CN1141144C - Magnetic contrast medium composition and its preparing method - Google Patents
Magnetic contrast medium composition and its preparing method Download PDFInfo
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- CN1141144C CN1141144C CNB011351640A CN01135164A CN1141144C CN 1141144 C CN1141144 C CN 1141144C CN B011351640 A CNB011351640 A CN B011351640A CN 01135164 A CN01135164 A CN 01135164A CN 1141144 C CN1141144 C CN 1141144C
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Abstract
The present invention relates to a magnetic contrast agent composition, which is a preparation used for the diagnosis of a nuclear magnetic resonance image. In the preparation, magnetic substances, such as traditional Chinese medicine lodestones, etc., are used as main raw materials, and raw materials of the magnetic substances are processed into micro powder of 2 to 20 mu m through fine pulverization; auxiliary agents, such as a surface active agent, a stabilizing agent, an ode type agent, a chelating agent, correctant, etc., are added into the micro powder; stable and homogeneous suspension is obtained through surface shaping, stable dispersion and homogenization processing. The present invention can be used as a contrast agent for the nuclear magnetic resonance medicine examinations of gastrointestinal tracts and peripheral organs thereof, has the advantages of high safety, good gastrointestinal tract filling performance and continuity and good absorbability resistance in the gastrointestinal tracts, is favorable for the forming images of the complete gastrointestinal tracts and drawing organs in the abdominal cavity, has the preferable superparamagnetism negative contrast effect, effectively solves the problem the nuclear magnetic resonance has bad scanning effects in the stomach, the intestine and the abdomen, improves diagnosis level, and enlarges the application field of nuclear magnetic resonance.
Description
Technical field:
The present invention is relevant with the preparation that is used for medical inspection, the relevant production technology that is used for a kind of chemicals of nuclear magnetic resonance medicine inspection of more specifically saying so.
Background technology:
Nuclear magnetic resonance, NMR is widely used in clinical medicine with characteristics such as resolving power height, multiparameter imagings, becomes imaging examination important means commonly used.But, bigger influence the application of magnetic resonance in gastrointestinal and abdomen examination because human gastrointestinal tract tortuously, overlapped holds, self wriggling, natural contrast differences, the nuclear magnetic resonance time such as grows at characteristics in addition.Restricted the application of magnetic resonance to a great extent at gastrointestinal and abdominal part.Therefore, solve nuclear magnetic resonance, NMR gastrointestinal imaging definition, the diagnosis that can improve the pathological changes of gastrointestinal tract own helps around auxiliary the demonstration and the organum retroperitoneale simultaneously.Need be with clothes barium sulfate contrast medium as X line gastrointestinal examination, oral mr contrast agent occupies important status in abdomen scanning, and it directly influences picture quality and diagnostic level.Though clinical water, oils, the CD-DTPA etc. of making because of it all belongs to opaque contrast medium, all have very big defective on acceptability and the diagnostic value as the oral contrast agent in taking at present.Magnetic contrast medium can effectively shorten T
2The relaxation picture does not influence T
1Relaxation makes contrast agent arrive the zone and is the dark space at various scanning sequences, and organizing of contrast-agent-free then keeps original signal intensity, thereby helps showing gastrointestinal tract and surrounding tissue pathological changes, improved the range of application of nuclear magnetic resonance, NMR at abdominal part.
Abroad having developed in the eighties, is the positive vein contrast agent of representative with gadolinium-divinyl five amine acetic acid (CD-DTPA), as the oral gastrointestinal tract contrast medium time spent because of T
2All be high signal with pathological changes on the weighting picture, in diagnosis, have little significance, limited in gastrointestinal tract and used.The current research of also paying much attention to negative contrast medium in the world, also developing the single ferrite of main employing chemosynthesis abroad in recent years is raw material, is applied to phlebography after the processing of albumin parcel framework, to show reticuloendothelial system.And doublely do gastrointestinal contrast agent for oral use, and but its finished product instability, easily oxidation, promptly produce precipitation after a few hours, provisional configuration when taking only, mouthfeel is poor, complex process, cost an arm and a leg (1900 yuan/part), is difficult to be applied to medical inspection.
