CN1330380C - X-ray contrast agent composition and its preparation method - Google Patents
X-ray contrast agent composition and its preparation method Download PDFInfo
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- CN1330380C CN1330380C CNB2005100425676A CN200510042567A CN1330380C CN 1330380 C CN1330380 C CN 1330380C CN B2005100425676 A CNB2005100425676 A CN B2005100425676A CN 200510042567 A CN200510042567 A CN 200510042567A CN 1330380 C CN1330380 C CN 1330380C
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Abstract
The present invention provides an X-ray contrast agent composition and a preparation method thereof. The composition contains raw materials with the following weight part compounding ratios: 40 to 240 of solid contrast substances, 0.1 to 3.5 of surface active agents, 0.3 to 3.0 of excipient, 0.2 to 2.0 of stabilizing agents, 0.01 to 0.05 of chelating agents, 0.01 to 0.06 of correctant, and right amount of water. The composition comprises the preparation method that firstly, the surface active agents and the stabilizing agents are added in the fine powder of the medical solid contrast substances, and are ground so as to form dispersed granules for coating the stabilizing agents; then, the excipient, the chelating agents and the correctant are added, and after preparations are blent, the preparations are processed by a high-pressure homogenizing machine under a liquid state; the preparations are aged, pH values are regulated to 7 to 9, and finally, degassing is carried out on the preparations so as to obtain manufactured products.
Description
Technical field
The present invention relates to medical preparation, relate in particular to a kind of x-ray contrast agent composition and method of making the same.
Background technology
Digestive tract is being undertaken absorption, absorption and the metabolic function of human nutrition, comprises organs such as oral cavity, esophagus, stomach and duodenum, small intestinal, colon.Because its two ends all directly communicate with the external world, so easily suffer from various diseases.Because digestive tract is duct-like organ, be in tortuous, coiling, adhesion and wriggling state, so checking, it also is different from other parenchymal viscera.
What use always in the digestive tract examining is X line barium sulfate agent radiography, divides esophagus radiography, gastrointestinal series and colon radiography.Actybaryte can be divided into thin and evenly two kinds on type and plucked type.Carefully and evenly the agent of type barium mostly is synthetic barium, and granule is thin and even, is generally circle, and density is lower, and sedimentation is slow and consistent, is applicable to the contrast contrast examination of esophagus, stomach, 12 fat intestinal, small intestinal, colon.The agent of the uneven type barium of thickness mostly is natural barium, and grain thickness does not wait, and form is irregular, density is heavier, evenly coats gastric mucosa, and coarse granule easily falls to the stomach ditch earlier, with after fall to area gastrica fine grained form good density contrast, thereby delineate area gastrica is clear.
Doing barium agent radiography clinically is exactly with medical contrast agent barium sulfate furnishing pasty state, does the X ray examination after swallowing.Because barium sulfate is than great, though add suspending agent and dispersant, add water transfer mix after, general 10 minutes postprecipitations, hardening can not redispersion, seriality and poor stability in gastrointestinal tract.Several barium sulfate suspensions of existing market exploitation, make and be placed in the hermetic container, reach purpose easy to use, but preparation stability is poor, and layering easily needs jolting during use, unsuitable redispersion after long-term the placement, and the body internal stability is poor, has had a strong impact on the use on clinical medicine, and therefore developing a kind of X-ray suspension contrast agent that can suspend for a long time has important medical to be worth.
Summary of the invention
The purpose of this invention is to provide a kind of bulky grain and big proportion solid contrast material and under low viscosity state, can stablize the x-ray contrast agent compositions that safety is good, stability is strong, viscosity is low, easy to use, cheap of suspendible.
Purpose of the present invention can realize by following technical measures:
This x-ray contrast agent compositions contains following raw materials in weight portion: it contains following raw materials in weight portion: solid contrast material 40-240, soil temperature-80 0.1-3.5, xanthan gum 0.3-0.8, cyclodextrin 0.3-0.5, ethylenediaminetetraacetic acid 0.02-0.04, Fructus Citri Limoniae oil 0.01-0.03, water are an amount of.
Water of the present invention is best with the aequum deionized water in right amount.
Described solid contrast material is a big proportion high stable material such as medicinal barium sulfate micropowder, medical clay micropowder; Described surfactant is linoleic acid, soil temperature class and polysaccharose substance; Described excipient is sodium alginate, arabic gum, xanthan gum; Described stabilizing agent is cyclodextrin, agar; Described chelating agen is sodium tripolyphosphate, ethylenediaminetetraacetic acid (EDTA); Described correctives is vanillic acid, take off cerebrol, Fructus Citri Limoniae oil.
