CN102657605A - Tiopronin injection and preparation method thereof - Google Patents
Tiopronin injection and preparation method thereof Download PDFInfo
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- CN102657605A CN102657605A CN2012101670533A CN201210167053A CN102657605A CN 102657605 A CN102657605 A CN 102657605A CN 2012101670533 A CN2012101670533 A CN 2012101670533A CN 201210167053 A CN201210167053 A CN 201210167053A CN 102657605 A CN102657605 A CN 102657605A
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- tiopronin
- chelator
- light stabilizer
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Abstract
The invention discloses a stable tiopronin injection and a preparation method thereof. The tiopronin injection includes tiopronin, light stabilizer and metal-chelator, wherein concentration of the metal-chelator in the injection ranges from 10mg/ml to 20mg/ml. By the aid of the tiopronin injection, the defect that the tiopronin is prone to be oxidized in aqueous solution is overcome, influence from illumination is reduced, stability is improved, generation of relative tiopronin substances during long storing period can be effectively reduced, and safety of clinical medication is improved.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of injection that contains the active component tiopronin and preparation method thereof.
Background technology
(Tiopronin MPG), is a kind of sulfydryl glycine compounds that contains to tiopronin.
Chemistry is by name: N-(2-mercapto radical propionyl group)-glycine
Structural formula is following:
(SH) be the metabolic protective agent of human body, it is through knowing interior free yl, protection hepatic mitochondria structure and many clocks substance metabolism enzyme for free sulfhydryl groups on the tiopronin side chain; Participate in hepatocyte Proteometabolism and carbohydrate metabolism, keep hepatocyte glutathion inside content, strengthen the function of detoxification of liver; To resist various hepatic injurys, protection hepatocyte structure is improved liver function; Promote hepatocyte to repair and regeneration, be used to recover the auxiliary therapy of liver function and chronic hepatitis.
The poor stability of tiopronin in water; There is document to show that tiopronin is prone to by metal ion and photocatalytic oxidation free sulfhydryl groups (SH) in aqueous solution; And decompose a large amount of by-product of generation, and product gas purity is descended, this can influence the medicinal safety of this product undoubtedly and effectively use.
The pharmaceutical preparation of tiopronin at present has tablet and injection powder pin and liquid drugs injection.
Patent CN1305845C and CN488343A disclose the freeze-dried powder of tiopronin and sodium salt thereof, but want water to dissolve to raise variety when the clinical practice, very easily cause because of medicine dissolution insufficiently, when injecting to the people, produce danger.And the production technology of freeze-dried powder is strict to equipment requirements, and working condition is relatively harsher, and energy resource consumption is bigger, is unfavorable for industrialized great production.
Patent CN1669553A and CN1704049A, CN1690595B, CN101143139, CN10126911A disclose the method for preparing of tiopronin hydro-acupuncture preparation; Their method for preparing mainly is on antioxidant or metal-chelator, to study and select, but does not all comprehensively investigate and safeguard measure.
Summary of the invention
The object of the present invention is to provide a kind of is active component with the tiopronin, can significantly improve the stability of tiopronin in water, reduces the content of related substance, improves the tiopronin injection of clinical drug safety property.
Another object of the present invention provides the method for preparing of this tiopronin injection.
The objective of the invention is to realize in the following manner:
A kind of tiopronin injection, the raw material components of this injection comprises tiopronin, light stabilizer and metal-chelator, the concentration range of light stabilizer in injection is 10～20mg/ml.
The weight ratio of above-mentioned metal-chelator and tiopronin is 1:2000 ~ 2500, and preferred weight ratio is 1:2000; Metal-chelator is preferably calcium disodium edetate.
The preferred 15mg/ml of the concentration range of above-mentioned light stabilizer in injection, light stabilizer is preferably the D-sorbitol.
Injection of the present invention also contains regulates pH value in 4.5 ~ 5.5 pH regulator agent, and it is 10% sodium hydroxide solution that the pH regulator agent can be mass concentration, and the character of injection of the present invention under this condition can be more stable.
