CN103446049A - Clarithromycin injection and preparation method thereof - Google Patents
Clarithromycin injection and preparation method thereof Download PDFInfo
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- CN103446049A CN103446049A CN2013104205256A CN201310420525A CN103446049A CN 103446049 A CN103446049 A CN 103446049A CN 2013104205256 A CN2013104205256 A CN 2013104205256A CN 201310420525 A CN201310420525 A CN 201310420525A CN 103446049 A CN103446049 A CN 103446049A
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Abstract
The invention relates to a clarithromycin injection which is prepared from the following raw materials: 26g of clarithromycin, 25g of ascorbic acid, 15g of lactic acid, 65g of polyethylene glycol 4000, and 2000ml of injection water, wherein pH is adjusted to 4.3-4.5.
Description
Technical field
The present invention relates to Kelamycin injection and preparation method thereof.
Background technology
Clarithromycin (clarithromycin) is the semi-synthetic erythromycin derivatives of fourteen-ring, chemistry CAMA by name, and its antimicrobial spectrum is similar to erythromycin, comprises most of gram positive bacterias and many gram negative bacterias.With erythromycin, compare, clarithromycin is more stable to acid, and antibacterial activity strengthens, and oral bioavailability improves, and blood drug level increases, and the gastrointestinal compatibility is also better, is clinical antibacterials commonly used.
The conventional dosage forms of clarithromycin is conventional tablet, slow releasing tablet, capsule, granule, dry suspension and intravenous injection.Adopt injection administration more can bring into play the drug effect of clarithromycin, but, due to its poorly water-soluble, the dissolubility of clarithromycin in water is 1:1000, limited it is made to injection type.Both at home and abroad except solid preparation, also developed the multiple dosage form that comprises injection at present, but injection poor stability mostly.
CN1452977A discloses a kind of clarithromycin injection, wherein clarithromycin is prepared into to water soluble salt, is being prepared into injection.
CN1316247A discloses a kind of Kelamycin injection, contains active component clarithromycin and cosolvent, chelating agen, blood plasma expansion agent, stabilizing agent and antioxidant, solution osmotic pressure regulator, pH adjusting agent.
Summary of the invention
The invention provides a kind of stable Kelamycin injection and preparation method thereof, described Kelamycin injection adjuvant is less, good stability, and clinical safety in utilization is higher.
Technical scheme provided by the invention is: Kelamycin injection, by following raw material, made: 26g clarithromycin, 25g ascorbic acid, 15g lactic acid, 65g Macrogol 4000,2000ml water for injection; Adjust pH to 4.3～4.5.
Wherein ascorbic acid and lactic acid have also played the effect of antioxidant when playing cosolvent.
The present invention also provides the preparation method of above-mentioned Kelamycin injection:
1, get ascorbic acid and the lactic acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Macrogol 4000 of recipe quantity, add the water for injection of 40% amount, stir 15 minutes, with hydrochloric acid (the preferably hydrochloric acid of 1mol/L), adjust PH to 3.0～3.5.
3,1,2 solution are merged, with PH regulator (the preferably sodium hydroxide solution of 1mol/L), adjust PH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming.
4, by specification, pour into respectively in the ampoule bottle of 2ml, inflated with nitrogen, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
The inventor finds amazedly, the ascorbic acid of use specified quantitative and the combination of lactic acid are as cosolvent, and the use Macrogol 4000 of specified quantitative rather than the Polyethylene Glycol of other molecular weight are as the injection proppant, the Kelamycin injection stability prepared is high, and its related substances is few.And Kelamycin injection adjuvant of the present invention is less, good stability, clinical safety in utilization is higher.
The specific embodiment
Below test further illustrates the present invention:
the investigation of cosolvent
The dissolving of clarithromycin needs acid cosolvent, and we are investigated several cosolvents.Respectively getting the 1g clarithromycin adds in the 200ml water that is 4.3～4.5 left and right with various cosolvents tune pH values respectively in advance.Place 10 days at 60 ℃, investigate the variation of clarithromycin content, the results are shown in Table 1:
Table 1
The result of the test surface, place after 10 days for 60 ℃, and the clarithromycin content that various cosolvents dissolve has obvious decline, but it is obviously less to do the sample size decline of cosolvent with ascorbic acid and lactic acid composition.
Further the ascorbic acid of our unexpected discovery specified quantitative of research and the quality stability of using improving clarithromycin of combining of lactic acid and Macrogol 4000 have played beyond thought remarkable result.