The preparation method of said composition is to add surfactant and stabilizing agent earlier in medical solid contrast material micropowder, grinds, and forms the discrete particles that coats stabilizing agent; Add excipient, chelating agen and correctives then and preparation is in harmonious proportion the back and under liquid state, handle with high pressure homogenizer; Again through aging back accent PH be 7-9, after outgas goods.
Described aging temperature be more than 2 ℃ to room temperature, the time is 20 to 30 hours; Described degassing temperature is 50 to 90 ℃; The described degassing time is 20-60 minute.
Preparation technology's flow process of the present invention is as follows:
Medicinal barium sulfate micropowder or the medical clay → screening → surperficial shaping → dispersion treatment → stabilized treatment → accent pH value → degassing → finished product.
The solution of success of the present invention a bulky grain and the stable suspendible difficult problem of big proportion contrast material under low viscosity state, made the suspension x-ray contrast agent compositions that safety is good, stability is strong, viscosity is low, easy to use, cheap.
X-ray contrast agent compositions of the present invention detects through Shandong Traditional Chinese Medicine University, and the result is as follows:
(1) quality standard:
1, organoleptic indicator
Color and luster: uniformity;
Structural state: be even suspension, do not have obvious layering and precipitating;
Flavour and abnormal smells from the patient: mouthfeel is smooth little sweet, slightly tool fragrance flavor.
2, physical and chemical index
Insoluble solid content 40-240% (W/V), pH value 6-9;
Content of beary metal meets national regulation beverage standard.
3, microbiological indicator
Total number of bacteria≤100/100mL;
Coliform≤3/100Ml;
Pathogenic bacterium must not inspection place.
(2) animal acute toxicity experiment research:
Suspension x-ray contrast agent compositions, for the safety that medical and clinical uses, the spy has carried out acute toxicity testing research to this sample, now the result is reported as follows:
1, experiment material and method:
Take and coloclysis after animal obvious toxicity does not appear, activity, diet, fur etc. all do not have change, do not have deadly yet, dissect animal perusal internal organs and do not have significant change, with the negative control group zero difference.
As the image diagnosis preparation, only need a drug before the person under inspection diagnosed, still only done the acute toxicity observation, the maximum tolerated dose of mice oral formulations is more than 22.65g/kg, be more than 105 times of ampoule of adult, oral and coloclysis administration is safe.
In order more fully to observe its safety, also observed the variation of taking all backs body weight, hemogram (leukocyte, erythrocyte, platelet), liver function (each pyruvic transaminase, each careless transaminase), total protein, albumin, globulin and kidney merit (blood urea nitrogen, creatinine) simultaneously, the result does not all have significant difference with the negative control group ratio, and all in normal range, be safe therefore as the image diagnosis preparation.
2, performance and operation instruction:
The suspension x-ray contrast agent makes up the needs of system at gastrointestinal X-ray and CT examination, a kind of negative contrast medium that gastrointestinal tract is shown of development.Mainly contain and do not have the solid contrast material of pharmaceutically active in vivo,, and adopt three-dimensional netted liquid suspension to disperse dispersion technology to make through the deactivation technical finesse, purpose be solve internal organs behind the peritoneum delineate the diagnosis of the pathological changes of gastrointestinal tract own.
Show that through various experiments this contrast agent safety is good, have that good gastrointestinal tract fills property and seriality, anti-absorbability is good in gastrointestinal tract, be beneficial to full gastrointestinal imaging, have superior negative contrast effect.
3, using method:
Because digestive tract is duct-like organ, divide esophagus radiography, gastrointestinal series and colon radiography.
Gullet radiography uses the about 100ml of low concentration contrast agent, as 80%, be applicable to the disease of esophagus own, as tumor, diverticulum, varicosis, foreign body, inflammation etc., esophagus adjacent organs pathological changes is done Differential Diagnosis as also available this kind inspections such as heart, aorta, vertical diaphragms.Gullet radiography should not carry out after food immediately, in order to avoid food debris adheres to tube wall, mistaken diagnosis takes place.The person that has the thoracic choke, should be after food a few hours check.
