CN102525909A - Method for preparing penehyclidine hydrochloride injection - Google Patents
Method for preparing penehyclidine hydrochloride injection Download PDFInfo
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- CN102525909A CN102525909A CN2012100495931A CN201210049593A CN102525909A CN 102525909 A CN102525909 A CN 102525909A CN 2012100495931 A CN2012100495931 A CN 2012100495931A CN 201210049593 A CN201210049593 A CN 201210049593A CN 102525909 A CN102525909 A CN 102525909A
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- China
- Prior art keywords
- injection
- ether hydrochloride
- amyl ethyl
- ethyl quin
- quin ether
- Prior art date
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- 239000007924 injection Substances 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 33
- DDTVVMRZNVIVQM-UHFFFAOYSA-N 2-(1-azabicyclo[2.2.2]octan-3-yloxy)-1-cyclopentyl-1-phenylethanol;hydrochloride Chemical compound Cl.C1N(CC2)CCC2C1OCC(O)(C=1C=CC=CC=1)C1CCCC1 DDTVVMRZNVIVQM-UHFFFAOYSA-N 0.000 title abstract 6
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a penehyclidine hydrochloride injection and belongs to the field of medicines. The specific preparation process of the injection is as follows: (1) washing inner packaging materials with purified water and water for injection and then pasteurizing and drying the inner packaging materials for standby application; (2) weighing penehyclidine hydrochloride based on the prescription dose, adding a defined amount of water for injection to dissolve penehyclidine hydrochloride, regulating the pH value of the liquid medicine to 4.6-4.8 with a pH regulator, then adding water for injection to reach the total amount and stirring the liquid medicine uniformly; and (3) measuring the pH value and the content, filtering the liquid medicine after the pH value and the content are qualified, filling and sealing the filtrate in the inner packaging materials for standby application and carrying out pasteurization, thus obtaining the penehyclidine hydrochloride injection. The method has the following beneficial effects: not only can the pH value and content of the penehyclidine hydrochloride injection product obtained by the method be more stable, but also the product quality is more easily ensured; and meanwhile, the final product is proved to be safe and effective by animal long-term toxicity tests and pharmacodynamics tests.
Description
Technical field
The present invention relates to a kind of method for preparing of injection medicinal liquid, be specifically related to a kind of method for preparing of selectivity anticholinergic agent amyl ethyl quin ether hydrochloride injection, belong to the medical drugs field.
Background technology
The amyl ethyl quin ether hydrochloride injection is the new selective anticholinergic agent, can combine with M, N cholinoceptor, and selectively acting is in M
1, M
3, N
1, N
2Receptor is to M
2Receptor does not have effect; Have the not available advantages of anticholinergic agents such as atropine, scopolamine;, acting duration strong like cholinolytic effect is long, protection heart rate two-ways regulation mechanism, microcirculation improvement, toxic and side effects are low etc.; Demonstrated wide application prospect clinically: the treatment of organophosphate poisoning, premedication, the application in respiratory system disease; Shock, to the protective effect of cerebral ischemia-reperfusion injury, application in digestive tract disease and acute abdominal pain or the like.
Discover through inventor's long term test: the amyl ethyl quin ether hydrochloride chemical compound is water-soluble; Direct again fill is in existing any commercially available ampoule bottle and cillin bottle without pre-treatment; Stability is not good, places for a long time to occur the significant change that pH value rises and content descends after 8 months, and pH value and changes of contents cause drug quality and curative effect instability; Even can exceed qualified limit, become defective medicine.
Do not find to have solution and the bibliographical information that proposes to the problems referred to above at present as yet.
Summary of the invention
It is not good that the present invention is intended to solve existing amyl ethyl quin ether hydrochloride injection stability in without the commercially available ampoule bottle of any processing and cillin bottle; The problem that pH value rises and content descends appears in long-term the placement after 8 months; A kind of novel method for preparing of amyl ethyl quin ether hydrochloride injection is provided, the method for especially before to the embedding of amyl ethyl quin ether hydrochloride injection, handling in advance.The amyl ethyl quin ether hydrochloride injection products that is obtained by this process is more stable aspect pH, the content, and product quality is guaranteed more easily, can prevent underproof medicine.
Concrete technical scheme of the present invention is following:
A kind of method for preparing of amyl ethyl quin ether hydrochloride injection; It is characterized in that: the amyl ethyl quin ether hydrochloride injection produce take the pH regulator agent to regulate amyl ethyl quin ether hydrochloride medicinal liquid pH in the process after; Fill is in pharmaceutical glass ampoule bottle or glass cillin bottle again, and high temperature sterilize promptly gets.