Summary of the invention:
The object of the present invention is to provide a kind of the have negative contrast effect of superparamagnetism, mri contrast agent production technology that safety is good.
Solution of the present invention is as magnetic contrast medium with a kind of main water suspension compositions of being made up of magnetisable material, surfactant, excipient, stabilizing agent, chelating agen and correctives.Wherein said magnetisable material: it is selected from ferromagnetic materials such as Chinese medicine Magnetitum, ferroso-ferric oxide, iron sesquioxide, ferrum micropowder, and its constituent content (weight %) is 0.01-0.1; Surfactant: it is selected from linoleic acid, tween and polysaccharose substance, and its constituent content (wt%) is 0.1-3.5; Excipient: it is selected from sodium alginate, arabic gum, xanthan gum, and its constituent content (wt%) is 0.3-3.0; Stabilizing agent: it is selected from cyclodextrin, agar, and its constituent content (wt%) is 0.2-2.0; Chelating agen: it is selected from sodium tripolyphosphate, EDTA, and its constituent content (wt%) is 0.01-0.05; Correctives: it is selected from vanillic acid, takes off cerebrol, Fructus Citri Limoniae oil, and its constituent content (wt%) is 0.02-0.06; Water is aequum.
An important feature of the present invention is that to select the Chinese medicine Magnetitum for use be magnetisable material, through special processing, forms the microgranule of specific size and form, handles through surfactant again, in specific excipient, is formed on homogenizing stabilized fluid in normality and the various field intensity magnetic field.The Chinese medicine Magnetitum is not that the Ore of exploitation is used as medicine, but through pyrolytic semlting, forms by strict process of preparing Chinese medicine of traditional Chinese medicine technology, and this method has been listed Chinese Pharmacopoeia in.With the Chinese medicine Magnetitum is the magnetic contrast medium of magnetisable material preparation, its preferred ingredients content (wt%) is: Chinese medicine Magnetitum 0.01-0.1, tween 0.1-3.5, it is selected from arabic gum, xanthan gum excipient 0.3-0.8, it is selected from cyclodextrin, agar stabilizing agent 0.3-0.6, EDTA0.02-0.04, it is selected from the water that takes off cerebrol, Fructus Citri Limoniae oil and aequum correctives 0.02-0.03.
Contrast agent is used in diagnosis as nuclear magnetic resonance image, produces the characteristic of " superparamagnetism " when magnetic resonance imaging, and it requires preparation to have following properties:
1, high dispersion.Be that magnetic-particle is uniformly dispersed not coagulation in the projection agent;
2, diamagnetic coagulating property is strong.Promptly require under 30000 gauss magnetic fields, the magnetic-particle homodisperse of preparation does not condense;
3, low viscosity.Promptly require preparation viscosity less than 0.8Pa.s, make contrast agent have practicality, be convenient to oral and take in vivo.
4, high stability.Be homogenizing fluid when require placing, precipitated and separated not, and leave standstill and keep stable more than 1 year.Acid or alkali environment variation in the gastrointestinal tract can be resisted in vivo, the stability more than 4 hours should be kept.
These all are the maximum technical barriers that exists for the feedstock production magnetic contrast medium with the ferromagnetic material.
The present invention to the solution of above technical barrier is: at first by ferromagnetic particle is carried out surperficial shaping, make ferromagnetic particle have dispersibility, biocompatibility and the stability of height; Besides by adding the excipient that some have tridimensional network, form three-dimensional netted liquid suspension and disperse, make preparation keep a kind of permanent homogeneous state, and can stand highfield and gradient fields effect and keep good stable.
