CN1676162A - Thymic penta peptide injection liquid - Google Patents
Thymic penta peptide injection liquid Download PDFInfo
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- CN1676162A CN1676162A CN 200410029852 CN200410029852A CN1676162A CN 1676162 A CN1676162 A CN 1676162A CN 200410029852 CN200410029852 CN 200410029852 CN 200410029852 A CN200410029852 A CN 200410029852A CN 1676162 A CN1676162 A CN 1676162A
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- thymopentin
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- glycine
- injection
- thymus gland
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Abstract
The present invention discloses a thymus pentapeptide injection. Said injection can be directly used in clinical application. Said invented thymus pentapeptide injection is basically formed from thymus pentapeptide whose concentration is 0.1-100 mg/ml, glycine whose concentration is 2-100 my/ml and sodium nitrate whose concentration is 10-50 mmol/L, the optimum concentration of thymus pentapeptite is 10-100 mg/ml, the optimum concentration of glycine is 20-30 mg/ml and the optimum concentration of sodium nitrate is 20-30 mmol/L, and the injection pH is 7.0-7.2.
Description
Technical field
The present invention relates to a kind of injection, particularly relate to a kind of thymus gland pentapeptide injection.
Background technology
Thymopentin (Thymopentin is called for short TP-5) is the 32nd to 36 the aminoacid segment of thymopoietin II (Thymopoietin).People such as Goldstein find that this segment is the immunocompetence center of thymopoietin II, and have kept biological activity and the physiological function of thymopoietin II, and its major physiological act as the two-ways regulation body's immunological function, and then the overall immunity of enhancing body.
Thymopentin has been widely used in clinical at present, treats multiple disease, as: the immunologic function degression due to the malignant tumor; Chronic second, hepatitis C and complication thereof; Various constitutionales or Secondary cases T cell defect disease are as child's innate immunity defective disease; Some autoimmune disease is as rheumatoid arthritis, systemic lupus erythematosus (sle), child's bronchial asthma and asthma bronchitis etc.; The disease that various cellular immune functions are low is as viral hepatitis, prevention upper respiratory tract infection, intractable oral cavity ulcer or the like.
The same with most peptide quasi-molecules, Thymopentin stability in common aqueous solution is lower.The stability of polypeptide in aqueous solution is subjected to influence of various factors such as salt ion kind and concentration, acid-base value, the concentration of polypeptide, the composition of additive (people such as Manning, 1986, Pharmaceutical Research magazine the 6th volume 903-918 page or leaf).Present clinical use be the freeze-dried powder dosage form, every contains 1 milligram of Thymopentin, is dissolved in before the use in 1 milliliter the water for injection.The complex manufacturing of freeze-dried powder, the doctor uses also inconvenient.
Summary of the invention
The purpose of this invention is to provide a kind of thymus gland pentapeptide injection.
Thymus gland pentapeptide injection provided by the present invention is the Thymopentin of 0.1-100mg/ml basically by concentration, and the glycine of 2-100mg/ml and the sodium citrate of 10-50mmol/L are formed.
In the above-mentioned injection, the concentration of Thymopentin can be selected 1-100mg/ml, and Thymopentin can be preserved the longer time in aqueous solution when 10-100mg/ml; The concentration of glycine can be chosen as 10-50mg/ml, and is better to the effect that strengthens Thymopentin stability in aqueous solution when 20-30mg/ml; The preferred concentration of sodium citrate is 20-30mmol/L; Injection is generally regulated pH with NaOH and is advisable with 7.0-7.2.
Thymus gland pentapeptide injection provided by the present invention has ambient-temp-stable, long characteristics of holding time, and Thymopentin purity remains on about 99% after 120 days, and easy to use, can be directly used in clinical.