Said pH regulator agent is any one in following: aqueous hydrochloric acid solution, aqueous sulfuric acid, aqueous acetic acid, phosphate aqueous solution, aqueous solution of nitric acid or oxalic acid aqueous solution, its concentration is 0.1mol/L～0.5mol/L, preferred 0.1mol/L.
The pH value of said amyl ethyl quin ether hydrochloride medicinal liquid is 4.6 ~ 4.8.
The concrete method for preparing step of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride; Add injection water dissolving, with in 0.1mol/L～0.5mol/L aqueous hydrochloric acid solution or aqueous sulfuric acid, aqueous acetic acid, phosphate aqueous solution, aqueous solution of nitric acid, the oxalic acid aqueous solution any one, adjusting pH to 4.6 ~ 4.8; Add to the full amount of water for injection again; Stir, survey pH and content, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling;
In the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the membrane filtration.
Said high temperature sterilize is a pharmaceutical industry injection conventional production process, and wherein: the preferred value of high temperature sterilize: temperature is 100 ~ 121 ℃, and the time is 12 ~ 30 minutes.
Useful technique effect of the present invention shows:
1, the present invention is through after taking pH regulator agent adjusting amyl ethyl quin ether hydrochloride medicinal liquid pH to 4.6 ~ 4.8; Fill is in pharmaceutical glass ampoule bottle or glass cillin bottle again; Its stability is improved significantly; The problem that pH value rises and content descends can not appear in long-term placement, thereby makes the amyl ethyl quin ether hydrochloride injection products more stable aspect pH, content, and product quality is guaranteed more easily.
2, the amyl ethyl quin ether hydrochloride injection that obtains through method for preparing of the present invention is placed its pH value for a long time and still can be remained in 4.5 ~ 6.5 the acceptability limit; Simultaneously content also can be stabilized in 90% ~ 110% the acceptability limit.
3, the amyl ethyl quin ether hydrochloride injection that obtains through preparation technology of the present invention, not only safe but also effective through long-term toxicity test for animals and pharmacodynamics test proof.
4, regulate the pH value mode owing to the present invention takes specific aqueous acid, and be directed against the characteristic of specific amyl ethyl quin ether hydrochloride injection,, thereby realized ensureing the purpose that the amyl ethyl quin ether hydrochloride injection is stable through control pH value scope.
Below in conjunction with experiment the present invention made and to further specify:
Test confirming of 1 amyl ethyl quin ether hydrochloride injection pH value 4.5-6.5 scope
Prescription: amyl ethyl quin ether hydrochloride 0.1g
Water for injection adds to 100ml
(specification: 1ml: 1mg)
Preparation technology:
1. uncomfortable pH: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, add to the full amount of water for injection again,
Survey pH=5.78,Content=100.2%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and sealing compound seals, and is subsequent use.
2. regulate pH=4: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, regulate with the 0.1mol/L hydrochloric acid solution
PH=3.96, add to the full amount of water for injection again, survey pH=4.16, content=98.6%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and sealing compound seals, and is subsequent use.
3. regulate pH=4.5: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, regulate with the 0.1mol/L hydrochloric acid solution
PH=4.53, add to the full amount of water for injection again, survey pH=4.53, content=99.6%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and sealing compound seals, and is subsequent use.
4. regulate pH=6.5: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, regulate with phosphate buffer
PH=6.49, add to the full amount of water for injection again, survey pH=6.01, content=100.6%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and sealing compound seals, and is subsequent use.
5. regulate pH=7: take by weighing amyl ethyl quin ether hydrochloride 0.1g, add the dissolving of 80ml water for injection, regulate with phosphate buffer
PH=7.13, add to the full amount of water for injection again, survey pH=6.96, content=99.1%.Medicinal liquid is loaded in the 100ml volumetric flask of clean dry behind 0.22 μ m membrane filtration, and sealing compound seals, and is subsequent use.
With above-mentioned 1., 2., 3., 4., 5. the amyl ethyl quin ether hydrochloride injection detects pH value and content 100 ℃ of hot conditions held 10 days respectively at sampling in 1 day, 5 days, 10 days, the result sees table 1
The different pH value of table 1 are to the influence of amyl ethyl quin ether hydrochloride injection stability
Note: the labelled amount that content is meant, its acceptability limit interval is 90%-110% of a labelled amount.
The result: experimentation shows that the amyl ethyl quin ether hydrochloride injection of pH 4～7 is more stable in volumetric flask; Especially the sample solution of pH 4.5～6.5; Place 10 days its pH value and content has no significant change for 100 ℃; Have good stability, the amyl ethyl quin ether hydrochloride injection o'clock has good stability in pH4.5～6.5.