The method for preparing of above-mentioned tiopronin injection comprises the following steps:
Get water for injection gross mass 70 ~ 80% and filled nitrogen 10 ~ 20 minutes; Light stabilizer and metal-chelator joined to stir in this water for injection make dissolving; Add the tiopronin stirring again and make dissolving; And then slowly add pH regulator agent adjusting pH4.5 ~ 5.5, and benefit adds to the full amount of water for injection, and medicinal charcoal (being to add the 0.01g medicinal charcoal in every 100ml injection) the insulation absorption under 55 ~ 65 ℃ of conditions that adds injection 0.01% obtained medicinal liquid in 15 ~ 25 minutes; Said process keeps whole process to fill nitrogen, and filtration, sterilization promptly get.
The above-mentioned medicinal liquid that is filtered into filters at least once through 0.22 μ m micropore filter element before the embedding after 0.45 μ m micropore filter element filters at least once again, the preferred 100 ℃ of sterilizations 30 minutes of sterilizing.The container preferred glass container that the inventive method is used.It is 10% sodium hydroxide solution that the pH regulator agent is preferably mass concentration.
The method for preparing of tiopronin injection of the present invention preferably includes following steps:
A. weighing: prepare adjuvant according to ratio range, get 70 ~ 80% of water for injection gross mass and filled nitrogen 15 minutes;
B. preparation: load weighted D-sorbitol and calcium disodium edetate joined to stir in 70 ~ 80% waters for injection make dissolving, again tiopronin is added that stirring makes dissolving in the D-sorbitol solution; And then slowly to add mass concentration be that 10% sodium hydroxide solution is regulated pH4.5 ~ 5.5, and benefit adds to the full amount of water for injection; Add 60 ℃ ± 5 ℃ insulation absorption of injection 0.01% medicinal charcoal (being to add the 0.01g medicinal charcoal in every 100ml injection) 20 minutes; Filter through 0.45 μ m micropore filter element, keep whole process to fill nitrogen in the process for preparation.
C. embedding sterilization: intermediate is detected qualified medicinal liquid be filtered in the glass surge flask, fill the nitrogen embedding then,, promptly get in 100 ℃ of sterilizations 30 minutes through twice 0.22 μ m micropore filter element.
The inventor is through deep discovering; Tiopronin itself just has strong antioxidant action; The adding of antioxidant can not guarantee effectively that it is not oxidized, and the use of metal-chelator also leaves some room for improvement, and the use of light stabilizer also can improve the stability of product greatly in addition.
The present invention has passed through experiment screening use amount and each item indexs such as light stabilizer kind and consumption of metal-chelator in the tiopronin injection, the content of control tiopronin impurity is to improve the clinical drug safety.
1, the screening of metal-chelator consumption:
The use of metal-chelator mainly is to stop free metal ion in the medicinal liquid influence stability of tiopronin, but the metal-chelator use amount too much can influence the intravital ionic equilibrium of people, screens so we have carried out optimizing to the consumption of metal-chelator.
Test method:
Sample according to five kinds of different process of table 1 prescription preparation; Other step and raw material using dosage are with embodiment 1, and embedding respectively was 100 ℃ of sterilizations 30 minutes; And (T=60 ℃) placed 10 days under the high temperature experiment condition, investigated the situation of change of related substance in the tiopronin solution.
The preparation of table 1 metal-chelator screening study sample
| 1 | 2 | 3 | 4 | 5 | |
| Tiopronin (g) | 5.0 | 5.0 | 5.0 | 5.0 | 5.0 |
| Calcium disodium edetate (g) | 0 | 0.0010 | 0.0020 | 0.0025 | 0.0050 |
| The weight proportion of metal-chelator and principal agent | 0 | 1:5000 | 1:2500 | 1:2000 | 1:1000 |
| Water for injection adds to (ml) | 100 | 100 | 100 | 100 | 100 |
Table 2 chelating agen screening study result
Table 2 result shows, adds the stability that metal-chelator can improve tiopronin, and the weight proportion scope between metal-chelator and the tiopronin is in 1:1000 ~ 2500 time; Can guarantee that this quality is more stable; But the use amount that the inventor finds chelating agen is when certain low scope, and this quality is more stable; Weight proportion scope between our preferred sequestrant and the tiopronin is in 1:2000 ~ 2500, and most preferably the weight proportion scope is at 1:2000.
2, the screening of light stabilizer kind and consumption:
Have bibliographical information tiopronin injection adverse reaction rate when intravenous drip high, its reason is a tiopronin injection when being diluted to 0.9% sodium chloride injection, 5% glucose injection and 10% glucose injection, and it is to the poor stability of light.We find in medicinal liquid, to add an amount of D-sorbitol or mannitol can improve its stability to light greatly, through testing us D-sorbitol and mannitol and consumption thereof have been carried out screening study.