Description of drawings
Figure 1A-Fig. 1 E is Thymopentin HPLC figure, shows glycine concentration to the Thymopentin stability influence, and wherein Figure 1A-Fig. 1 E is respectively that glycine concentration is 0, preserves the HPLC figure of Thymopentin after 90 days when 20mg/ml, 30mg/ml, 40mg/ml, 50mg/ml
Fig. 2 A-Fig. 2 E is Thymopentin HPLC figure, shows sodium citrate concentration to the Thymopentin stability influence, and wherein Fig. 2 A-Fig. 2 E is respectively that sodium citrate concentration is 0,15,20,25, preserves the HPLC figure of Thymopentin after 90 days during 30mmol/L
Fig. 3 A-Fig. 3 E is Thymopentin HPLC figure, shows Thymopentin concentration to its stability influence, and wherein Fig. 3 A-Fig. 3 E is respectively that Thymopentin concentration is 1,10,20,40, preserves the HPLC figure after 120 days during 60mg/ml
The specific embodiment
(according to Thymopentin purity in the sample is 100% to 103.6 milligrams of Thymopentin of precision weighing, moisture is 3.5% calculating, the weight of Thymopentin is: 103.6 milligrams * (1-3.5%)=100 milligram), 735 milligrams of sodium citrates (containing 2 molecular crystalline water), Different Weight glycine (0,0.2,0.5,1,2,3,4,5,7,10 gram) are in 100 milliliters of volumetric flasks, add about 90 ml waters, jolting makes it fully dissolve the back and regulates pH value to 7.0 with 1M NaOH, adds water to scale then.
Solution in the volumetric flask is removed other insoluble impurities and the antibacterial that exists in the solution with 0.22 μ m membrane filtration.
Solution branch after filtering is filled in 1 milliliter the ampere bottle.
Get 45 bottles of solution and place, adopted HPLC to carry out content detection respectively at the 0th, 30,90 day and follow the tracks of at 25 ℃ of condition lower seals.Chromatographic condition is:
Chromatographic column: Vydac 238DE54 (4.6 * 250mm) C18 posts
Mobile phase A: 0.1% trifluoroacetic acid is dissolved in 10% acetonitrile
Mobile phase B: 0.1% trifluoroacetic acid is dissolved in 90% acetonitrile
Elution program (as shown in table 1): 1.0 ml/min, linear gradient
The gradient elution program of table 1, HPLC
| Time (min) | ??A％ | ??B％ | Remarks |
| ????0-30 | ?100-70 | ?0-30 | Linear gradient elution |
| ????30-31 | ?70-0 | ?30-100 | Linear gradient |
| ????31-40 | ?0 | ?100 | Constant gradient cleans chromatographic column |
| ????40-41 | ?0-100 | ?100-0 | Linear gradient |
| ????41-55 | ?100 | ?0 | Constant gradient balance chromatographic column |
All processes adopts Ultraviolet Detector (wavelength 275nm) monitoring, calculates the purity of Thymopentin according to the peak area normalization method.Result of the test is as shown in table 2, and numerical value is Thymopentin purity in the table.
Table 2, glycine concentration are to the influence of aqueous solution Thymopentin purity
| Glycine concentration (mg/ml) | 0 | ?2 | ?5 | ?10 | ?20 | ?30 | ?40 | ?50 | ?70 | ?100 |
| 0 | 100 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 |
| 30 days | 93.1 | ?97.2 | ?98.2 | ?99.0 | ?99.8 | ?100 | ?99.7 | ?100 | ?99.5 | ?98.6 |
| 90 days | 83.2 | ?93.3 | ?95.2 | ?97.6 | ?99.2 | ?99.4 | ?98.8 | ?98.1 | ?98.3 | ?96.6 |
Glycine concentration is 0, preserve the HPLC separation graph of 90 days Thymopentin samples shown in Figure 1A-Fig. 1 E when 20mg/ml, 30mg/ml, 40mg/ml, 50mg/ml.
Glycine concentration all can increase the stability of Thymopentin in aqueous solution in the 2-100mg/ml scope as can be found from Table 2, and preferably concentration is 10-50mg/ml, most preferably is 20-30mg/ml.
(according to Thymopentin purity in the sample is 100% to 103.6 milligrams of Thymopentin of precision weighing, moisture is 3.5% calculating, the weight of Thymopentin is: 103.6 milligrams * (1-3.5%)=100 milligram), 3 gram glycine, Different Weight contain the sodium citrate (0,147 milligram, 294 milligrams, 441 milligrams, 588 milligrams, 735 milligrams, 882 milligrams, 1.18 grams, 1.47 grams) of 2 molecular crystalline water in 100 milliliters of volumetric flasks, add about 90 ml waters, jolting makes it fully dissolve the back and regulates pH value to 7.1 with 1M NaOH, adds water to scale then.