Experiment 2 (adopt ampoule bottle that medicinal liquid is carried out fill, medicinal liquid is not carried out pH value and regulate)
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.58, content=99.3%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content, and the result sees table 2
Table 2 experiment 2 samples (ampoule bottle) study on the stability result
Note: the pH value acceptability limit is 4.5-6.5; The content acceptability limit is 90%-110% of a labelled amount.
The result: it is not good 1, not regulate the stability of amyl ethyl quin ether hydrochloride injection in ampoule bottle of pH, pH value especially, come-up obviously, near the acceptability limit upper limit; Content also has obvious decline.
2, different sterilising conditions are little to the pH value and the content influence of amyl ethyl quin ether hydrochloride injection products, and especially pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more littler.
Experiment 3 (adopt cillin bottle that medicinal liquid is carried out fill, medicinal liquid is not carried out the adjusting of pH value)
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.67, content=100.9%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content, and the result sees table 3
Table 3 experiment 3 (cillin bottle) sample stability is investigated the result
Note: the pH value acceptability limit is 4.5-6.5; The content acceptability limit is 90%-110% of a labelled amount.
The result: 1, with bottled similar of ampoule, the stability of amyl ethyl quin ether hydrochloride injection in cillin bottle of not regulating pH is not good, pH value especially, come-up obviously, near the acceptability limit upper limit; Content also has obvious decline.
2, different sterilising conditions are little to the pH value and the content influence of amyl ethyl quin ether hydrochloride injection products, and especially pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more littler.
According to above-mentioned experiment:
Take the preparation technology who does not regulate pH value to carry out further experiment; Accelerated tests study on the stability result show the amyl ethyl quin ether hydrochloride injection ampoule bottle (1ml: 1mg) and cillin bottle (1ml: stability is not good 0.5mg); Especially pH value; Come-up is (from floating to about 6.3 about 5.6) obviously, and near the acceptability limit upper limit, content also has obvious decline.
When below any a collection of raw material of proof was taked the amyl ethyl quin ether hydrochloride injection not to be regulated the preparation technology of pH value, pH value and content all can change
Experiment 4 (different batches raw materials)
1. 090201 batch of & ampoule bottle
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.43, content=99.5%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
2. 090201 batch of & cillin bottle
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.57, content=100.3%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
3. 090701 batch of & ampoule bottle
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.82, content=99.6%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
4. 090701 batch of & cillin bottle
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.93, content=100.2%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
5. 090801 batch of & ampoule bottle
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.59, content=99.1%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
6. 090801 batch of & cillin bottle
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.70, content=98.6%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
7. 090901 batch of & ampoule bottle
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.65, content=98.8%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.
8. 090901 batch of & cillin bottle
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, add to the full amount of water for injection again, survey pH=5.78, content=101.1%.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples (40 ℃ ± 2 ℃) under acceleration environment is placed and is investigated, and sampling regularly detects pH value and content.Investigate the result and see table 4
Table 4 experiment 4 samples (different batches raw material) study on the stability result
Note: the pH value acceptability limit is 4.5-6.5; The content acceptability limit is 90%-110% of a labelled amount.
The result: 1, the stability of the amyl ethyl quin ether hydrochloride injection of different batches feedstock production (not regulating pH value) in ampoule bottle and cillin bottle is not good, and especially pH value floats obviously, near the acceptability limit upper limit; Content also has obvious decline.
2, different sterilising conditions are little to the pH value and the content influence of amyl ethyl quin ether hydrochloride injection products, and especially pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more littler.
Conclusion: 090201 batch, 090701 batch, 090801 batch, 090901 batch acidity of amyl ethyl quin ether hydrochloride has nothing in common with each other; Be respectively 5.11,5.78,5.51,5.64; But the amyl ethyl quin ether hydrochloride injection for preparing; No matter interior packaging material is ampoule bottle or cillin bottle, no matter whether sterilize, it is all unstable to quicken to place back pH value and content.These article of this shows pH value and content are unstable little with raw material relation itself.