Embodiment 1:
Clarithromycin: 26g
Ascorbic acid and lactic acid: 25g ascorbic acid+15g lactic acid
Macrogol 4000: 65g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get ascorbic acid and the lactic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Macrogol 4000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming, pour into respectively in the ampoule bottle of 2ml inflated with nitrogen by specification, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 1:
Clarithromycin: 26g
Ascorbic acid and lactic acid: 25g ascorbic acid+15g lactic acid
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get ascorbic acid and the lactic acid of recipe quantity, add 80% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, adjust PH to 4.3～4.5 by pH adjusting agent (sodium hydroxide solution), add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, by specification, pour into respectively in the ampoule bottle of 2ml, inflated with nitrogen, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 2:
Clarithromycin: 26g
Macrogol 4000: 65g
PH adjusting agent: appropriate
Water for injection: 2000ml
Technique:
1, get the Macrogol 4000 of recipe quantity, add 80% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.The clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, adjust PH to 4.3～4.5 by pH adjusting agent (sodium hydroxide solution), add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, by specification, pour into respectively in the ampoule bottle of 2ml, inflated with nitrogen, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 3:
Clarithromycin: 26g
Ascorbic acid and lactic acid: 25g ascorbic acid+15g lactic acid
Polyethylene glycol 6000: 65g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get ascorbic acid and the lactic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the polyethylene glycol 6000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming, pour into respectively in the ampoule bottle of 2ml inflated with nitrogen by specification, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 4:
Clarithromycin: 26g
Ascorbic acid: 40g
Macrogol 4000: 65g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the ascorbic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Macrogol 4000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming, pour into respectively in the ampoule bottle of 2ml inflated with nitrogen by specification, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 5:
Clarithromycin: 26g
Lactic acid: 40g
Macrogol 4000: 65g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the ascorbic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Macrogol 4000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming, pour into respectively in the ampoule bottle of 2ml inflated with nitrogen by specification, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
Comparative examples 6:
Clarithromycin: 25g
Ascorbic acid and lactic acid: 15g ascorbic acid+15g lactic acid
Macrogol 4000: 30g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get ascorbic acid and the lactic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Macrogol 4000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming, pour into respectively in the ampoule bottle of 2ml inflated with nitrogen by specification, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
The product that above-mentioned 7 embodiment are made and the Kelamycin injection (positive reference substance) of CN1316247A are positioned in 60 ℃ of climatic chambers, in sampling calibrating in the 5th, 10 days, and result and comparison in 0 day:
Related substance, content are pressed high effective liquid chromatography for measuring (in Table 2).
Table 2
Result shows: embodiment 1 compares with comparative examples 1-6, positive reference substance, and pH, related substance, stable content have obvious advantage, and obvious advantage is used more separately in the use of combining of ascorbic acid and lactic acid and Macrogol 4000.
The Kelamycin injection of the embodiment of the present invention 1 preparation and the Kelamycin injection of comparative examples 1-6, CN1316247A are carried out to long-time stability investigation (25 ℃ ± 2 ℃, RH 60% ± 10%), the results are shown in Table 5:
Table 5
Result shows: Kelamycin injection prepared by the present invention (embodiment 1) is compared with comparative examples 1-7, positive reference substance, and quality stability increases significantly.
Claims (3)
1. a Kelamycin injection, wherein active component is clarithromycin.
2. Kelamycin injection as claimed in claim 1, it is made by following raw material: 26g clarithromycin, 25g ascorbic acid, 15g lactic acid, 65g Macrogol 4000,2000ml water for injection; Adjust pH to 4.3～4.5.
3. the preparation method of Kelamycin injection as claimed in claim 1 is characterized in that:
(1) get ascorbic acid and the lactic acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the clarithromycin of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes;
(2) get the Macrogol 4000 of recipe quantity, add the water for injection of 40% amount, stir 15 minutes, with hydrochloric acid, adjust PH to 3.0～3.5;
(3) 1,2 solution are merged, use the PH regulator, adjust PH to 4.3～4.5, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming;
(4) by specification, pour into respectively in the ampoule bottle of 2ml, inflated with nitrogen, sealing by fusing, 121 ℃ of moist heat sterilizations 15 minutes, after the assay was approved, packing.
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| CN201310420525.6A CN103446049B (en) | 2013-09-16 | 2013-09-16 | Clarithromycin injection and preparation method thereof |
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| CN201310420525.6A CN103446049B (en) | 2013-09-16 | 2013-09-16 | Clarithromycin injection and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317314A (en) * | 2000-11-07 | 2001-10-17 | 国家药品监督管理局四川抗菌素工业研究所 | Kelamycin injection and its preparing process |
| CN1452977A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Clarithromycin injection |
| CN101045063A (en) * | 2006-03-28 | 2007-10-03 | 广州朗圣药业有限公司 | Clarithromycin water soluber preparation for injection use |
| CN102058521A (en) * | 2009-11-17 | 2011-05-18 | 天津天成制药有限公司 | Injection preparation containing Entecavir serving as active ingredient |
-
2013
- 2013-09-16 CN CN201310420525.6A patent/CN103446049B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317314A (en) * | 2000-11-07 | 2001-10-17 | 国家药品监督管理局四川抗菌素工业研究所 | Kelamycin injection and its preparing process |
| CN1452977A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Clarithromycin injection |
| CN101045063A (en) * | 2006-03-28 | 2007-10-03 | 广州朗圣药业有限公司 | Clarithromycin water soluber preparation for injection use |
| CN102058521A (en) * | 2009-11-17 | 2011-05-18 | 天津天成制药有限公司 | Injection preparation containing Entecavir serving as active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| 宋克谦: "盐酸阿克拉霉素水溶液的稳定性", 《国外医药.抗生素分册》, no. 01, 2 March 1981 (1981-03-02), pages 135 * |
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