CN104306998A - Iohexol injection and preparation method thereof - Google Patents
Iohexol injection and preparation method thereof Download PDFInfo
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- CN104306998A CN104306998A CN201410604677.6A CN201410604677A CN104306998A CN 104306998 A CN104306998 A CN 104306998A CN 201410604677 A CN201410604677 A CN 201410604677A CN 104306998 A CN104306998 A CN 104306998A
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Abstract
The invention belongs to the technical field of pharmaceutical preparations and relates to an iohexol injection and a preparation method thereof. The iohexol injection comprises the following constituents in parts by weight: 50-85 parts of iohexol, 0.05-0.25 part of a stabilizer, 0.01-0.05 part of a chelating agent, and 80-100 parts of water for injection, and is prepared by mixing the constituents, and at last using hydrochloric acid with a concentration of 1 mol/L to regulate the pH value to be 7.0-7.4. Compared to the prior art, the iohexol injection adopts the chelating agent with appropriate amount to avoid complexation between the basic remedy and polyvalent metal ions, so as to increase the product stability, ensure that the injection in each batch is undifferentiated in the color, obviously reduce the visible foreign matters and greatly increase the production yield as the product cannot be influenced by the polyvalent metal ions during the preparation process; the preparation duration can be shortened as the injection is prepared with water at 60-65 DEG C; after low-temperature adsorption, the carbon is removed to avoid that the novel visible foreign matter appears as the injection is recrystallized due to cooling after high-temperature adsorption and filling, so as not to cause low yield.
Description
Technical field
The invention belongs to technical field of medicine, specifically, relate to a kind of iohexol inj and preparation method thereof.
Background technology
Iohexol, iodo-1, the 3-benzenedicarboxamide of chemical name 5-[N-(2,3-dihydroxypropyl) acetamido]-N, N ＇-bis-(2,3-dihydroxypropyl)-2,4,6-tri-.Iohexol is the water solublity X-CT contrast agent that the eighties, Norway's Metrizamide company released.With the iohexol inj that it is main component, be widely used in blood vessel and the intracoelomic injection of adult and child, carry out in clinical cerebral angiography, coronarography, around and visceral arteriography, ventriculography, head and body CT strengthen radiography, IVU, also articular irrigation, ERCP, percutaneous transhepatic cholangiography, hernia or fistulogrphy, gastrointestinal imaging, " T " line pipe road radiography etc. can be carried out, therefore, it is considered to one of nonionic X-CT contrast agent best at present.
At present, although iohexol contrasting effects is remarkable, sales volume is very large, and because medicine itself is easily by the impact of polyvalent metal ion, product instability, the problem such as easily occur its colour changed into yellow, visible foreign matters increases, causes the yield rate in production process low.The rate that manufactures a finished product of current domestic enterprise is all lower than 95%.In addition, easily there is irritated and many untoward reaction in existing iohexol inj.Clinical study results shows, the untoward reaction such as iohexol inj can cause cardiopalmus, shiver, incidence rate is 3.1%.Untoward reaction caused by iohexol inj can divide gently, in, severe reaction, mild reaction has headache, feels sick, slight vomiting, slight cardiopalmus, local urticaria etc.Moderate reaction has serious vomiting, urticaria, slight bronchospasm, slight laryngeal edema, stomachache etc.Severe reaction has shock, convulsions, stupor, severe laryngeal edema or bronchospasm, renal failure, death.Delayed onset untoward reaction can be there is in a few hours to a few days in some patients after radiography.
Prior art
Component: 75.5g iohexol, 120mg trometamol, water for injection are settled to 100ml.In batch production, the one time to produce amount of iohexol inj is 25L.
Method for making: 1) first add in material-compound tank 1/3 boil water for injection, be cooled to 80 DEG C, drop into iohexol and also dissolve; 2) open cooling, in material-compound tank, add trometamol, mend in material-compound tank simultaneously and add to the full amount of water for injection, stir; 3) adjust PH to 7.34 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) get the active carbon of injection 0.625wt%, in advance with the injection water-wet of cooling, add rear stirring 15 minutes, carry out filtration de-carbon with 0.5um titanium rod, 0.45 μm of filter, and squeeze in stainless steel cask successively; 4) sample presentation inspection content, related substance, the content of calcium disodium edetate, color, carries out fill by medicinal liquid after qualified; 5) carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C; 6) lamp inspection, labeling, packaging.
Embodiment 1-4 products obtained therefrom and prior art products are compared, with conforming product rate and cause irritated rate for inspection target, conforming product rate adopts lamp inspection, and cause anaphylaxis and adopt active anaphylaxis inspection technique, result of study is in table 1.
Table 1 conforming product rate and cause irritated rate
| Sample | Qualification rate | Cause irritated rate |
| Embodiment 1 | 99％ | 2.7％ |
| Embodiment 2 | 98％ | 3.0％ |
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of safe, stable iohexol inj and preparation method thereof.
A kind of iohexol inj of the present invention, described injection calculates by mass parts, its composition comprises iohexol, the stabilizing agent of 0.05-0.25 part, the chelating agen of 0.01-0.05 part, the water for injection of 80-100 part of 50-85 part, finally adjusts pH to 7.0-7.4 with 1mol/L hydrochloric acid.