Experiment 5 (is regulated pHZhi & Ampoule bottle)
Prescription: amyl ethyl quin ether hydrochloride 2g
Water for injection adds to 2000ml
(specification: 1ml: 1mg)
Preparation technology:
1. regulate pH=4.6: take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=4.61, add to the full amount of water for injection again, survey pH=4.88, content=100.9% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
2. regulate pH=4.8: take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=4.82, add to the full amount of water for injection again, survey pH=4.96, content=99.3% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
3. regulate pH=5.0: take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=5.03, add to the full amount of water for injection again, survey pH=5.16, content=100.3% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
4. regulate pH=5.2: take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=5.21, add to the full amount of water for injection again, survey pH=5.31, content=98.9% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
5. regulate pH=5.4: take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=5.40, add to the full amount of water for injection again, survey pH=5.49, content=100.5% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.Investigate the result and see table 5
Table 5 sample is accelerated test study on the stability result 1. ~ 5.
Note: the pH value acceptability limit is 4.5-6.5; The content acceptability limit is 90%-110% of a labelled amount.Visible foreign matters is checked according to pharmacopeia appendix visible foreign matters inspection technique.
Result: the best stability of regulating the amyl ethyl quin ether hydrochloride injection (ampoule bottle) of pH value to 4.6～4.8 during preparation.
Experiment 6 (is regulated pHZhi & Cillin bottle)
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 2000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
1. regulate pH=4.6: take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=4.56, add to the full amount of water for injection again, survey pH=4.86, content=100.1% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
2. regulate pH=4.8: take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=4.78, add to the full amount of water for injection again, survey pH=4.99, content=99.5% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
3. regulate pH=5.0: take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=5.01, add to the full amount of water for injection again, survey pH=5.18, content=98.7% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
4. regulate pH=5.2: take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=5.18, add to the full amount of water for injection again, survey pH=5.32, content=101.1% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.
5. regulate pH=5.4: take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=5.39, add to the full amount of water for injection again, survey pH=5.46, content=100.7% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid through embedding behind the 0.22 μ m membrane filtration in the ampoule bottle of cleaning sterilizing-drying.The sample average that embedding obtains is divided into 3 parts, and is a unsterilised, and a 100 ℃, sterilization in 30 minutes, a 121 ℃, sterilization in 12 minutes.All samples is investigated in the acceleration environment held, and sampling regularly detects pH value and content.Investigate the result and see table 6
Table 6 sample is accelerated test study on the stability result 1. ~ 6.
Note: the pH value acceptability limit is 4.5-6.5; The content acceptability limit is 90%-110% of a labelled amount.Visible foreign matters is checked according to pharmacopeia appendix visible foreign matters inspection technique.
Result: the best stability of regulating the amyl ethyl quin ether hydrochloride injection (cillin bottle) of pH value to 4.6～4.8 during preparation.
Be described further below in conjunction with specific embodiment of the present invention
Embodiment 1 (regulates pH& Ampoule bottle)
Prescription:
Amyl ethyl quin ether hydrochloride 20g
Water for injection adds to 20000ml
(specification: 1ml: 1mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 20.0g, add the dissolving of 16000ml water for injection, regulate pH=4.72, add to the full amount of water for injection again, survey pH=4.88, content=101.5% with the 0.1mol/L hydrochloric acid solution.Medicinal liquid behind 0.22 μ m membrane filtration embedding in the ampoule bottle of clean dry.121 ℃ in the sample that embedding obtains, sterilization in 12 minutes.Be up to the standards and promptly get embodiment 1 sample.
Embodiment 2 (regulates pH& Cillin bottle)
Prescription:
Amyl ethyl quin ether hydrochloride 10g
Water for injection adds to 20000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 10.0g, add the dissolving of 16000ml water for injection, regulate pH=4.75, add to the full amount of water for injection again, survey pH=4.87, content=100.7% with the 0.5mol/L aqueous hydrochloric acid solution.Medicinal liquid behind 0.22 μ m membrane filtration embedding in the cillin bottle of clean dry.121 ℃ in the sample that embedding obtains, sterilization in 12 minutes.Be up to the standards and promptly get embodiment 2 samples.
Embodiment 3 (regulates pH& Cillin bottle)
Prescription:
Amyl ethyl quin ether hydrochloride 10g
Water for injection adds to 20000ml
(specification: 1ml: 0.5mg, every dress 1ml)
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 10.0g, add the dissolving of 16000ml water for injection, regulate pH=4.65, add to the full amount of water for injection again, survey pH=4.87, content=100.7% with the 0.3mol/L aqueous hydrochloric acid solution.Medicinal liquid behind 0.22 μ m membrane filtration embedding in the cillin bottle of clean dry.121 ℃ in the sample that embedding obtains, sterilization in 12 minutes.Be up to the standards and promptly get embodiment 2 samples.
Embodiment 4
As aforementioned, as a same reason and step, said pH regulator agent is aqueous sulfuric acid or aqueous acetic acid or phosphate aqueous solution or aqueous solution of nitric acid or oxalic acid aqueous solution, can realize the object of the invention equally.