High concentration 200ml is used in the conventional contrast examination of gastrointestinal tract, as 160%, is applicable to stomach and small intestinal pathological changes, as has or not tumor, inflammation, foreign body, diverticulum, fistula, deformity etc.Have and block and the careful usefulness of massive hemorrhage person, gastric-intestinal perforation person forbidding.Patient prohibits the medicine that clothes influence gastrointestinal function or the development of X line during checking preceding 21 hours and checking, as preparations such as cathartic, astringent, bismuth, iodine, calcium, ferrum.Check dinner the previous day as usual, the late night to morning can not be advanced any diet.If hyperchylia or when a large amount of food entrapment is arranged should be found time earlier.
The colon barium examination can oral or enema method 150ml, uses high concentration, as 200%, is applicable to diseases such as colon tumor, polyp, granuloma, regional enteritis, ulcerative colitis.Acute bad the dead of vermiform appendix forbidding.Check and prohibit any medicine that influences function of intestinal canal and the development of X line of clothes in preceding 24 hours.The influent stream food of checking evening before that day is exempted from dinner in case of necessity.Check saline enema in 9 o'clock evenings the previous day or clothes laxative such as Folium Sennae etc.Check last hour morning, cleansing enema, emptying enteral excrement piece.Behind the contrast enema, also can inject an amount of air, the dual contrast contrast examination of row.
4, practical application test effect:
Through the approval of medicine prison department, such contrast agent is on probation in Shandong Prov. Hospital and the People's Hospital, Distributions in Liaocheng of Shandong Province city 60 examples respectively, and patient takes the back and observes a week continuously dosage form and mouthfeel satisfaction rate 100%, does not all have any delay side effect and takes place.Its dosage form easily is accepted, and the body internal dynamics is good, and is safe and reliable.Be a kind of easy to use, stable performance, mouthfeel good, have no side effect, the video picture concentration range is wide, the X-ray practical product of good dynamics characteristic is arranged, and has filled up domestic and international blank.
A specification requirement of the present invention and a difficult problem:
This contrast agent composition utilizes solid contrast material to produce negative contrast effect on the X-ray shows, but solid contrast material proportion is big, is difficult for stable suspersion in low-viscosity (mobile) liquid.This requires preparation to have following properties.
1, high dispersion:
Solid contrast material grains is uniformly dispersed not coagulation in preparation.
2, low viscosity
Require preparation compositions viscosity less than 500mPa.S, make contrast agent have practicality, be convenient to oral and take in vivo.
3, high stability
Be homogenizing fluid when requiring preparation compositions to place, not obvious precipitated and separated reached more than 2 years.The internal energy variation of resisting acid or alkali environment in the gastrointestinal tract of body keeps the stability more than 4 hours.
The technical barrier solution:
1, deactivation is handled
Solid matter particle is carried out surperficial shaping and through the surfactant processing, makes microgranule have dispersibility, biocompatibility and the stability of height.
2, adopt three-dimensional netted liquid suspension to disperse dispersion technology
By composite excipient, make preparation keep a kind of permanent homogeneous state, and can stand big proportion sinking effect and keep good stability with tridimensional network.
The contrast agent composition characteristic:
The contrast agent composition that this Technology of process makes:
1, bottled leaving standstill more than 1 year keeps not stratified, precipitation, variable color and physicochemical property constant.
2, in simulated gastric fluid, can keep 2 hours stability.
3, in vivo test, contrast agent can keep 6 hours stability, greater than 4 hours clinical practice.
The specific embodiment:
Embodiment 1:
Formulation examples
Barium sulfate 45, soil temperature-80 3.5, arabic gum 0.3, agar 0.2, PTPP (potassium tripolyphosphate) 0.01, vanillic acid 0.01, aequum deionized water.
Preparation technology's flow process of the present invention is as follows:
Get the medicinal barium sulfate micropowder, screen less than 2um, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 2 ℃ aging 20 hours, transferring PH with sodium bicarbonate then is 7, the degassing 40 minutes under 50 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
The above-mentioned preparation homogenizing fluid that is white in color, viscosity 0.6Pa.s, proportion 1.2, pH value 6.8.
Embodiment 2:
Formulation examples
Barium sulfate 230, linoleic acid 0.5, xanthan gum 0.8, cyclodextrin 2.0, ethylenediaminetetraacetic acid 0.02, take off cerebrol 0.02, aequum deionized water.
Preparation technology's flow process of the present invention is as follows:
Get medical clay, screen less than 2um, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 30 ℃ aging 25 hours, transferring PH with sodium bicarbonate then is 9, the degassing 20 minutes under 80 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
Above-mentioned preparation is light grey homogenizing fluid, viscosity 0.3Pa.s, proportion 1.12, pH value 8.