The present invention has realized the object of the invention by following preparation technology.This preparation method mainly may further comprise the steps:
1, the pulverizing of magnetisable material: Chinese medicine Magnetitum or the ferromagnetic material and the superparamagnetism material that obtain with other known methods, be broken into 2-20 μ m micropowder state with the high velocity air pulverizing, its particle diameter difference should be less than 10%;
2, surperficial shaping: add surfactant and stabilizing agent in the micropowder, then by roll-type barreling mill, microgranule is carried out surperficial shaping, make the granule of original needle-like, prismatic and irregular status, form the micropowder of the class spherical particle state of size and form unanimity, and forming the spherical discrete particles of the class that is coated with stabilizing agent, its clad ratio should reach more than 95%;
3, stable dispersion is handled: add excipient, chelating agen, correctives and water, the solid-liquid mixture after the mediation uses the high pressure homogenizer repeated treatments for several times, and wears out 24 hours at 2 ℃;
4, the modulation of homogenizing fluid: transfer pH7-9, follow high-temperature degassing, degassing temperature is generally 80 ℃, handles through a homogenizing after the degassing again, can obtain the homogenizing fluid of ability highfield effect, is magnetic contrast medium of the present invention.
Contrast agent of the present invention has good stable, bottled leave standstill 1 year after, keep not stratified, do not precipitate, invariant color, keep physicochemical property constant; Test can keep stablizing in 24 hours in simulated gastric fluid; The magnetic resonance in vivo test can keep stablizing in 6 hours.Product meets following quality index:
(1) organoleptic indicator
Color and luster: uniformity
Structural state: be even cloudy state, no layering and precipitating, free from admixture.
Flavour and abnormal smells from the patient: mouthfeel is smooth little sweet, slightly tool lasting abnormal smells from the patient.
(2) physical and chemical index
Iron content: 0.1-1mg/ml.Soluble solids: 10-12%.PH value 6-9.Content of beary metal meets the beverage standard of national regulation.
(3) microbiological indicator
Total number of bacteria≤100/100ml, coliform≤3/100ml, pathogenic bacterium must not detect.
During use, more than 6 hours, gastric retention liquid estimator should be less than 100ml to the examinate on an empty stomach, oral contrast material 800-1000ml divides four clothes down, about at every turn 200-250ml in 2 hours, after taking for the last time, the MR abdomen scanning adopts conventional SE sequence axle position T at once
1WI, T
2WI scanning and GE sequence T
2The WI picture.Sweep limits is abdominal part and pelvic cavity.
Use the contrast agent that magnetic contrast medium of the present invention can be used as the nuclear magnetic resonance medicine inspection of gastrointestinal tract and surrounding tissue thereof.
For showing safety of the present invention, done animal acute toxicity experiment research by Shandong Traditional Chinese Medicine University.Because oral superparamagnetism resonance contrast agent is as the diagnostic imaging preparation, only need a drug before the person under inspection is diagnosed, still only done the acute toxicity observation.Carry out the chmice acute toxicity test according to a conventional method, the maximum tolerated dose of oral preparation of mice is more than 105 times of ampoule of adult's diagnosis more than 22.65g/kg.Take the back mice and obvious toxicity do not occur, activity, diet, fur etc. all do not have change, do not have death yet, dissect animal perusal internal organs and do not have significant change, with the negative control group zero difference.
In order more fully to observe its safety, also observed the variation of taking all backs body weight, hemogram (leukocyte, erythrocyte, platelet), liver function (transaminase, each careless transaminase in each), total protein, albumin, globulin and renal function (blood urea nitrogen, flesh acyl) simultaneously, result and negative control group ratio, all there is not significant difference, and all in normal range, therefore, as the image diagnosis preparation, oral magnetic contrast medium of the present invention is safe.
For showing progressive of the present invention, 120 routine clinical practice tests have been done in Shandong Prov. Hospital and the People's Hospital, Distributions in Liaocheng of Shandong Province city respectively.Patient takes the back and observes a week continuously dosage form of the present invention and mouthfeel satisfaction rate 100%, does not all have any delay side effect and takes place.
Take back MR abdomen scanning, the gastrointestinal tract display rate brings up to 98% by average 20%.At T
2Can show gastrointestinal cavity and wall well on the WI picture, the demonstration of intraperitoneal Different Organs image all has clear improvement, bring up to 90% by contrast preceding 20% behind the peritoneum, bladder brings up to 100% by contrast preceding 50%, kidney brings up to 90% by 40%, spleen brings up to 80% by 50%, and is full good to near-end and distal small bowel.