Embodiment 5
As aforementioned, as a same reason and step, when said pH regulator agent concentration is 0.2mol/L or 0.4mol/L, can realize the object of the invention equally.
Embodiment 6
As aforementioned, as a same reason and step, add that the pH value of described amyl ethyl quin ether hydrochloride medicinal liquid is 4.6 or 4.8 after the pH regulator agent, can realize the object of the invention equally.
Embodiment 7
As aforementioned, as a same reason and step, the exsiccant temperature of described high temperature sterilization is 100 ℃, 118 ℃ or 121 ℃, when being 30 minutes, 21 minutes, 12 minutes at once, can realize the object of the invention equally.
Below in conjunction with pharmacodynamics test and long-term toxicity test for animals the present invention is described further
Contrast medicine (medicinal liquid not being carried out the adjusting of pH value during production)
Prescription: amyl ethyl quin ether hydrochloride 1g
Water for injection adds to 1000ml
Preparation technology:
Take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 800ml water for injection, add to the full amount of water for injection again, survey pH=5.86, content=99.6%.Medicinal liquid behind 0.22 μ m membrane filtration embedding in the subsequent use volumetric flask of clean dry.Be up to the standards promptly to get and contrast medicine.
Each embodiment sample pharmacodynamics test---to the spasmolysis of anesthesia rabbit stomach, small intestinal, colon, gallbladder, bladder
1, experiment material
1.1 receive the reagent thing
Blank: 0.9% sodium chloride injection, commercially available, produce by Kelun Pharm Ind Co., Ltd., Sichuan.
The contrast medicine: self-control amyl ethyl quin ether hydrochloride injection, be loaded in the volumetric flask, face with preceding and be diluted to desired concn with water for injection.
Test specimen: self-control embodiment 1, embodiment 2 samples, be colourless liquid, face with preceding and be diluted to desired concn with water for injection.
1.2 laboratory animal
The big ear rabbit of healthy adult Japan, about body weight 2kg, male and female all have, and one grade, purchase the Experimental Animal Center in Sichuan University.
2, experimental technique
Water 8～12h is can't help in the rabbit fasting, and auricular vein is injected 25% urethane 0.75g/kg anesthesia.Tracheal intubation, open abdomen, (the sacculus volume is 0.5～1.0ml) to insert in stomach, gallbladder, small intestinal, colon and the bladder with the conduit of 5 dribbling capsules respectively; Full with normal saline; The conduit other end links through pressure transducer and four road physiology monitors or two road physiology monitors, changes with record organ internal pressure.Stablized 15～20 minutes; Write down each organ normal contraction; With contractive amplitude (mmHg) as the normal pressure index; Intramuscular injection gives amyl ethyl quin ether hydrochloride injection test specimen 0.02mg/kg then, amyl ethyl quin ether hydrochloride injection contrast medicine 0.02mg/kg and NS contrast (volumetric injection 0.25ml/kg), every group of 8 animals; After the administration 30 minutes, dripped 0.01%Ach (small intestinal, bladder) at each organ surface respectively in 60 minutes, 0.05%Ach (colon, stomach, gallbladder), 0.5ml, stomach are 1ml, measure each organ internal pressure immediately and change, and with test of significance between T check work group.
3, result
Table 7 intramuscular injection amyl ethyl quin ether hydrochloride injection to anesthesia rabbit gastrointestinal smooth muscle spasmolysis (
, n=8)
Annotate: compare with the NS group * P 0.05, * * P 0.01, * * * P < 0.001
Compare with contrast medicine group Δ P 0.05, Δ Δ P 0.01, as follows.
Table 8 intramuscular injection amyl ethyl quin ether hydrochloride to the spasmolysis of anesthesia rabbit gallbladder, bladder (
, n=8)
4, conclusion
Visible by table 7, table 8, amyl ethyl quin ether hydrochloride injection intramuscular injection prepared according to the methods of the invention all has tangible relexation to the spastic contraction of stomach, small intestinal, colon, gallbladder, bladder due to the anesthesia rabbit Ach.Compare with sodium chloride injection blank group and to have significant difference, compare zero difference with the amyl ethyl quin ether hydrochloride injection contrast medicine group that capacity is bottled.Show that the bottled amyl ethyl quin ether hydrochloride injection of amyl ethyl quin ether hydrochloride injection prepared according to the methods of the invention and capacity has equal drug effect.
Each embodiment sample long-term toxicity test for animals---to the long term toxicity (intramuscular injection) of Canis familiaris L.