Solution in the volumetric flask is removed other insoluble impurities and the antibacterial that exists in the solution with 0.22 μ m membrane filtration.
Solution branch after filtering is filled in 1 milliliter the ampere bottle.
Get 45 bottles of solution and place, adopted HPLC to carry out content detection respectively at the 0th, 30,90 day and follow the tracks of at 25 ℃ of condition lower seals.Chromatographic condition is identical with embodiment 1.
All processes adopts Ultraviolet Detector (wavelength 275nm) monitoring, calculates the purity of Thymopentin according to the peak area normalization method.Result of the test is as shown in table 3, and numerical value is Thymopentin purity in the table.
Table 3, sodium citrate concentration are to the influence of aqueous solution Thymopentin purity
| Sodium citrate concentration | ??0 | ??5mM | ??10mM | ??15mM | ????20mM | ????25mM | ??30mM | ????40mM | ???? |
| 0 day | ??100.0 | ??100.0 | ??100.0 | ??100.0 | ????100.0 | ????100.0 | ??100.0 | ????100.0 | ????100.0 |
| 30 days | ??92.7 | ??97.0 | ??99.2 | ??99.6 | ????100.0 | ????99.0 | ??99.7 | ????100.0 | ????99.1 |
| 90 days | ??82.4 | ??93.9 | ??97.9 | ??98.8 | ????99.2 | ????98.9 | ??98.9 | ????98.0 | ????98.3 |
Sodium citrate concentration is 0,15,20,25, preserve the HPLC separation graph of 90 days Thymopentin samples shown in Fig. 2 A-Fig. 2 E during 30mmol/L.
Sodium citrate all can increase the stability of Thymopentin in aqueous solution in concentration 10-50mmol/L scope as can be found from Table 3, and preferred concentration is 20-30mmol/L.
(it is an amount of to get Thymopentin for the Thymopentin of 735 milligrams of sodium citrates of precision weighing (containing 2 molecular crystalline water), 3 gram glycine and Different Weight, the accurate title, decide, according to Thymopentin purity in the sample is 100%, moisture is 3.5% calculating, make Thymopentin weight reach 10,50,100,500 milligrams, 1,2,4,6,8 respectively, 10 the gram) in 100 milliliters of volumetric flasks, add about 90 ml waters, jolting makes it fully dissolve the back and regulates pH value to 7.2 with 1M NaOH, adds water to scale then.
Solution in the volumetric flask is removed other insoluble impurities and the antibacterial that exists in the solution with 0.22 μ m membrane filtration.
Solution branch after filtering is filled in 1 milliliter the ampere bottle.
Get 45 bottles of solution and place, adopted HPLC to carry out purity detecting respectively at the 0th, 60,120 day and follow the tracks of at 37 ℃ of condition lower seals.Chromatographic condition is identical with embodiment 1.
All processes adopts Ultraviolet Detector (wavelength 275nm) monitoring, calculates the purity of Thymopentin according to the peak area normalization method.Result of the test is as shown in table 4, and numerical value is Thymopentin purity in the table.
Table 4, Thymopentin concentration concentration are to the influence of its aqueous solution purity
| Thymopentin concentration (mg/ml) | ????0.1 | ????0.5 | ????1.0 | ????5.0 | ????10.0 | ????20.0 | ????40.0 | ????60.0 | ????80.0 | ????100.0 |
| 0 day | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 | ????100.0 |
| 60 days | ????93.3 | ????97.6 | ????98.2 | ????98.3 | ????99.0 | ????99.0 | ????99.4 | ????99.6 | ????99.8 | ????100.0 |
| 120 days | ????87.2 | ????94.2 | ????97.2 | ????97.9 | ????98.1 | ????98.7 | ????99.1 | ????99.3 | ????99.4 | ????99.7 |
The HPLC separation graph that Thymopentin concentration is 1,10,20,40, preserve 120 days Thymopentin samples during 60mg/ml is seen accompanying drawing 3A-Fig. 3 E.
The result shows that Thymopentin concentration is all more stable when the 0.1-100 mg/ml, and still along with the increase of Thymopentin concentration, its stability in aqueous solution slightly improves, and preferably the 1-100 mg/ml most preferably is the 10-100 mg/ml.
