CN101366953B - Small numerator modified iron oxide nano-granule freeze-dried powder for injection and preparation method thereof - Google Patents
Small numerator modified iron oxide nano-granule freeze-dried powder for injection and preparation method thereof Download PDFInfo
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- CN101366953B CN101366953B CN200810156259XA CN200810156259A CN101366953B CN 101366953 B CN101366953 B CN 101366953B CN 200810156259X A CN200810156259X A CN 200810156259XA CN 200810156259 A CN200810156259 A CN 200810156259A CN 101366953 B CN101366953 B CN 101366953B
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Abstract
The invention provides micromolecule modifying iron oxide nano particle freeze-dry powder for injection, which consists of micromolecule modifying iron oxide nano particles, freeze-dry protectants and additives, wherein the powder comprises the following components in weight percentage: 0.1 to 40 percent of micromolecule modifying iron oxide nano particle based on iron, 5 to 95 percent of freeze-dry protectant and 1 to 60 percent of stabilizer. The preparation process comprises the following steps: the micromolecule modifying iron oxide nano particle liquid passes through a G3 hammer fused hopper, is evenly mixed with the injection aqueous solution of the freeze-dry protectant and the stabilizer by mechanical stirring, is subjected to ultrasonic or high pressure homogenization to be further dispersed, passes through a G3 hammer fused hopper, is charged with nitrogen gas, is sterilized at the temperature of 100 DEG C for 30 minutes or sterilized by passing a filter membrane with the hole diameter of 0.22mu m, is pre-frozen at the temperature between 40 and 15 DEG C below zero for 6 to 12 hours and is subjected to freeze-drying for 10 to 24 hours, and the micromolecule modifying iron oxide nano particle freeze-dry powder is finally obtained.
Description
Technical field
The present invention relates to NMR contrast agent, be specifically related to injection small numerator modified iron oxide nano-granule contrast agent lyophilized powder and preparation method.
Background technology
Nuclear magnetic resonance (Magnetic resonance imaging, MRI) be to utilize hydrone proton in the organism different tissues to come a kind of diagnostic techniques that has potentiality of imaging adding the different resonance signal of generation under the influence of magnetic field, the power of its signal depends on the content of water in the tissue and the relaxation time of water proton.(Computer assisted tomography, CT), X-ray and radio nuclide imaging are compared does not have radioactive ionization infringement, and resolution is higher with computerized tomography.From first MRI contrast agent Gd-DTPA (gadolinium-diethylenetriamine pentaacetic acid in 1988, trade name: magnetic shows Portugal's amine) successfully develop by German Schering Corp (Schering AG) since, because of its rapid dynamic scan and the extra advantage such as contrast that increases between normal and pathological tissues, the sensitivity and the specificity of MRI diagnosis all are improved, so is accepted very soon, and provide a new breakthrough mouth for the development of MRI technology by people.Subsequently, research worker has been developed a series of MRI contrast agent again, as Gd-DOTA (gadoterlc acid meglumine saltlniection), Gd-BOPTA (Gadobenate Dimeglumine), Mn-DPDP (two pyridoxol diphosphonic acid manganese), Superparamagnetic Iron Oxide etc.The MRI contrast agent generally is divided into paramagnetism, ferromagnetism and superparamagnetism contrast agent.Gd-DTPA studies and uses maximum paramagnetic contrast mediums at present, is mainly used in central nervous system's nuclear magnetic resonance.There is not specific target organ owing to distribute in its body, and eliminate too fast (rapidly by intercellular substance and through renal excretion) in the body, in the clinical diagnosis process, be difficult to keep desired concn, simultaneously again must outfit can rapid scanning equipment, therefore have the superparamagnetism contrast agent of organizing specific targeting and longer blood circulation half-life and arise at the historic moment.