1, receives the reagent thing
Blank: 0.9% sodium chloride injection, commercially available, produce by Kelun Pharm Ind Co., Ltd., Sichuan.
The contrast medicine: self-control amyl ethyl quin ether hydrochloride injection, be loaded in the volumetric flask, face with preceding warp and be condensed into desired concn for 100 ℃.
Test specimen: self-control embodiment 1, embodiment 2 samples, be colourless liquid, face with preceding warp and be condensed into desired concn for 100 ℃.
2, experimental animal
Beasle dog, about body weight 10Kg, male and female half and half are purchased the Experimental Animal Center in Sichuan University.
3, dosage
Conversion method according to providing in the document " in the pharmacological testing between animal and the dose,equivalent between the animals and human beings body convert " goes out the dose,equivalent of Canis familiaris L., amplifies 50 times on this basis and carries out long term toxicity test.
The dose,equivalent conversion coefficient (1.85) of the dosage of Canis familiaris L. (intramuscular injection)=people's consumption every day (1mg) ÷ body weight (60Kg) * people and Canis familiaris L. * medication multiple (50)=1.54mg/Kg.
The intramuscular injection capacity is 0.05ml/Kg.
4, administration phase and convalescent period and route of administration
Amyl ethyl quin ether hydrochloride mainly adopts intramuscular injection to be used to treat organophosphorus poison poisoning and premedication clinically, and periodically the administration phase of treatment is generally in a week.But consider from now on to be used for other indications, so adopt intramuscular injection, the administration phase was 12 weeks, and convalescent period was 1 week.
5, experimental technique and observation index
The experimental animal random packet is divided into contrast medicine group, 1 group of embodiment, 2 groups of embodiment and blank group, and except that the blank group gave 0.9% sodium chloride injection, all the other group drug doses were 1.54mg/Kg, 6 of every treated animals.Each treated animal every morning behind cropping of hind leg buttocks and routine disinfection, by waiting 1 single-point intramuscular injection of capacity (Canis familiaris L. 0.05ml/kg), left and right sides hind leg in turn, 12 weeks of successive administration; Matched group is injected 0.9% sodium chloride injection under the same conditions.
Overview: it is movable to observe general behavior, feces character, appetite and body weight change etc., gait, mental act, heart rate, pupil size, nose and oral cavity secretion and have or not nausea and vomiting etc.In 1 week after preceding 7 days of administration to the last administration, every day, observed and recorded was 1 time; Wherein heart rate and pupil were measured 1 time in per 2 days, and body weight is claimed weekly 1 time.
Electrocardiographic examination: Canis familiaris L. is taken from right erect position, traces II and leads, and administration was traced 2 times in preceding 7 days, and per 3 weeks are traced 1 time after the administration.
The blood blood examination is looked into: extracting vein blood,, leukocyte red with Couter blood count (Britain's product) counting and quantitative hemoglobin; With general microscopic counting platelet and leukocyte differential count.In preceding 2 weeks of administration, check weekly 1 time; Per 3 weekly checks are 1 time after the administration.
Blood biochemistry checking: vein is got blood, anticoagulant heparin, separated plasma; (Corona, Sweden produces) measures glutamate pyruvate transaminase (GPT) and creatinine (CRTN) with automatic biochemical analyzer, measures blood urea nitrogen (BUN) and sulfobromophthalein sodium (BSP) retention rate with the laboratory conventional method; The same hematological examination of sampling and measuring time.
Uroscopy: red matter of urine pH, albumen, glucose, ketoboidies, UBG, gallbladder of the urine test paper inspection Canis familiaris L. that produces with the Beijing Chemical Plant and occult blood etc., microscopy cast, RBC and WBC etc., same hematological examination of the time of taking a sample to check.
System's postmortem: each work of every treated animal in 24 hours is killed 3 after the last administration, and 1 week lived and enters the postmortem of capable system after other Canis familiaris L. last administrations.
Histological examination: divide 2 batches, check (time homologous ray postmortem) for every batch every group each 3.The scope of examination comprises brain, the heart, lung, liver, kidney, adrenal gland, spleen, stomach, jejunum, pancreas and testis.
Convalescent period inspection: convalescent period, it is identical with the administration phase that it detects content except that not received the reagent.
6, result of the test
6.1 overview
After administration 2-3 week contrast medicine group, each embodiment treated animal obvious xerostomia (dry nasal cavity and oral secretion are few) all occurs, feel sick, vomiting and loss of appetite (feed minimizing); But movable and behavior and feces character there is not obvious influence.The 9th week obviously alleviated after above-mentioned symptom or sign to the administration, all disappeared all animals survived after 1 week of drug withdrawal.The blank group does not have above-mentioned unusual.