Test method:
The sample that contains D-sorbitol and three kinds of concentration of mannitol according to the preparation in glass container of table 3 prescription; Preparation process is with embodiment 1, and embedding respectively was 100 ℃ of sterilizations 30 minutes; And five prescription samples are down investigated 10 days in illumination 4500LX, investigate the situation of change of related substance in the obtain solution.
The preparation of table 3 light stabilizer screening study sample
Table 4 light stabilizer research related substance testing result
Visible by table 4 data, after having added D-sorbitol or mannitol in the tiopronin injection, medicinal liquid reduces because of the influence of illumination, and related substance produces and reduces, and stability improves.The stable effect of unit concentration D-sorbitol light is high than mannitol in addition.For guaranteeing the quality of these article, confirming to select for use the D-sorbitol concentration is the consumption of 10～20mg/ml as stabilizing agent in these article, wherein preferred 15mg/ml.
Conclusion: in sum,, confirmed the optimizing prescriptions and the technology of tiopronin injection of the present invention through preferred tiopronin injection light stabilizer kind and consumption, amount of chelant, specific as follows:
Prescription:
Preparation technology:
A. weighing: prepare adjuvant according to ratio range, get 70 ~ 80% of water for injection gross mass and filled nitrogen 15 minutes;
B. preparation: load weighted D-sorbitol and calcium disodium edetate joined to stir in 70 ~ 80% waters for injection make dissolving, again tiopronin is added that stirring makes dissolving in the D-sorbitol solution; And then slowly to add mass concentration be that 10% sodium hydroxide solution is regulated pH value 4.5 ~ 5.5, and benefit adds to the full amount of water for injection; Add 60 ℃ ± 5 ℃ insulation absorption of 0.01% medicinal charcoal (being to add the 0.01g medicinal charcoal in every 100ml injection) 20 minutes; Filter through 0.45 μ m micropore filter element, keep whole process to fill nitrogen in the process for preparation.
C. embedding sterilization: medicinal liquid is filtered in the glass surge flask through 0.22 μ m micropore filter element, uses then and fill the nitrogen embedding,, promptly get in 100 ℃ of sterilizations 30 minutes.
The tiopronin injection that makes through above prescription and technology compared with prior art has following beneficial effect:
(1) in tiopronin injection, use light stabilizer, particularly the D-sorbitol can reduce the influence of illumination to product, has more comprehensively improved the stability of product, has guaranteed safety of clinical administration.
(2) under the prerequisite that guarantees tiopronin injection stability, significantly reduced the consumption of chelating agen, potential safety hazard when reducing clinical use.
In order to prove beneficial effect of the present invention, further prove through following Test Example, but should not be construed as limitation of the present invention.
The stability experiment of experimental example 1 tiopronin injection of the present invention and listing tiopronin injection
Laboratory sample:
Sample A: tiopronin injection of the present invention, prescription and method for preparing are seen embodiment 1;
Sample B: prescription and preparation technology according to the said embodiment 1 of Chinese invention patent application of granted patent CN1698595B make this sample.
During to above-mentioned two kinds of sample preparations before and after the sterilization, and in accelerated tests (T=40 ℃, RH=75%) the condition held is 90 days, investigates the situation of change of tiopronin solution character and pH value, content and related substance.The result sees table 5:
The investigation of table 5 accelerated tests
Visible by table 5 data; The tiopronin injection of tiopronin injection of the present invention and granted patent CN1698595B relatively; The situation of change of tiopronin content and related substance all is superior to the latter; So tiopronin injection of the present invention has better stability, security of products is more guaranteed.
The stability of experimental example 2 tiopronin injections of the present invention during with the clinical use of listing tiopronin injection
Laboratory sample:
Sample A: tiopronin injection of the present invention, prescription and method for preparing are seen embodiment 1;
Sample B: prescription and preparation technology according to the said embodiment 1 of Chinese invention patent application of granted patent CN1698595B make this sample.