Show that through various experiments contrast agent safety of the present invention is good, full property of good gastrointestinal tract and seriality are arranged, anti-absorbability is good in gastrointestinal tract, is beneficial to full gastrointestinal imaging.Have the negative contrast effect of superior superparamagnetism, non-magnetic pseudo-shadow, the imaging concentration range is wide, is applicable to various field intensity MR equipment, can improve and enlarge MR quality and range of application in abdomen examination.
Description of drawings
Fig. 1 is a magnetic contrast medium technological process of production sketch map of the present invention
1 is the micropowder that magnetisable material is ground into 2-20 μ m among the figure; The 2nd, adding surfactant and stabilizing agent carry out surperficial shaping to micro powder granule in micropowder, and coat stabilizing agent on the surface; The 3rd, add excipient, chelating agen, correctives and water, make suspended substance after the mediation; The 4th, suspended substance worn out make stabilized treatment; The 5th, the pH to 7-9 of adjusting suspension; 6 pairs of suspensions are made high-temperature degassing; 7 do a homogenizing processing to suspension at last again obtains magnetic contrast medium of the present invention.
The specific embodiment:
The invention will be further described for the several concrete instances of following reuse.
1, prepares magnetic contrast medium with the Chinese medicine Magnetitum as magnetisable material.
After producing the Chinese medicine Magnetitum by the technology of putting down in writing in the Chinese Pharmacopoeia, be broken into the micropowder of 2-20 μ m with the high velocity air pulverizing; Add surfactant tween, the grinding in the roll-type mill of stabilizing agent agar, do the microparticle surfaces shaping, and be enclosed with one deck stabilizing agent on the surface after the shaping, its clad ratio reaches more than 95%; Then add excipient, chelating agen, correctives and water, make suspended substance for several times with the high pressure homogenizer repeated treatments after being in harmonious proportion, and make aging stabilized treatment at 2 ℃; Modulate pH of suspension then to 7-9,, remake a homogenizing at last and handle, then make a kind of even cloudy suspensions, be magnetic contrast medium of the present invention again at 80 ℃ of following high-temperature degassings.
2, ferroso-ferric oxide is that magnetisable material prepares magnetic contrast medium
After producing ferroso-ferric oxide with known method, detect with particle size analyzer, the powder of screening 2-20 μ m adds linoleic acid and carries out surperficial shaping, then add xanthan gum, vanillic acid, EDTA and deionized water, make suspension emulsion after the mediation, and under 2 ℃, make burin-in process, then modulate pH to 7-9, at 80 ℃ of following high-temperature degassings, remake the processing that once homogenizes at last, make the suspension emulsion of even muddiness, be magnetic contrast medium of the present invention.
Enumerate some Formulation Examples below again, can be prepared into magnetic contrast medium of the present invention as stated above.
Formulation examples 1
Chinese medicine Magnetitum 0.6g, tween 80 19g, arabic gum 4g, agar 5g, vanillic acid 0.2g, PTPP (potassium tripolyphosphate) 0.3g adds deionized water to 1000g.
Above-mentioned preparation presents the Dark grey homogenizing fluid, viscosity 0.6Pa.s, and proportion 1.2, pH value 6.8, each sequence scanning of MR presents low signal.
Formulation examples 2
Ferroso-ferric oxide 0.3g, linoleic acid 10g, cyclodextrin 3g, xanthan gum 4g, vanillic acid 0.2g, EDTA 0.3g adds deionized water to 1000g.
Above-mentioned preparation is light grey homogenizing fluid, viscosity 0.3Pa.s, and proportion 1.12, pH value 6.5, each sequence scanning of MR is low signal.
Formulation examples 3
Iron sesquioxide 0.9g, tween 80,20g, arabic gum 4g, cyclodextrin 5g, vanillic acid 0.1g takes off cerebrol 0.2g, and EDTA 0.4g adds deionized water to 1000g.
Above-mentioned preparation is orange homogenizing fluid, viscosity 0.8Pa.s, and proportion 1.22, pH value 6.5, each sequence scanning of MR is low signal.