6.2 body weight
As if body weight does not have obvious change before and after contrast medicine group, each embodiment treated animal medicine, and has received inhibition with the blank group than its body weight gain, but does not all have obviously through statistical procedures.
6.3 pupil
Contrast medicine group, each embodiment treated animal have tangible platycoria phenomenon, no matter be with administration before relatively or with the blank group more all have notable difference (p 0.05 or p 0.01).
6.4 heart rate
Heart rate appears in contrast medicine group, each embodiment treated animal in early days to be accelerated, and fluctuation is bigger; After the 5th week, heart rate slows down gradually, and further slows down after the drug withdrawal.Heart rate relatively removes after the administration the 3rd all hearts rate and obviously accelerates (p < 0.05) in above-mentioned alteration in heart rate and before the administration; Obviously slow down with heart beating after the drug withdrawal (p 0.01) outside, the equal no significant difference of variation At All Other Times (p 0.05); As with the alteration in heart rate of corresponding time of blank group relatively, the 3rd all hearts rate are obviously accelerated (p < 0.05) after administration, the equal no significant difference of variation At All Other Times (p>0.05).
6.5 electrocardiogram
Electrocardiogram after contrast medicine group, the administration of embodiment treated animal except that the quickening of the property of stopping up heart rate is arranged in early days, does not have other obvious changes.
6.6 blood biochemical
GPT after each treated animal administration, BSP retention rate, blood urea nitrogen (BUN) and creatinine all do not have obvious change, and showing does not have obvious influence to hepatic and renal function.
6.7 hematology
RBC after each treated animal administration and WBC sum, Hb, platelet and leukocyte differential count have no significant change.
6.8 urine
Reach the blank group before red matter of urine pH, albumen, glucose, ketoboidies, gallbladder after each treated animal administration and occult blood and microscopy finding and the administration and compare, all do not have obviously change.
6.9 system's postmortem
The blank group and contrast medicine group, each embodiment treated animal of after administration, living after 12 weeks and 1 week of drug withdrawal and killing, system's postmortem no significant difference, each organizes also no abnormality seen change.
6.10 histological examination
After 12 weeks and 1 week of drug withdrawal, all do not find pathological change and the blank group no significant difference relevant after each treated animal administration with drug toxicity at 11 kinds of internal organs such as brains.
7, conclusion
The result shows the amyl ethyl quin ether hydrochloride injection that gives the bottled amyl ethyl quin ether hydrochloride injection of identical high dose (50 times) capacity (contrast medicine group) and the inventive method preparation simultaneously; The significantly common drug reaction of anticholinergic agent appears in each treated animal;, but behavioral activity, body weight and feces state are not had obvious influence; The drug reaction that occurs alleviated in the 9th week of administration, the back disappearance of 1 week of drug withdrawal.After all 12 weeks of animals administer and 1 week of drug withdrawal, urine, hematology and blood biochemical are learned inspection, system's postmortem and histological examination and are had no significant change.Also there was no significant difference between each group.The amyl ethyl quin ether hydrochloride injection safety that shows the inventive method preparation is credible.
Claims (10)
1. the method for preparing of an amyl ethyl quin ether hydrochloride injection; It is characterized in that: the amyl ethyl quin ether hydrochloride injection produce take the pH regulator agent to regulate amyl ethyl quin ether hydrochloride medicinal liquid pH in the process after; Fill is in pharmaceutical glass ampoule bottle or glass cillin bottle again, and high temperature sterilize promptly gets.
2. the method for preparing of amyl ethyl quin ether hydrochloride injection according to claim 1; It is characterized in that: said pH regulator agent is any one in following: aqueous hydrochloric acid solution, aqueous sulfuric acid, aqueous acetic acid, phosphate aqueous solution, aqueous solution of nitric acid or oxalic acid aqueous solution, its concentration is 0.1mol/L～0.5mol/L.
3. the method for preparing of amyl ethyl quin ether hydrochloride injection according to claim 2 is characterized in that: the concentration of said pH regulator agent is 0.1mol/L.
4. the method for preparing of amyl ethyl quin ether hydrochloride injection according to claim 1 and 2 is characterized in that: the pH value of said amyl ethyl quin ether hydrochloride medicinal liquid is 4.6 ~ 4.8.
