CN103536539A - Dextromethorphan hydrobromide lyophilized powder and preparation method thereof - Google Patents
Dextromethorphan hydrobromide lyophilized powder and preparation method thereof Download PDFInfo
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- CN103536539A CN103536539A CN201310420598.5A CN201310420598A CN103536539A CN 103536539 A CN103536539 A CN 103536539A CN 201310420598 A CN201310420598 A CN 201310420598A CN 103536539 A CN103536539 A CN 103536539A
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Abstract
The invention relates to dextromethorphan hydrobromide lyophilized powder. The dextromethorphan hydrobromide lyophilized powder is prepared from the following raw materials: 16g of dextromethorphan hydrobromide, 11g of lactic acid, 8g of sorbic acid, 45g of polyethylene glycol 2000 and 2000ml of water for injection; and the pH of adjusted to 3.3-3.6.
Description
Technical field
The present invention relates to dextromethorphan hydrobromide freeze-dried powder and preparation method thereof.
Background technology
Dextromethorphan hydrobromide is that Switzerland Hoffman Roche company passes through the right-hand helicity morphinan derivative to morphine structure of modification synthetic in nineteen fifty, as isomer, its levorotation compound has analgesic activity, and dextrogyre is that dextromethorphan does not have analgesic activity and has obvious antitussive effect.Animal and clinical research show, dromethan is a kind of effective maincenter cough medicine, Main Function is in oblongata coughing centre, the codeine of antitussive effect and same dose is suitable, and do not suppress respiratory center, without addiction, in urine, with dromethan original shape or demethyl metabolite Dextrorphan, drained, its toxicity is low, untoward reaction is few, is therefore widely used in the cough that a variety of causes causes.Commercially available dextromethorphan hydrobromide injection is to obtain stable dextromethorphan hydrobromide injection often to have added a large amount of adjuvants, but the use of more adjuvant makes again product have higher security risk when increasing product cost.
Summary of the invention
The invention provides a kind of stable dextromethorphan hydrobromide freeze-dried powder and preparation method thereof, described dextromethorphan hydrobromide freeze-dried powder adjuvant is less, good stability, and clinical safety in utilization is higher.
Technical scheme provided by the invention is: dextromethorphan hydrobromide freeze-dried powder, by following raw material, made: 16g dextromethorphan hydrobromide, 11g lactic acid, 8g sorbic acid, 45g Macrogol 2000,2000ml water for injection; Adjust pH to 3.3～3.6.
Wherein lactic acid and sorbic acid have also played the effect of antioxidant when playing cosolvent.
The present invention also provides the preparation method of above-mentioned dextromethorphan hydrobromide freeze-dried powder:
1, get lactic acid and the sorbic acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, get the Macrogol 2000 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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Inventor finds amazedly, use the lactic acid of specified quantitative and the combination of sorbic acid as cosolvent, and the use Macrogol 2000 of specified quantitative rather than the Polyethylene Glycol of other molecular weight are as frozen-dried supporting agent, the dextromethorphan hydrobromide lyophilized injectable powder stability preparing is high, and its related substances is few.And dextromethorphan hydrobromide freeze-dried powder 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 dextromethorphan hydrobromide needs acid cosolvent, and we investigate several cosolvents.Respectively getting that 1g dextromethorphan hydrobromide adds is in advance in the 200ml water of 3.3～3.6 left and right with various cosolvents tune pH values respectively.At 60 ℃, place 10 days, investigate the variation of dextromethorphan hydrobromide content, the results are shown in Table 1:
Table 1
Result of the test surface, places after 10 days for 60 ℃, and the dextromethorphan hydrobromide content that various cosolvents dissolve has obvious decline, but it is obviously less by lactic acid and sorbic acid compositions, to do the sample size decline of cosolvent.
Further study us and surprisingly find that the lactic acid of specified quantitative and the quality stability of using raising dextromethorphan hydrobromide of combining of sorbic acid and Macrogol 2000 have played beyond thought remarkable result.