Described chelating agen is selected from one or more in citric acid, disodium edetate, calcium disodium edetate; Described stabilizing agent is selected from one or more in trometamol, sodium sulfite, sodium sulfite, (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, sodium thiosulfate.
A kind of iohexol inj of the present invention, the component of described injection comprises 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, uses water for injection that injection is settled to 100ml, finally adjusts pH to 7.0-7.4 with 1mol/L hydrochloric acid.
A kind of iohexol inj of the present invention, the component of described injection comprises 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, 20mg (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, use water for injection that injection is settled to 100ml, finally adjust pH to 7.0-7.4 with 1mol/L hydrochloric acid.
The preparation method of a kind of iohexol inj of the present invention, described preparation method concrete steps are: the water for injection boiled 1) first adding 1/3-1/2 in material-compound tank, is cooled to 60-65 DEG C, drop into iohexol and dissolve; 2) open cooling, in material-compound tank, add chelating agen, stabilizing agent, mend in material-compound tank simultaneously and add to the full amount of water for injection, stir; 3) adjust pH to 7.0-7.4 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) add in advance with the active carbon of the injection moistening of cooling, active carbon addition is the 0.01-0.8wt% of injection, stirs after 15 minutes and carries out filtering active carbon with 0.5 μm of titanium rod, 0.45 μm of filter successively; 5) finally carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C.
Compared with prior art, iohexol inj of the present invention adopts appropriate chelating agen, principal agent and polyvalent metal ion complexation can be avoided, improve product stability, in preparation process, product is not by the impact of polyvalent metal ion, can ensure each batch of color zero difference, visible foreign matters significantly reduces, and the rate that manufactures a finished product significantly improves.Adopt 60-65 DEG C of injection use water preparation, decrease the preparation time; Decarburization after cryogenic absorption, because fluid temperature reduces the visible foreign matters that crystallization again makes new advances after avoiding high temperature adsorption fill, causes yield rate low.
Detailed description of the invention
Below in conjunction with specific embodiment, iohexol inj of the present invention is described further, but protection scope of the present invention is not limited to this.
Embodiment 1
Component: 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, water for injection are settled to 100ml.In batch production, the one time to produce amount of iohexol inj is 25L.
Method for making: 1) first add in material-compound tank 1/3 boil water for injection, be cooled to 60 DEG C, drop into iohexol and also dissolve; 2) open cooling, in material-compound tank, add calcium disodium edetate, trometamol, mend in material-compound tank simultaneously and add to the full amount of water for injection, stir; 3) adjust PH to 7.34 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) get the active carbon of injection 0.625wt%, in advance with the injection moistening of cooling, add rear stirring 15 minutes, carry out filtration de-carbon with 0.5 μm of titanium rod, 0.45 μm of filter, and squeeze in stainless steel cask successively; 5) sample presentation inspection content, related substance, the content of calcium disodium edetate, color, carries out fill by medicinal liquid after qualified; 6) carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C; 7) lamp inspection, labeling, packaging.
Embodiment 2
Component: 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, water for injection are settled to 100ml.In batch production, the one time to produce amount of iohexol inj is 25L.
Method for making: 1) first add in material-compound tank 1/3 boil water for injection, be cooled to 65 DEG C, drop into iohexol and also dissolve; 2) open cooling, in material-compound tank, add calcium disodium edetate, trometamol, mend in material-compound tank simultaneously and add to the full amount of water for injection, stir; 3) adjust PH to 7.34 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) get the active carbon of injection 0.02wt%, in advance with the injection moistening of cooling, add rear stirring 15 minutes, carry out filtration de-carbon with 0.5um titanium rod, 0.45 μm of filter, and squeeze in stainless steel cask successively; 5) sample presentation inspection content, related substance, the content of calcium disodium edetate, color, carries out fill by medicinal liquid after qualified; 6) carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C; 7) lamp inspection, labeling, packaging.
Embodiment 3
Component: 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, 20mg (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, water for injection are settled to 100ml.In batch production, the one time to produce amount of iohexol inj is 25L.
Method for making: 1) first add in material-compound tank 1/3 boil water for injection, be cooled to 60 DEG C, drop into iohexol and also dissolve; 2) open cooling, in material-compound tank, add calcium disodium edetate, (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, trometamol, mends in material-compound tank simultaneously and add to the full amount of water for injection, stirring; 3) adjust PH to 7.34 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) get the active carbon of injection 0.8wt%, in advance with the injection moistening of cooling, add rear stirring 15 minutes, carry out filtration de-carbon with 0.5um titanium rod, 0.45 μm of filter, and squeeze in stainless steel cask successively; 5) sample presentation inspection content, related substance, the content of calcium disodium edetate, color, carries out fill by medicinal liquid after qualified; 6) carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C; 7) lamp inspection, labeling, packaging.
Embodiment 4
Component: 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, 20mg (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, water for injection are settled to 100ml.In batch production, the one time to produce amount of iohexol inj is 25L.