5. the method for preparing of amyl ethyl quin ether hydrochloride injection according to claim 1 is characterized in that: the concrete step of preparation process of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride; Add injection water dissolving, with in 0.1mol/L～0.5mol/L aqueous hydrochloric acid solution or aqueous sulfuric acid, aqueous acetic acid, phosphate aqueous solution, aqueous solution of nitric acid, the oxalic acid aqueous solution any one, adjusting pH to 4.6 ~ 4.8; Add to the full amount of water for injection again; Stir, survey pH and content, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling;
In the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the membrane filtration.
6. the method for preparing of amyl ethyl quin ether hydrochloride injection according to claim 1 is characterized in that: the temperature of said high temperature sterilize is 100 ~ 121 ℃, and the time is 12 ~ 30 minutes.
7. according to the method for preparing of claim 1 or 5 described amyl ethyl quin ether hydrochloride injection, it is characterized in that: the concrete step of preparation process of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride, add the dissolving of injection water, regulate pH to 4.6 ~ 4.8, add to the full amount of water for injection again, stir survey pH and content, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling with the 0.1mol/L aqueous hydrochloric acid solution;
In the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the membrane filtration;
The temperature of said high temperature sterilize is 100 ~ 121 ℃, and the time is 12 ~ 30 minutes.
8. according to the method for preparing of claim 1 or 5 described amyl ethyl quin ether hydrochloride injection, it is characterized in that: the concrete step of preparation process of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=4.61, add to the full amount of water for injection again, stir, survey pH=4.88, content=100.9%, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling with the 0.1mol/L aqueous hydrochloric acid solution;
In the ampoule bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the 0.22 μ m membrane filtration;
The temperature of said high temperature sterilize is 100 ℃, and the time is 30 minutes.
9. according to the method for preparing of claim 1 or 5 described amyl ethyl quin ether hydrochloride injection, it is characterized in that: the concrete step of preparation process of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride 2.0g, add the dissolving of 1600ml water for injection, regulate pH=4.82, add to the full amount of water for injection again, survey pH=4.96, content=99.3%, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling with the 0.1mol/L aqueous hydrochloric acid solution;
In the ampoule bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the 0.22 μ m membrane filtration;
The temperature of said high temperature sterilize is 121 ℃, and the time is 12 minutes.
10. according to the method for preparing of claim 1 or 5 described amyl ethyl quin ether hydrochloride injection, it is characterized in that: the concrete step of preparation process of said amyl ethyl quin ether hydrochloride injection is following:
A, take by weighing amyl ethyl quin ether hydrochloride 1.0g, add the dissolving of 1600ml water for injection, regulate pH=4.56, add to the full amount of water for injection again, survey pH=4.86, content=100.1%, the amyl ethyl quin ether hydrochloride medicinal liquid after must handling with the 0.1mol/L aqueous hydrochloric acid solution;
In the cillin bottle of cleaning sterilizing-drying, high temperature sterilize promptly gets amyl ethyl quin ether hydrochloride medicinal liquid after B, the processing through embedding behind the 0.22 μ m membrane filtration;
The temperature of said high temperature sterilize is 110 ℃, and the time is 20 minutes.
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| CN107638383A (en) * | 2016-07-21 | 2018-01-30 | 王琴 | The preparation technology of penehyclidine hydrochloride injection |
| CN112716889A (en) * | 2020-12-25 | 2021-04-30 | 武汉大安制药有限公司 | Preparation method of penehyclidine hydrochloride injection |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103271872A (en) * | 2013-05-14 | 2013-09-04 | 成都自豪药业有限公司 | Industrial production method of penehyclidine hydrochloride injection |
| CN103271872B (en) * | 2013-05-14 | 2016-05-11 | 成都自豪药业有限公司 | The industrialized preparing process of penehyclidine hydrochloride injection |
| CN107638383A (en) * | 2016-07-21 | 2018-01-30 | 王琴 | The preparation technology of penehyclidine hydrochloride injection |
| CN112716889A (en) * | 2020-12-25 | 2021-04-30 | 武汉大安制药有限公司 | Preparation method of penehyclidine hydrochloride injection |
| CN112716889B (en) * | 2020-12-25 | 2022-05-06 | 远大生命科学(武汉)有限公司 | Preparation method of penehyclidine hydrochloride injection |
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Application publication date: 20120704 Assignee: Chengdu Lisite Pharmaceutical Co., Ltd. Assignor: Huang Shaoyuan|Zhang Hao|Jin Hongdi|Liu Xinchun|Zhu Dengjun Contract record no.: 2015510000011 Denomination of invention: Method for preparing penehyclidine hydrochloride injection Granted publication date: 20130123 License type: Exclusive License Record date: 20150303 |
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