Embodiment 1:
Dextromethorphan hydrobromide: 16g
Lactic acid and sorbic acid: 11g lactic acid+8g sorbic acid
Macrogol 2000: 45g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, lactic acid and the sorbic acid of getting recipe quantity, add 50% water for injection, is heated to 50～55 ℃, stirs it is dissolved, and the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, get the Macrogol 2000 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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 1:
Dextromethorphan hydrobromide: 16g
Lactic acid and sorbic acid: 11g lactic acid+8g sorbic acid
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, lactic acid and the sorbic acid of getting recipe quantity, add 80% water for injection, is heated to 50～55 ℃, stirs it is dissolved, and the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, by pH adjusting agent (sodium hydroxide solution), adjust PH to 3.3～3.6, 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, pours into filtrate in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 2:
Dextromethorphan hydrobromide: 16g
Macrogol 2000: 45g
PH adjusting agent: appropriate
Water for injection: 2000ml
Technique:
1, get the Macrogol 2000 of recipe quantity, add 80% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.The dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, by pH adjusting agent (sodium hydroxide solution), adjust PH to 3.3～3.6, 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, pours into filtrate in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 3:
Dextromethorphan hydrobromide: 16g
Lactic acid and sorbic acid: 11g lactic acid+8g sorbic acid
Polyethylene glycol 6000: 45g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, lactic acid and the sorbic acid of getting recipe quantity, add 50% water for injection, is heated to 50～55 ℃, stirs it is dissolved, and the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 4:
Dextromethorphan hydrobromide: 16g
Lactic acid: 19g
Macrogol 2000: 45g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the lactic acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, get the Macrogol 2000 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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 5:
Dextromethorphan hydrobromide: 16g
Tartaric acid: 19g
Macrogol 2000: 45g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the tartaric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, get the Macrogol 2000 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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Control Example 6:
Dextromethorphan hydrobromide: 16g
Lactic acid and sorbic acid: 15g lactic acid+4g sorbic acid
Macrogol 2000: 30g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, lactic acid and the sorbic acid of getting recipe quantity, add 50% water for injection, is heated to 50～55 ℃, stirs it is dissolved, and the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving.
2, get the Macrogol 2000 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 3.3～3.6, 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, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
The product that above-mentioned 7 embodiment are made and commercial dextromethorphan hydrobromide freeze-dried powder (positive reference substance) 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 and control Example 1-6, positive reference substance comparison, and pH, related substance, stable content have obvious advantage, and obvious advantage is used more separately in the use of combining of lactic acid and sorbic acid and Macrogol 2000.
Dextromethorphan hydrobromide freeze-dried powder and control Example 1-6, the commercially available dextromethorphan hydrobromide freeze-dried powder of the embodiment of the present invention 1 preparation are carried out to long-time stability investigation (25 ℃ ± 2 ℃, RH 60% ± 10%), the results are shown in Table 3:
Table 3
Result shows: dextromethorphan hydrobromide freeze-dried powder prepared by the present invention (embodiment 1) is compared with control Example 1-7, positive reference substance (listing product), and quality stability increases significantly.
Claims (3)
1. dextromethorphan hydrobromide freeze-dried powder, wherein active component is dextromethorphan hydrobromide.
2. dextromethorphan hydrobromide freeze-dried powder as claimed in claim 1, it is made by following raw material: 16g dextromethorphan hydrobromide, 11g lactic acid, 8g sorbic acid, 45g Macrogol 2000,2000ml water for injection; Adjust pH to 3.3～3.6.
3. the preparation method of dextromethorphan hydrobromide freeze-dried powder as claimed in claim 2:
(1) get lactic acid and the sorbic acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the dextromethorphan hydrobromide of getting recipe quantity adds in solution, continues to stir 15 minutes after stirring and dissolving;
(2) get the Macrogol 2000 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, with PH regulator, adjust PH to 3.3～3.6, 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) filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
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| CN103536539B CN103536539B (en) | 2015-03-25 |
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| CN1634061A (en) * | 2004-10-11 | 2005-07-06 | 贵阳云岩西创药物科技开发有限公司 | Pharmaceutical formulation of pseudoephenrine hydrochloride and its preparing process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634061A (en) * | 2004-10-11 | 2005-07-06 | 贵阳云岩西创药物科技开发有限公司 | Pharmaceutical formulation of pseudoephenrine hydrochloride and its preparing process |
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