Method for making: 1) first add in material-compound tank 1/3 boil water for injection, be cooled to 65 DEG C, drop into iohexol and also dissolve; 2) open cooling, in material-compound tank, add calcium disodium edetate, (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, trometamol, mends in material-compound tank simultaneously and add to the full amount of water for injection, stirring; 3) adjust PH to 7.34 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) get the active carbon of injection 0.4wt%, in advance with the injection moistening of cooling, add rear stirring 15 minutes, carry out filtration de-carbon with 0.5um titanium rod, 0.45 μm of filter, and squeeze in stainless steel cask successively; 5) sample presentation inspection content, related substance, the content of calcium disodium edetate, color, carries out fill by medicinal liquid after qualified; 6) carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C; 7) lamp inspection, labeling, packaging.
| Embodiment 3 | 100％ | 0.3％ |
| Embodiment 4 | 100％ | 0.3％ |
| Prior art | 91％ | 3.3％ |
Can be found out by table 1, after adding chelating agen, the yield rate of embodiment 1-4 is more than 98%, and the yield rate of prior art is then about 91%; Especially add by (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5, stabilizing agent (5Z, 7E)-4, the 4-dimethyl-5-ethyl ketone base-5 that the sodium hydroxide of 7-nonadienoic acid and equimolar amounts is obtained, after 7-nonadienoic acid sodium, embodiment 3-4 causes irritated rate obviously except low.Compared with prior art, iohexol inj of the present invention adopts appropriate chelating agen, principal agent and polyvalent metal ion complexation can be avoided, improve product stability, in preparation process, product is not by the impact of polyvalent metal ion, can ensure each batch of color zero difference, visible foreign matters significantly reduces, and the rate that manufactures a finished product significantly improves.Adopt 60-65 DEG C of injection use water preparation, decrease the preparation time; Decarburization after cryogenic absorption, because fluid temperature reduces the visible foreign matters that crystallization again makes new advances after avoiding high temperature adsorption fill, causes yield rate low.
Claims (5)
1. an iohexol inj, it is characterized in that, described injection calculates by mass parts, and its composition comprises iohexol, the stabilizing agent of 0.05-0.25 part, the chelating agen of 0.01-0.05 part, the water for injection of 80-100 part of 50-85 part, finally adjusts pH to 7.0-7.4 with 1mol/L hydrochloric acid.
2. a kind of iohexol inj according to claim 1, is characterized in that, described chelating agen is selected from one or more in citric acid, disodium edetate, calcium disodium edetate; Described stabilizing agent is selected from one or more in trometamol, sodium sulfite, sodium sulfite, (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium, sodium thiosulfate.
3. a kind of iohexol inj according to claim 2, it is characterized in that, described injection consist of 75.5g iohexol, 120mg trometamol, 10mg calcium disodium edetate, use water for injection that injection is settled to 100ml, finally adjust pH to 7.0-7.4 with 1mol/L hydrochloric acid.
4. a kind of iohexol inj according to claim 3, is characterized in that, the composition of described injection also comprises (5Z, 7E)-4,4-dimethyl-5-ethyl ketone base-5,7-nonadienoic acid sodium of 20mg.
5. the preparation method of a kind of iohexol inj according to claim 1, it is characterized in that, described preparation method concrete steps are: the water for injection boiled 1) first adding 1/3-1/2 in material-compound tank, is cooled to 60-65 DEG C, drop into iohexol and dissolve; 2) open cooling, in material-compound tank, add chelating agen, stabilizing agent, mend in material-compound tank simultaneously and add to the full amount of water for injection, stir; 3) adjust pH to 7.0-7.4 with 1mol/L hydrochloric acid, circulate 20 minutes through head tank; 4) add in advance with the active carbon of the injection moistening of cooling, active carbon addition is the 0.01-0.8wt% of injection, stirs after 15 minutes and carries out filtering active carbon with 0.5 μm of titanium rod, 0.45 μm of filter successively; 5) finally carry out sterilizing, sterilising conditions is 115.5 DEG C, 30min, and the sterilizing temperature that offers for sale is 40 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410604677.6A CN104306998A (en) | 2014-10-30 | 2014-10-30 | Iohexol injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410604677.6A CN104306998A (en) | 2014-10-30 | 2014-10-30 | Iohexol injection and preparation method thereof |
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| CN104306998A true CN104306998A (en) | 2015-01-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105999306A (en) * | 2016-05-12 | 2016-10-12 | 万承兴 | Positioning technique used under X ray |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103169988A (en) * | 2011-12-23 | 2013-06-26 | 中央医疗服务有限公司 | Contrast medium composition with contrast enhancement effect by comprising highly concentrated agent |
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- 2014-10-30 CN CN201410604677.6A patent/CN104306998A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103169988A (en) * | 2011-12-23 | 2013-06-26 | 中央医疗服务有限公司 | Contrast medium composition with contrast enhancement effect by comprising highly concentrated agent |
Non-Patent Citations (1)
| Title |
|---|
| 荆文光 等: "芸薹子化学成分研究", 《中国中药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105999306A (en) * | 2016-05-12 | 2016-10-12 | 万承兴 | Positioning technique used under X ray |
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