The diagnosis of cancer and treatment are global difficult problems, and hepatocarcinoma to be China occupy second cancer " killer ", how effectively control is the task of top priority, early discovery clinically, early diagnosis are its keys.Superparamagnetic Iron Oxide (Superparamagnetic iron oxide, SPIO) be a kind of nano level magnetic material, with it as the molecular image probe material, be prepared into magnetic resonance imaging contrast with liver specific target tropism, aspect the recall rate of liver focal lesion especially small liver cancer, Small Liver Cancer, qualitative identification diagnosis, started the bonded new world of cell function and image.In the earlier detection of hepatocarcinoma, bring up to the Small Liver Cancer that detects below the 5mm by the small liver cancer that can only detect originally below the 3cm, promptly before clinical symptoms appears in the patient or before cancer is soaked into, made a definite diagnosis, thereby get timely medical treatment, and then take this to improve prognosis, reach the purpose that improves cure rate, reduces death.In addition, SPIO also have particle diameter little, to the externally-applied magnetic field hypersensitivity, withdraw from advantages such as no clean remanent magnetism behind the magnetic field, relaxation rate height, little, the non-target organ of using dosage distribute less, toxic and side effects is little, therefore become the research focus of MRI contrast agent in recent years.
Because SPIO assembles easily, so need its surface is modified to improve the stability in the solution, modal is that macromole is glucan-modified.At present, using maximum SPIO selectivity liver target MRI contrast agent clinically is the AMI-25 (Ferumoxides, trade name Feridex, luxuriant and rich with fragrance upright magnetic) that is produced by U.S. Advanced Magnetic company, also is unique SPIO contrast agent that enters Chinese market.Feridex is a kind of by glucan-modified iron oxides colloid solution, and liver target good (through the intravenously administrable post dose be distributed in liver more than 80%).But it is, very fast from Chinese market exit owing to cost an arm and a leg.Compare the small molecule monomer chelating agen with glucosan cheap, and safety non-toxic can improve the stability of SPIO, and the Related product listing of small numerator modified SPIO is not arranged at present as yet.In addition, small numerator modified SPIO also has following special benefits: 1, micromolecule can form stable water-soluble compound with magnetic particle, this complex can be in many external environments stable existence, as bigger pH scope (3-11), suitable ionic strength (＜0.35mol/l) and multiple biochemical buffer (acetic acid, citric acid, phosphoric acid, Tris); 2, the active group in the micromolecule can the grafting various biomolecules, further is applied to the imaging of receptor-mediated magnetic label probe.Though the small numerator modified stability that can improve the SPIO solution state greatly still can not satisfy the not accumulative requirement of long storage time.
Summary of the invention
Technical problem: the purpose of this invention is to provide a kind of small numerator modified iron oxide nano-granule freeze-dried powder for injection and preparation method, overcome instability problems such as the gathering that occurs in the small numerator modified SPIO contrast agent liquid form storage process, precipitation, be made into loose porous freeze-dried powder and can avoid phenomenon such as gathering, precipitation in the fluid storage process, prevent the problems such as capillary embolism that cause after the aggregation intravenous injection, can also prolong the effect duration of product greatly, increase the market share and the competitiveness of product.
Technical scheme: the invention provides a kind of small numerator modified iron oxide nano-granule freeze-dried powder for injection and preparation method.This is a kind of new formulation-freeze-dried powder of small numerator modified iron oxide nano-granule mri contrast agent, but clinical use is preceding with intravenous injection behind its dissolved dilution, is used for the NMR (Nuclear Magnetic Resonance)-imaging and the molecular probe of liver, spleen, lymph node.At present, prescription and the preparation technology who small numerator modified iron oxide nano-granule is made freeze-dried powder do not appear in the newspapers.
Small numerator modified iron oxide nano-granule freeze-dried powder for injection of the present invention consist of small numerator modified iron oxide nano-granule, freeze drying protectant, additives; It is composed as follows by weight percentage:
Small numerator modified iron oxide nano-granule is in ferrum 0.1-40%
Freeze drying protectant 5-95%
Stabilizing agent 1-60%.
In the small numerator modified iron oxide nano-granule, ferrum oxide is iron sesquioxide or ferroso-ferric oxide; The mean diameter of ferric oxide nano granulated iron nuclear is in 1～50 nanometer; The micromolecule that is used for modified iron oxide nano-granule is a kind of of aminoacid, 'alpha '-hydroxy acids, hydroximic acid, dimercaptosuccinic acid, silicon dioxide.
Described freeze drying protectant is one or more the mixture in glucose, lactose, mannitol, sorbitol, inositol, xylitol, sucrose, trehalose, fatty acid cane sugar ester, maltose, maltotriose, maltodextrin, levan, dextran, starch, the hetastarch.