With above-mentioned two kinds of samples with 0.9% sodium chloride injection, 5% glucose injection and 10% glucose injection 250ml dilution after, under the condition of lucifuge not, investigate the situation of change of tiopronin solution related substance and content in 6 hours.The result sees table 5:
The investigation of stability during the clinical use of table 6
Visible by table 6 data; When clinical use; The tiopronin injection of tiopronin injection of the present invention and granted patent CN1698595B relatively; Will get well with 0.9% sodium chloride injection, 5% glucose injection and 10% glucose injection dilution back tiopronin injection stability of the present invention, so tiopronin injection of the present invention has better stability, the safety of the clinical use of product is more guaranteed.
Experimental example 3 tiopronin injection safety testing result of the present invention and evaluations:
(1) adopt Cavia porcellus to carry out the hypersensitive test of these article: result of the test shows that the tiopronin injection intravenously administrable does not have allergenic effect.
(2) adopt rabbit to carry out the hemolytic test of these article: when result of the test shows tiopronin injection final concentration is 4mg/ml tame rabbit erythrocyte not to be had haemolysis in vitro.
(3) adopt rabbit to carry out the blood vessel irritation test of these article: result of the test shows that the tiopronin injection intravenously administrable does not have the venous stimulation effect.
Increased light stabilizer though result of the test shows these article, its intravenously administrable is safe.
Related substance detection method of the present invention is: according to national drug standards WS
1-(X-053)-the related substance detection of 2010Z under method.
According to HPLC (two appendix I of Chinese Pharmacopoeia version in 2010 D)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler, and (regulating pH value to 3.2 with phosphoric acid)-acetonitrile (95:5) is a mobile phase with the 0.1mol/ potassium dihydrogen phosphate, and the detection wavelength is 210nm.The separating degree of tiopronin peak and adjacent impurity peaks should meet the requirements.
Related substance is got these article, adds mobile phase and is diluted to scale, shakes up, as contrast solution.Sample introduction immediately after the solution preparation according to assay item chromatographic condition down, is got contrast solution 20 μ l, and injecting chromatograph respectively, record chromatogram be 3.5 times of main composition peak retention time extremely.In the need testing solution chromatogram if any impurity peaks, each impurity peak area with must not be greater than contrast solution main peak area (2.5%).
Detection method of content of the present invention is: according to national drug standards WS
1-(X-053)-the assay detection of 2010Z under method.
According to HPLC (two appendix I of Chinese Pharmacopoeia version in 2010 D)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler, and (regulating pH value to 3.2 with phosphoric acid)-acetonitrile (95:5) is a mobile phase with the 0.1mol/ potassium dihydrogen phosphate, and the detection wavelength is 210nm.The separating degree of tiopronin peak and adjacent impurity peaks should meet the requirements.
The algoscopy precision is measured these article an amount of (being equivalent to tiopronin 0.2g approximately), puts in the 100ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up; Precision is measured in right amount, and the solution with containing 0.1mg among the every 1ml of mobile phase dilution title shakes up, as need testing solution; It is an amount of that other gets the tiopronin reference substance, and accurate the title decides, and measures with method., promptly get with calculated by peak area by external standard method.
The specific embodiment
Below further specify the present invention through specific embodiment.But the detail of embodiment only is used to explain the present invention, should not be construed as the qualification to the total technical scheme of the present invention.
Embodiment 1
1, prescription:
2, preparation technology:
A. weighing: prepare adjuvant according to ratio range, 1600ml water for injection was filled nitrogen 15 minutes;
B. preparation: load weighted D-sorbitol 30g and calcium disodium edetate 0.05g joined to stir in 80% water for injection make dissolving, again tiopronin 100g is added that stirring makes dissolving in the D-sorbitol solution; And then slowly to add mass concentration be that 10% sodium hydroxide solution is regulated pH value 4.5 ~ 5.5, and benefit adds to the full amount of water for injection; 60 ℃ ± 5 ℃ of the insulations of 0.01% medicinal charcoal (being to add the 0.01g medicinal charcoal in every 100ml injection) that add injection were adsorbed 20 minutes; Filter through 0.45 μ m micropore filter element, it is qualified that sampling detects to the intermediate detection.Keep whole process to fill nitrogen in the process for preparation.
C. embedding sterilization: intermediate is detected qualified medicinal liquid be filtered in the glass surge flask, fill the nitrogen embedding then, in 100 ℃ of sterilizations 30 minutes through 0.22 μ m micropore filter element.
D. leak detection, lamp inspection, finished product is examined entirely;
E. packing is put in storage.
Embodiment 2
1, prescription:
2, preparation technology: with embodiment 1.
