CN1781482A - Nizatidine freeze-dried powder injection and preparing method - Google Patents
Nizatidine freeze-dried powder injection and preparing method Download PDFInfo
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- CN1781482A CN1781482A CN 200410081388 CN200410081388A CN1781482A CN 1781482 A CN1781482 A CN 1781482A CN 200410081388 CN200410081388 CN 200410081388 CN 200410081388 A CN200410081388 A CN 200410081388A CN 1781482 A CN1781482 A CN 1781482A
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- nizatidine
- freeze
- dried powder
- powder injection
- acid
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Abstract
The present invention is freeze-dried Nizatidine powder for injection and its preparation process. The freeze-dried Nizatidine powder for injection has the main components including Nizatidine in 0.25-3 weight portions, water soluble freeze drying supporting agent in 0.1-10 weight portions and co-solvent in 0.1-10 weight portions. The water solution with Nizatidine content of 25 mg/ml has pH value of 5-11.
Description
Technical field
The present invention relates to be used for the treatment of the medicine Nizatidine freeze-dried powder injection and the preparation method of peptic ulcer.
Background technology
Peptic ulcer comprises diseases such as duodenal ulcer, gastric ulcer, suction (acid) syndrome, dyspepsia, reflux esophagitis and Zollinger-Eillison syndrome, be one of principal disease that is detrimental to health, and the patient with severe symptoms often needs drug administration by injection.Nizatidine is a kind of novel histamine H
2Receptor antagonist pharmaceuticals, United States Patent (USP) 4,375,547 have reported this chemical compound and preparation method thereof.Existing at present solid preparation of this medicine and liquid drugs injection are used.Because nizatidine is extremely unstable in water, is subjected to influence of various factors such as light, heat, oxygen, water, the very fast decline of the content in aqueous solution, impurity content raises rapidly, and color can't satisfy the stability requirement of long term store and use by the colourless yellow that becomes.
Summary of the invention
In view of the foregoing, the present invention will provide a kind of helping to keep the stable of ingredient, and be convenient to operate and be suitable for Nizatidine freeze-dried powder injection of large-scale production and preparation method thereof.This medicine can provide the intravenous drip administration, the toxic and side effects of avoiding intravenous injection to cause.
Nizatidine freeze-dried powder injection of the present invention is characterized in that main component is nizatidine, aqueous frozen-dried supporting agent and cosolvent, and the pH value of water solution when nizatidine content is 25mg/ml is 5～11, and the predominant quantity ratio is:
0.25～3 part of nizatidine,
0.1～10 part of frozen-dried supporting agent,
0.1～10 part of cosolvent.
Test shows that in above-mentioned Nizatidine freeze-dried powder injection, said water solublity frozen-dried supporting agent is to select mannitol, sorbitol, glucose, lactose, dextran, at least a for well among the NaCl etc. is preferred water solublity frozen-dried supporting agent with mannitol wherein.
Said cosolvent wherein is preferred with the hydroxypropyl beta cyclodextrin to select at least a for well in lecithin, poloxamer, soybean phosphatide, the hydroxypropyl beta cyclodextrin etc.After adding said cosolvent, can increase the dissolubility of medicine greatly, help reducing the difficulty of lyophilizing operation, save cost.Under the condition that guarantees safety, its additional proportion scope can be 3%-40% (weight).
Except that each above-mentioned main component,, therefore as required, can also use suitable pH regulator agent because Nizatidine freeze-dried powder injection of the present invention has particular requirement to pH.For example, can select hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, acetic acid, Metaphosphoric acid, tartaric acid, citric acid, sodium hydroxide, potassium hydroxide, ammonia, organic amine, and at least a in the pH regulator agent commonly used in the pharmacy such as salt compounds.
As above-mentioned, nizatidine under acid condition to instabilities such as light, heat, oxygen, water.Result of the test under 80 ℃ of conditions shows; liquid (25mg/ml) pH value before the lyophilizing of nizatidine is controlled at 5 when above; the stability of prepared freeze-dried powder injecta medicine can obviously improve, and the freeze-dried powder that when pH8 is above, makes, later degraded is very slow.The pH value that changes the preceding liquid of lyophilizing is as follows to the result of the test of medicine stability influence:
| Liquid pH value before the lyophilizing | Outward appearance | Nizatidine content (%) |
| 4 4.5 5 6 7 8 9 10 11 | Little yellow white white white white white white white white | 90.2 92.7 95.8 97.4 98.7 99.1 99.0 99.2 98.9 |
Therefore, stable in storage process for improving pharmaceutical preparation, the pH value of medicine to be controlled to be in the scope of neutrality and/or meta-alkalescence be suitable and need.
On the basis of above-mentioned pH value scope, if further increase pH value, make alkalescence too high, after can causing diluting routinely with 0.9%Nacl or 5% glucose injection agent in use, the pH value of medicinal liquid was difficult to reduce in the normal range that body can bear, and the body of user is caused consequence unfavorable even infringement.