Embodiment 3:
Formulation examples
Clay 40, soil temperature-80 0.1, arabic gum 0.3, cyclodextrin 0.3, ethylenediaminetetraacetic acid 0.05, Fructus Citri Limoniae oil 0.03.
Preparation technology's flow process of the present invention is as follows:
Get the medicinal barium sulfate micropowder, screen less than 2um, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 10 ℃ aging 30 hours, transferring PH with sodium bicarbonate then is 8, the degassing 60 minutes under 90 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
Above-mentioned preparation is orange homogenizing fluid, viscosity 0.8Pa.s, proportion 1.22, pH value 7.
Embodiment 4:
Formulation examples
Clay 240, ferrum micropowder 0.3-0.4, xanthan gum 0.3, cyclodextrin 1.5, sodium tripolyphosphate 0.05, Fructus Citri Limoniae oil 0.03.
Preparation technology's flow process of the present invention (medical clay) is as follows:
Get medical clay, (less than 2um) screening, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 20 ℃ aging 30 hours, transferring PH with sodium bicarbonate then is 7, the degassing 30 minutes under 90 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
Above-mentioned preparation is light grey homogenizing fluid, viscosity 0.7Pa.s, proportion 1.14, pH value 6.7.
Embodiment 5:
Formulation examples
Barium sulfate 100, linoleic acid 3.2, sodium alginate 0.3, agar 1.0, PTPP (potassium tripolyphosphate) 0.03, vanillic acid 0.06, aequum deionized water.
Preparation technology's flow process of the present invention (barium sulfate) is as follows:
Get the medicinal barium sulfate micropowder, screen less than 2um, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 5 ℃ aging 24 hours, transferring PH with sodium bicarbonate then is 8, the degassing 30 minutes under 60 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
The above-mentioned preparation homogenizing fluid that is white in color, viscosity 0.5Pa.s, proportion 1.13, pH value 7.
Embodiment 6:
Formulation examples
Barium sulfate 200, sodium alginate 3.0, agar 0.6, PTPP (potassium tripolyphosphate) 0.02, take off cerebrol 0.01, aequum deionized water.
Preparation technology's flow process of the present invention (medical clay) is as follows:
Get medical clay, screening, add surfactant and stabilizing agent, grind, when forming the discrete particles that coats stabilizing agent＞95%, add excipient, chelating agen and correctives and under liquid state, use high pressure homogenizer (colloid mill) to handle 2 times preparation mediation back, again in 5 ℃ aging 20 hours, transferring PH with sodium bicarbonate then is 9, the degassing 50 minutes under 70 ℃ of conditions at last, reuse colloid mill homogenizing 1 time gets finished product.
The above-mentioned preparation homogenizing fluid that is white in color, viscosity 0.6Pa.s, proportion 1.17, pH value 7.8.
Claims (1)
1, a kind of x-ray contrast agent compositions is characterized in that it is made up of following raw materials in weight portion: medicinal barium sulfate or medical clay 40-240, tween 80 0.1-3.5, xanthan gum 0.3-0.8, cyclodextrin 0.3-0.5, ethylenediaminetetraacetic acid 0.02-0.04, Fructus Citri Limoniae oil 0.01-0.03, water are an amount of.
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| CNB2005100425676A CN1330380C (en) | 2005-03-18 | 2005-03-18 | X-ray contrast agent composition and its preparation method |
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| CNB2005100425676A CN1330380C (en) | 2005-03-18 | 2005-03-18 | X-ray contrast agent composition and its preparation method |
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| CN1330380C true CN1330380C (en) | 2007-08-08 |
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| CN105903039A (en) * | 2016-05-06 | 2016-08-31 | 李彬 | Nuclear magnetic resonance contrast agent |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1147206A (en) * | 1994-04-21 | 1997-04-09 | 耐克麦德英梅金公司 | X-ray contrast compositions contg. pharmaceutically acceptable clays |
| CN1351889A (en) * | 2001-11-13 | 2002-06-05 | 山东省医学影像学研究所 | Magnetic contrast medium composition and its preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1147206A (en) * | 1994-04-21 | 1997-04-09 | 耐克麦德英梅金公司 | X-ray contrast compositions contg. pharmaceutically acceptable clays |
| CN1351889A (en) * | 2001-11-13 | 2002-06-05 | 山东省医学影像学研究所 | Magnetic contrast medium composition and its preparing method |
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