphate, carbonate.
2. preparation method according to claim 1, is characterized in that
:the preferred sodium chloride of described bridge agent, ammonium sulfate, potassium chloride, sodium sulfate, magnesium sulfate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, sodium carbonate.
3. preparation method according to claim 1, is characterized in that: organic solvent described in step 1) is alcohols, ketone, amide-type or sulfoxide type, preferred alcohol, the tert-butyl alcohol, acetone, N,N-dimethylacetamide, dimethyl sulfoxine.
4. preparation method according to claim 1, is characterized in that: step 2) described protein is albumin, hemoglobin, Myoglobin, lysozyme, immunoglobulin, transferrins, globulin, collagen protein; Be preferably human albumin.
5. preparation method according to claim 1, is characterized in that: the multiple of rapid dilution described in step 5) is 1 ~ 500 times, is preferably 10-50 doubly.
6. preparation method according to claim 1, is characterized in that: described medicine is that antitumor drug is selected from paclitaxel, Docetaxel, Cabazitaxel, amycin, CCI-779, sirolimus, mitomycin, romidepsin, SN38, cisplatin and derivant thereof, irinotecan, topotecan, Epothilones, Yi Sha dragon, bortezomib, is preferably paclitaxel.
7. preparation method according to claim 1, is characterized in that: the mean diameter of described protein particle system is 10nm ~ 10 μm, is preferably 50nm ~ 500nm, most preferably is 50nm ~ 250nm.
8. preparation method according to claim 1, is characterized in that: described medicine accounts for the proportion 0.01 ~ 50% of microgranule.
9. a stable human albumin carries decitabine microparticulate systems preparation method, it is characterized in that: first dissolve decitabine with dimethyl sulfoxine, then in organic facies, 1 ~ 15% sodium chloride solution is added, after mix homogeneously, add 10 ~ 500mg/ml pH 7 ~ 8 human albumin buffer, mixing is after homogeneous phase solution, subpackage, lyophilizing; Adopt the diluent compatibilities such as 5% glucose or normal saline to be diluted to stable protein and carry ground Xi Tabin microparticulate systems.
10. a stable human albumin carries paclitaxel microparticulate systems preparation method, it is characterized in that: first use anhydrous alcohol solution paclitaxel, then in organic facies, 1% ~ saturated nacl aqueous solution is added, after mix homogeneously, add 10 ~ 500mg/ml albumin aqueous solution, mixing is for after homogeneous phase solution, and rapid dilution is in 10 ~ 50 times of 0 ~ 70 DEG C of waters for injection, and human albumin's Rapid embedding paclitaxel forms human albumin and carries paclitaxel microparticulate systems.
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| CN106620663A (en) * | 2017-02-05 | 2017-05-10 | 中国医学科学院生物医学工程研究所 | Preparation method and application of sugar-hemoglobin nanoparticles |
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| CN107970216A (en) * | 2016-10-19 | 2018-05-01 | 上海现代药物制剂工程研究中心有限公司 | A kind of Docetaxel albumin nano granular lyophilized formulations, parenteral solution and its preparation |
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| CN106727356A (en) * | 2017-01-17 | 2017-05-31 | 上海理工大学 | One kind carries medicine protein microbeads and preparation method thereof |
| CN106727356B (en) * | 2017-01-17 | 2020-05-19 | 上海理工大学 | Drug-loaded protein particle and preparation method thereof |
| CN106620663A (en) * | 2017-02-05 | 2017-05-10 | 中国医学科学院生物医学工程研究所 | Preparation method and application of sugar-hemoglobin nanoparticles |
| CN107028898A (en) * | 2017-06-14 | 2017-08-11 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of Irinotecan medicine lyophilized formulations, preparation method and the usage |
| CN112972419A (en) * | 2019-12-02 | 2021-06-18 | 四川科伦药物研究院有限公司 | Preparation method of albumin nano-drug composition |
| CN112972419B (en) * | 2019-12-02 | 2024-03-08 | 四川科伦药物研究院有限公司 | Preparation method of albumin nano-drug composition |
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