Further result of the test shows, in the said above-mentioned pH value scope of Nizatidine freeze-dried powder injection of the present invention, the pH value of water solution so that nizatidine content is 25mg/ml is controlled in 7～11 scopes better, and serves as preferred with pH8～10 especially.Medicine in this pH value scope in use, during with 0.9%NaCl or 5% glucose injection dilution agent, pH value can be between 5～10, it is the scope that living organism can bear, even can reach near neutral preferable pH scope, and also can make nizatidine can keep stable in back 6 hours, realize having avoided the toxic and side effects that may cause because of intravenous injection for the purpose of clinical vein instillation use in dissolving.
A kind of operation of being convenient to provided by the invention, and be suitable for the preparation method of the above-mentioned Nizatidine freeze-dried powder injection of large-scale production, the main component of said proportional quantities can be mixed with the water for injection dissolving, the pH value of mixed aqueous solution is adjusted in the above-mentioned said scope when with suitable pH regulator agent nizatidine content being 25mg/ml, decolour with activated carbon etc. with 0.1～0.5% injection in the usual way, degerming, it is canned to filter the back, elder generation's precooling is to-70 ℃～-20 ℃, be incubated 2～8 hours, (for example can be for reference for 1-10Pa) be increased to temperature 10 ℃～50 ℃ and continue to keep vacuum 3～10 hours the sealing preservation in 10～30 hours under vacuum condition again.
Below example by the specific embodiment again foregoing of the present invention is described in further detail.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made include within the scope of the invention.
The specific embodiment
Embodiment 1
Medicine is formed: injection nizatidine 100g
Mannitol 280.0g
Hydroxypropyl beta cyclodextrin 80g
Dilute hydrochloric acid (pH regulator agent) is an amount of
Water for injection 2000ml
Be prepared into 1000.
Preparation method: with nizatidine, mannitol, hydroxypropyl beta cyclodextrin, add injection water 1900ml, stir and make dissolving, be adjusted to pH5～7 with dilute hydrochloric acid, add 0.3% pin activated carbon, stirring at room 20min filters de-carbon, after the microporous filter membrane degerming, add sterile water for injection to 2000ml, fill behind the mensuration content, every about 2ml pre-freeze is to-40 ℃, be incubated 2 hours, then evacuation and remain on and make its lyophilizing under the 1-10Pa condition.In 17 hours, temperature rises to 20 ℃ by-40 ℃, continue to keep vacuum 5 hours, take out to add the plug sealing, jewelling cover finished product.
Liquid and freeze-dried powder before the medicament freeze-drying in this example are all placed 60 ℃ of calorstats, place to take out after 5 days and do quality examination, the result is as follows:
| Index | Liquid before the lyophilizing | Freeze-dried powder |
| Outward appearance | Yellow solution | White powder |
| Content % (being labelled amount) | 91.4 | 99.6 |
| Impurity % (area normalization method) | 8.7 | 0.3 |
As seen freeze-dried powder has better stability than light water needle set.
Embodiment 2
Medicine is formed: injection nizatidine 100g
Glucose 300.0g
Lecithin 40g
Sodium hydroxide (pH regulator agent) is an amount of
Water for injection 2000ml
Be prepared into 1000.
Preparation method: with nizatidine, glucose, lecithin, add injection water 1900ml, stirring makes dissolving, transfer pH8～0.3% pin activated carbon with sodium hydroxide, stirring at room 20min filters de-carbon, after the microporous filter membrane degerming, add sterile water for injection to 2000ml, after measuring content, fill, every about 4ml pre-freeze is to-40 ℃, be incubated 2 hours and make its lyophilizing in a manner described, in 17 hours, temperature rises to 20 ℃ by-40 ℃, continues to keep vacuum 5 hours, taking-up adds plug sealing, jewelling cover finished product.
Embodiment 3
Medicine is formed: injection nizatidine 100g
Sodium chloride 270.0g
Fabaceous lecithin 40g
Sodium carbonate (pH regulator agent) is an amount of partially
Water for injection 2000ml
Be prepared into 1000.
Preparation method is with embodiment 2.
Embodiment 4
Medicine is formed: injection nizatidine 100g
Dextran 1 20.0g
Poloxamer 30g
Polymeric sodium metaphosphate. is an amount of
Water for injection 2000ml
Be prepared into 1000.
Preparation method is with embodiment 2.
Embodiment 5
Medicine is formed: injection nizatidine 300g
Mannitol 560.0g
Poloxamer 90g
Dilute hydrochloric acid is an amount of
Water for injection 6000ml
Be prepared into 1000.
Preparation method: with nizatidine, mannitol, poloxamer, add injection water 5900ml, stirring makes dissolving, transfers pH5～7 with dilute hydrochloric acid, adds 0.3% pin activated carbon, stirring at room 20min, filter de-carbon,, add sterile water for injection to 6000ml after the microporous filter membrane degerming, after measuring content, fill, every about 4ml presses the same manner pre-freeze to-40 ℃, be incubated 2 hours and make its lyophilizing, in 17 hours, temperature rises to 20 ℃ by-40 ℃, continues to keep vacuum 5 hours, taking-up adds plug sealing, jewelling cover finished product.