Embodiment 3
1, prescription:
2, preparation technology: with embodiment 1.
Claims (10)
1. a tiopronin injection is characterized in that this injection component comprises tiopronin, light stabilizer and metal-chelator, and the concentration range of light stabilizer in injection is 10～20mg/ml.
2. tiopronin injection according to claim 1 is characterized in that the weight ratio between described metal-chelator and the tiopronin is 1:2000 ~ 2500.
3. tiopronin injection according to claim 1 and 2 is characterized in that described metal-chelator is a calcium disodium edetate.
4. tiopronin injection according to claim 1 is characterized in that the concentration of described light stabilizer in injection is 15mg/ml.
5. according to claim 1 or 4 described tiopronin injections, it is characterized in that described light stabilizer is the D-sorbitol.
6. tiopronin injection according to claim 1 is characterized in that this injection also contains to make the injection pH value in 4.5 ~ 5.5 pH regulator agent that the pH regulator agent is that mass concentration is 10% sodium hydroxide solution.
7. the method for preparing of the described tiopronin injection of claim 1 is characterized in that described method comprises the following steps:
Get water for injection gross mass 70 ~ 80% and filled nitrogen 10 ~ 20 minutes; Light stabilizer and metal-chelator joined to stir in this water for injection make dissolving, add tiopronin again and stir and make dissolving, and then slowly add the pH regulator agent and regulate pH4.5 ~ 5.5; Benefit adds to the full amount of water for injection; Adding injection 0.01% (g/ml) medicinal charcoal is incubated absorption and obtained medicinal liquid in 15 ~ 25 minutes under 55 ~ 65 ℃ of conditions, said process keeps whole process to fill nitrogen, and filtration, sterilization promptly get.
8. the method for preparing of tiopronin injection according to claim 7; It is characterized in that the described medicinal liquid that is filtered into is after 0.45 μ m micropore filter element filters at least once; Filter at least once through 0.22 μ m micropore filter element before the embedding, described sterilization is 100 ℃ of sterilizations 30 minutes again.
9. the method for preparing of tiopronin injection according to claim 7 is characterized in that described pH regulator agent is that mass concentration is 10% sodium hydroxide solution.
10. the method for preparing of tiopronin injection according to claim 7 is characterized in that the container that described method is used is glass container.
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| CN2012101670533A CN102657605A (en) | 2012-05-25 | 2012-05-25 | Tiopronin injection and preparation method thereof |
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| CN2012101670533A CN102657605A (en) | 2012-05-25 | 2012-05-25 | Tiopronin injection and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555788A (en) * | 2004-01-02 | 2004-12-22 | 肖广常 | Thio pronine transfursion liquid and its preparation method |
| CN1669553A (en) * | 2004-03-18 | 2005-09-21 | 王玫 | Tiopronin injection and preparation method thereof |
| CN1698595A (en) * | 2005-04-28 | 2005-11-23 | 山东鲁抗辰欣药业有限公司 | Tiopronin injection and preparation method thereof |
| CN101143139A (en) * | 2007-08-09 | 2008-03-19 | 武汉远大制药集团有限公司 | Stable tiopronin injection and preparation method thereof |
| CN101269011A (en) * | 2008-04-17 | 2008-09-24 | 孙向阳 | Tiopronin injection and preparation method thereof |
-
2012
- 2012-05-25 CN CN2012101670533A patent/CN102657605A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555788A (en) * | 2004-01-02 | 2004-12-22 | 肖广常 | Thio pronine transfursion liquid and its preparation method |
| CN1669553A (en) * | 2004-03-18 | 2005-09-21 | 王玫 | Tiopronin injection and preparation method thereof |
| CN1698595A (en) * | 2005-04-28 | 2005-11-23 | 山东鲁抗辰欣药业有限公司 | Tiopronin injection and preparation method thereof |
| CN101143139A (en) * | 2007-08-09 | 2008-03-19 | 武汉远大制药集团有限公司 | Stable tiopronin injection and preparation method thereof |
| CN101269011A (en) * | 2008-04-17 | 2008-09-24 | 孙向阳 | Tiopronin injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 宗永斌等: "硫普罗宁注射液与3种输液的配伍稳定性考察", 《中国药师》 * |
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Application publication date: 20120912 |