Described stabilizing agent is one or more the mixture in polyvinylpyrrolidone, poloxalkol, Tween 80, the Polyethylene Glycol.
The preparation method of small numerator modified iron oxide nano-granule freeze-dried powder for injection is as follows: small numerator modified iron oxide nano-granule liquid is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously of freeze drying protectant and stabilizing agent, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen, 100 ℃ of heat sterilizations 30 minutes or cross 0.22 μ m filter membrane degerming;-40～-15 ℃ of pre-freezes are after 6～12 hours, lyophilization 10～24 hours, promptly.
Beneficial effect: it is very high to prepare the glucan-modified iron oxides colloid solution cost of stable macromole, its reason has two: 1, needs to adopt highly purified macromole to carry out the finishing of ferrum oxide, and the high macromole general technology complexity of production purity, and output is lower; 2, the iron oxide nano-granule particle diameter that generally prepares is difficult to homogeneous, all has certain distribution, and the particle size distribution heterogeneity is the unsettled key factor of liquid nano grain disperse system, so need separation and purification in several ways, in the hope of obtaining the iron oxide nano-granule of narrow diameter distribution, certainly will cause output to reduce like this, cost raises.Macromole is difficult to obtain high-purity product relatively, the easier purification of micromolecule, so select for use the cost of material of modified iron oxide nano-granule cheap among the present invention, can avoid liquid nano grain particle diameter uneven acceleration settled possibility after being made into solid-state freeze-dried powder in addition, thereby abandon the separating step that causes output to reduce greatly.As seen, the small numerator modified iron oxide freeze-dried powder that relates among the present invention has the outstanding market advantage.
The small numerator modified iron oxide freeze-dried powder that adopts prescription of the present invention and preparation technology to prepare, critical natures such as the magnetic property of iron oxide nano-granule, ferrum karyosome footpath, mean diameter, particle size distribution before after rebuilding aquation, not changing lyophilizing, solution after the aquation can be stablized more than 72 hours, haemolysis not, no blood vessel zest meets clinical vein injection requirement.
The specific embodiment
Freeze-dried powder consist of small numerator modified iron oxide nano-granule, freeze drying protectant, additives etc.Its prescription (by weight percentage) composed as follows:
Small numerator modified iron oxide nano-granule (in ferrum) 0.1-40%
Freeze drying protectant 5-95%
Stabilizing agent 1-60%
Its optimizing prescriptions is composed as follows:
Small numerator modified iron oxide nano-granule (in ferrum) 4-20%
Freeze drying protectant 20-80%
Stabilizing agent 10-40%
The micromolecule aminoacid that is used for modified iron oxide nano-granule is glutamic acid, L-cysteine, lysine, phenylalanine etc., and 'alpha '-hydroxy acids is that citric acid, tartaric acid, glucose etc., hydroximic acid are arginine hydroximic acid etc.
Preparation process is as follows:
Small numerator modified iron oxide nano-granule liquid is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously of freeze drying protectant and stabilizing agent, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen, 100 ℃ of heat sterilizations 30 minutes or cross 0.22 μ m filter membrane degerming;-40～-15 ℃ of pre-freezes are after 6～12 hours, lyophilization 10～24 hours, promptly.
Embodiment 1: citric acid modification iron oxide nano-granule colloid solution 56mg (in ferrum) is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously that contains 0.5g mannitol, 0.1g Tween 80, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen, the degerming in 30 minutes of 100 ℃ of heat sterilizations;-20 ℃ of pre-freezes are after 12 hours, lyophilization 12 hours, promptly.
Embodiment 2: dimercaptosuccinic acid modified iron oxide nano-granule colloid solution 56mg (in ferrum) is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously that contains 0.8g sorbitol, 0.05g PEG400, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen, the degerming in 30 minutes of 100 ℃ of heat sterilizations;-40 ℃ of pre-freezes are after 12 hours, lyophilization 24 hours, promptly.
Embodiment 3: glutamic acid modified iron oxide nano-granule colloid solution 56mg (in ferrum) is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously that contains 1g glucose, 0.12g polyvinylpyrrolidone, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen is crossed 0.22 μ m filter membrane degerming;-30 ℃ of pre-freezes are after 10 hours, lyophilization 18 hours, promptly.