Embodiment 6
Medicine is formed: injection nizatidine 300g
Glucose 450.0g
Hydroxypropyl beta cyclodextrin 240g
Sodium hydroxide is an amount of
Water for injection 6000ml
Be prepared into 1000.
Preparation method: get recipe quantity nizatidine, glucose, lecithin, add injection water 5900ml, stirring makes dissolving, transfers pH8～11 with sodium hydroxide, adds 0.3% pin activated carbon, stirring at room 20min, filter de-carbon,, add sterile water for injection to 6000ml after the microporous filter membrane degerming, fill behind the mensuration content, every about 4ml.The same manner pre-freeze be incubated 2 hours and lyophilizing to-40 ℃, and in 17 hours, temperature rises to 20 ℃ by-40 ℃, continues to keep vacuum 5 hours, take out to add plug and seal, jewelling cover finished product.
Embodiment 7
Medicine is formed: injection nizatidine 300g
Sodium chloride 405.0g
Fabaceous lecithin 120g
Sodium carbonate is an amount of
Water for injection 6000ml
Be prepared into 1000.
Preparation method is with embodiment 6.
Embodiment 8
Medicine is formed: injection nizatidine 300g
Dextran 360.0g
Poloxamer 90g
Polymeric sodium metaphosphate. is an amount of
Water for injection 6000ml
Be prepared into 1000.
Preparation method is with embodiment 6.
Embodiment 9
Medicine is formed: injection nizatidine 300g
Mannitol 280g
Poloxamer 90g
Anhydrous sodium phosphate is an amount of
Water for injection 6000ml
Be prepared into 1000.
Preparation method is with embodiment 6.
Claims (10)
1. Nizatidine freeze-dried powder injection is characterized in that main component is nizatidine, aqueous frozen-dried supporting agent and cosolvent, and the pH value of water solution when nizatidine content is 25mg/ml is 5～11, and the predominant quantity ratio is:
0.25～3 part of nizatidine,
0.1～10 part of frozen-dried supporting agent,
0.1～10 part of cosolvent.
2. Nizatidine freeze-dried powder injection as claimed in claim 1 is characterized in that said water solublity frozen-dried supporting agent is a mannitol, sorbitol, glucose, lactose, dextran, at least a among the NaCl.
3. Nizatidine freeze-dried powder injection as claimed in claim 2 is characterized in that said water solublity frozen-dried supporting agent is a mannitol.
4. Nizatidine freeze-dried powder injection as claimed in claim 1 is characterized in that said cosolvent is at least a in lecithin, poloxamer, soybean phosphatide, the hydroxypropyl beta cyclodextrin.
5. Nizatidine freeze-dried powder injection as claimed in claim 4 is characterized in that said cosolvent is a hydroxypropyl beta cyclodextrin.
6. Nizatidine freeze-dried powder injection as claimed in claim 1 is characterized in that also containing in the said composition pH regulator agent.
7. Nizatidine freeze-dried powder injection as claimed in claim 6, it is characterized in that said pH regulator agent is hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, acetic acid, Metaphosphoric acid, tartaric acid, citric acid, sodium hydroxide, potassium hydroxide, ammonia, organic amine, and at least a in the salt compounds.
8. as the described Nizatidine freeze-dried powder injection of one of claim 1 to 7, it is characterized in that said pH value of water solution when nizatidine content is 25mg/ml is 7～11.
9. Nizatidine freeze-dried powder injection as claimed in claim 8 is characterized in that said pH value of water solution when nizatidine content is 25mg/ml is 8～10.
10. the method for preparing the described Nizatidine freeze-dried powder injection of claim 1, it is characterized in that said each composition is mixed with the water for injection dissolving, pH value when the acid-base value of mixed aqueous solution is adjusted to nizatidine content and is 25mg/ml is 5～11, canned after the decolouring degerming, elder generation's precooling is to-70～-20 ℃, be incubated 2～8 hours, also continue to keep vacuum 3～10 hours the sealing preservation in 10～30 hours, temperature being increased to 10 ℃～50 ℃ under the vacuum condition again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410081388 CN1781482A (en) | 2004-12-03 | 2004-12-03 | Nizatidine freeze-dried powder injection and preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410081388 CN1781482A (en) | 2004-12-03 | 2004-12-03 | Nizatidine freeze-dried powder injection and preparing method |
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| CN1781482A true CN1781482A (en) | 2006-06-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462909A (en) * | 2013-09-12 | 2013-12-25 | 门毅 | Formulation of nizatidine for injection and preparation technology thereof |
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2004
- 2004-12-03 CN CN 200410081388 patent/CN1781482A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462909A (en) * | 2013-09-12 | 2013-12-25 | 门毅 | Formulation of nizatidine for injection and preparation technology thereof |
| CN103462909B (en) * | 2013-09-12 | 2015-03-11 | 门毅 | Formulation of nizatidine for injection and preparation technology thereof |
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Open date: 20060607 |