Claims (8)
1, a kind of thymus gland pentapeptide injection is the Thymopentin of 0.1-100mg/ml basically by concentration, and the glycine of 2-100mg/ml and the sodium citrate of 10-50mmol/L are formed.
2, thymus gland pentapeptide injection according to claim 1 is characterized in that: the concentration of described Thymopentin is 1-100mg/ml,
3, thymus gland pentapeptide injection according to claim 2 is characterized in that: the concentration of described Thymopentin is 10-100mg/ml.
4, thymus gland pentapeptide injection according to claim 1 is characterized in that: the concentration of described glycine is 10-50mg/ml.
5, thymus gland pentapeptide injection according to claim 4 is characterized in that: the concentration of described glycine is 20-30mg/ml.
6, thymus gland pentapeptide injection according to claim 1 is characterized in that: the concentration of described sodium citrate is 20-30mmol/L.
7, according to the arbitrary described thymus gland pentapeptide injection of claim 1 to 6, it is characterized in that: described injection pH is 7.0-7.2.
8, thymus gland pentapeptide injection according to claim 1 is characterized in that: Thymopentin concentration is 1mg/ml, and glycine concentration is 30mg/ml, and sodium citrate concentration is 25mmol/L, and pH is 7.0-7.2.
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| CN 200410029852 CN1676162A (en) | 2004-03-30 | 2004-03-30 | Thymic penta peptide injection liquid |
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| CN 200410029852 CN1676162A (en) | 2004-03-30 | 2004-03-30 | Thymic penta peptide injection liquid |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100435843C (en) * | 2006-04-21 | 2008-11-26 | 北京国丹药物技术开发有限公司 | Compsns. of thymopentin and interferon |
| CN102085364A (en) * | 2010-12-23 | 2011-06-08 | 宁波市三生药业有限公司 | Application of thymopentin in emulsion type injection vaccine |
| CN102085365A (en) * | 2010-12-23 | 2011-06-08 | 宁波市三生药业有限公司 | Application of thymopentin in intranasal vaccine |
| CN102380088A (en) * | 2010-08-31 | 2012-03-21 | 海南中化联合制药工业股份有限公司 | Prescription and preparation method of thymopeptide-5 injection |
| CN102488884A (en) * | 2011-12-14 | 2012-06-13 | 中国人民解放军第三0二医院 | Thymopoietin for large dosage injection and application thereof for treating severe hepatitis |
| CN103565731A (en) * | 2012-08-02 | 2014-02-12 | 江苏金丝利药业有限公司 | Thymopentin injection composition |
| CN105012232A (en) * | 2015-08-14 | 2015-11-04 | 北京世桥生物制药有限公司 | Thymopentin injection and preparation method thereof |
-
2004
- 2004-03-30 CN CN 200410029852 patent/CN1676162A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100435843C (en) * | 2006-04-21 | 2008-11-26 | 北京国丹药物技术开发有限公司 | Compsns. of thymopentin and interferon |
| CN102380088A (en) * | 2010-08-31 | 2012-03-21 | 海南中化联合制药工业股份有限公司 | Prescription and preparation method of thymopeptide-5 injection |
| CN102085364A (en) * | 2010-12-23 | 2011-06-08 | 宁波市三生药业有限公司 | Application of thymopentin in emulsion type injection vaccine |
| CN102085365A (en) * | 2010-12-23 | 2011-06-08 | 宁波市三生药业有限公司 | Application of thymopentin in intranasal vaccine |
| CN102488884A (en) * | 2011-12-14 | 2012-06-13 | 中国人民解放军第三0二医院 | Thymopoietin for large dosage injection and application thereof for treating severe hepatitis |
| CN103565731A (en) * | 2012-08-02 | 2014-02-12 | 江苏金丝利药业有限公司 | Thymopentin injection composition |
| CN103565731B (en) * | 2012-08-02 | 2015-08-12 | 江苏金丝利药业有限公司 | A kind of thymopentin injection composition |
| CN105012232A (en) * | 2015-08-14 | 2015-11-04 | 北京世桥生物制药有限公司 | Thymopentin injection and preparation method thereof |
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