Claims (4)
1. small numerator modified iron oxide nano-granule freeze-dried powder for injection, what it is characterized in that this lyophilized powder consists of small numerator modified iron oxide nano-granule, freeze drying protectant, stabilizing agent; It is composed as follows by weight percentage:
Small numerator modified iron oxide nano-granule is in ferrum 0.1-40%
Freeze drying protectant 5-95%
Stabilizing agent 1-60%;
In the small numerator modified iron oxide nano-granule, ferrum oxide is iron sesquioxide or ferroso-ferric oxide; The mean diameter of ferric oxide nano granulated iron nuclear is in 1～50 nanometer; The micromolecule that is used for modified iron oxide nano-granule is a kind of of aminoacid, hydroximic acid, dimercaptosuccinic acid, silicon dioxide.
2. small numerator modified iron oxide nano-granule freeze-dried powder for injection according to claim 1 is characterized in that described freeze drying protectant is one or more the mixture in glucose, lactose, mannitol, sorbitol, inositol, xylitol, sucrose, trehalose, fatty acid cane sugar ester, maltose, maltotriose, maltodextrin, levan, dextran, starch, the hetastarch.
3. small numerator modified iron oxide nano-granule freeze-dried powder for injection according to claim 1 is characterized in that described stabilizing agent is one or more the mixture in polyvinylpyrrolidone, poloxalkol, Tween 80, the Polyethylene Glycol.
4. the preparation method of a small numerator modified iron oxide nano-granule freeze-dried powder for injection as claimed in claim 1 is characterized in that preparation process is as follows: small numerator modified iron oxide nano-granule liquid is crossed G
3The molten funnel of hammer with the aqueous solution for injection mechanical agitation mix homogeneously of freeze drying protectant and stabilizing agent, adopts ultrasonic or high pressure homogenize further disperses, mistake G
3The molten funnel of hammer; Inflated with nitrogen, 100 ℃ of heat sterilizations 30 minutes or cross 0.22 μ m filter membrane degerming;-40～-15 ℃ of pre-freezes are after 6～12 hours, lyophilization 10～24 hours, promptly.
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| CN101991857B (en) * | 2009-08-26 | 2011-12-07 | 温州医学院 | Stable pharmaceutical preparation and preparation method thereof |
| CN101672771B (en) * | 2009-09-23 | 2011-05-18 | 东南大学 | Method for applying magnetic gamma-Fe2O3 nano-particle mimetic enzyme to biological detection |
| CN101991866B (en) * | 2010-10-19 | 2013-10-30 | 东南大学 | Nanometer gamma-Fe2O3 relaxation rate standard substance and preparation method thereof |
| CN103316361B (en) * | 2013-07-08 | 2015-04-01 | 武汉百仕康生物科技有限公司 | Stable nanoscale superparamagnetic iron oxide solution as well as preparation method and application thereof |
| CN104512910A (en) * | 2013-09-30 | 2015-04-15 | 吴学文 | Preparation method of manganese hexacyanoferrate and nanoparticle thereof |
| CN104512912A (en) * | 2013-10-08 | 2015-04-15 | 吴学文 | Preparation methods of manganese ferricyanide crystal and nano particle thereof |
| JP2017509570A (en) * | 2013-12-23 | 2017-04-06 | インヴェンション センター コルラートルト フェレレーシュシェーギュー タールシャシャーグ | Soil-binding composition containing iron (III) oxide |
| CN105381475B (en) * | 2015-12-01 | 2018-08-03 | 华中科技大学 | A kind of magnetic resonance imaging contrast and the preparation method and application thereof |
| CN108993439A (en) * | 2018-06-27 | 2018-12-14 | 西南民族大学 | The preparation method of polyurethane/cationic base acid magnetic adsorbent |
| CN109879329B (en) * | 2019-03-27 | 2021-07-27 | 洛阳爱森生物科技有限公司 | Preparation method of nano magnetic beads for extracting ultra-micro nucleic acid |
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| CN101182041A (en) * | 2007-11-27 | 2008-05-21 | 辽宁大学 | Preparation method of spherical nano ferric oxide |
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