Formulation examples 4
Three Fe 3 O 0.4g, ferrum micropowder 3g, tween 80 20g, agar 4g.Arabic gum 4g, vanillic acid 0.2g, EDTA 0.4g adds deionized water to 1000g.
Above-mentioned preparation is light grey homogenizing fluid, viscosity 0.7Pa.s, and proportion 1.14, pH value 7.5, each sequence scanning of MR is low signal.
Claims (3)
1, a kind of magnetic contrast medium composition is characterized in that the main water suspension of being made up of magnetic properties, surfactant, excipient, stabilizing agent, chelating agen and correctives, and its constituent content is:
Magnetisable material 0.01-0.1wt%, it is selected from one or more complex and super paramagnetic meterial in the ferromagnetic materials such as Chinese medicine Magnetitum, ferroso-ferric oxide, iron sesquioxide, ferrum micropowder;
Surfactant 0.1-3.5wt%, it is selected from linoleic acid, tween and polysaccharose substance;
Excipient 0.3-3.0wt%, it is selected from sodium alginate, arabic gum, xanthan gum;
Stabilizing agent 0.2-2.0wt%, it is selected from cyclodextrin, agar;
Chelating agen 0.01-0.05wt%, it is selected from sodium tripolyphosphate, EDTA;
Correctives 0.02-0.06wt%, it is selected from vanillic acid, takes off cerebrol, Fructus Citri Limoniae oil, and the water of aequum.
2,, it is characterized in that with the Chinese medicine Magnetitum being that the constituent content of the magnetic contrast medium of magnetisable material preparation is according to the described compositions of claim 1:
Chinese medicine Magnetitum 0.01-0.1wt%,
Tween 0.1-3.5wt%,
Excipient 0.3-0.8wt%, it is selected from arabic gum, xanthan gum,
Stabilizing agent 0.3-0.6wt%, it is selected from cyclodextrin, agar,
EDTA0.02-0.04wt％，
Correctives 0.02-0.03wt%, it is selected from the water that takes off cerebrol, Fructus Citri Limoniae oil and aequum.
3,, it is characterized in that may further comprise the steps according to the preparation method of the described magnetic contrast medium composition of claim 1:
(1) pulverizing of magnetisable material: the magnetisable material by known method makes is broken into 2-20 μ m micropowder state with the high velocity air pulverizing;
(2) surperficial shaping: add surfactant and stabilizing agent in the micropowder, then by roll-type barreling mill, form the spherical discrete particles of the class that is coated with stabilizing agent, its clad ratio should reach more than 95%;
(3) stable dispersion processing: add excipient, chelating agen, correctives and water, the solid-liquid mixture after the mediation adopts high pressure homogenizer to handle for several times, and wears out 24 hours at 2 ℃, makes the suspension of homogenizing;
(4) modulation of homogenizing fluid: transfer pH to 7-9, behind the high-temperature degassing, obtain this product again through homogenizing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100518719C (en) * | 2006-07-05 | 2009-07-29 | 中国科学院大连化学物理研究所 | Method for preparing composite substrate multifunctional arterial embolic agent |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100452254C (en) * | 2004-12-02 | 2009-01-14 | 北京大学 | Ferroferric oxide magnetic fluid and its preparing method and use |
| CN1330380C (en) * | 2005-03-18 | 2007-08-08 | 山东师范大学 | X-ray contrast agent composition and its preparation method |
| CN102488904B (en) * | 2011-12-30 | 2013-01-09 | 山东师范大学 | Gastric mucosa targeting super-paramagnetic magnetic resonance contrast medium composition and preparation method thereof |
| CN105903039A (en) * | 2016-05-06 | 2016-08-31 | 李彬 | Nuclear magnetic resonance contrast agent |
| CN111467046A (en) * | 2020-03-16 | 2020-07-31 | 中科绿谷（深圳）医疗科技有限公司 | Developing ball and preparation method and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100518719C (en) * | 2006-07-05 | 2009-07-29 | 中国科学院大连化学物理研究所 | Method for preparing composite substrate multifunctional arterial embolic agent |
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