CN102525909B - Method for preparing penehyclidine hydrochloride injection - Google Patents
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- CN102525909B CN102525909B CN 201210049593 CN201210049593A CN102525909B CN 102525909 B CN102525909 B CN 102525909B CN 201210049593 CN201210049593 CN 201210049593 CN 201210049593 A CN201210049593 A CN 201210049593A CN 102525909 B CN102525909 B CN 102525909B
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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 preparation method of injection medicinal liquid, be specifically related to a kind of preparation method of selectivity anticholinergic agent penehyclidine hydrochloride injection, belong to the medical drugs field.
Background technology
Penehyclidine hydrochloride injection is the new selective anticholinergic agent, can be combined with M, N cholinoceptor, and selectively acting is in M
1, M
3, N
1, N
2Receptor is to M
2Receptor is without effect; have the not available advantages of anticholinergic agents such as atropine, scopolamine;, acting duration strong such as cholinolytic effect grown, protection heart rate two-ways regulation is machine-processed, improve microcirculation, toxic and side effects is low etc.; demonstrated clinically wide application prospect: the treatment of organophosphate poisoning; premedication; application in respiratory system disease; shock, to the protective effect of Brain Ischemia-reperfusion Injury, application in digestive tract disease and acute abdominal pain etc.
Research is found through inventor's long term test: the amyl ethyl quin ether hydrochloride chemical compound is water-soluble, direct fill is in existing any commercially available ampoule bottle and cillin bottle without pre-treatment again, stability is not good, the significant change of pH value rising and content decrease appears in long-term placement after 8 months, pH value and changes of contents cause drug quality and curative effect unstable, even can exceed qualified limit, become defective medicine.
Still find no at present solution and the bibliographical information that proposes for the problems referred to above.
Summary of the invention
It is not good that the present invention is intended to solve existing penehyclidine hydrochloride injection stability in without the commercially available ampoule bottle of any processing and cillin bottle, the long-term problem that occurs pH value rising and content decrease after 8 months of placing, provide a kind of novel preparation method of penehyclidine hydrochloride injection, the method for especially before to the penehyclidine hydrochloride injection embedding, processing in advance.The penehyclidine hydrochloride injection product that is obtained by this process is more stable aspect pH, the content, and product quality is easier to be guaranteed, and can prevent underproof medicine.
Concrete technical scheme of the present invention is as follows:
A kind of preparation method of penehyclidine hydrochloride injection, it is characterized in that: penehyclidine hydrochloride injection produce take pH adjusting 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, high temperature sterilize, and get final product.
Described pH adjusting 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 described amyl ethyl quin ether hydrochloride medicinal liquid is 4.6 ~ 4.8.
The concrete preparation method step of described penehyclidine hydrochloride injection is as follows:
A, take by weighing amyl ethyl quin ether hydrochloride, be dissolved in water for injection, 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, regulate pH to 4.6 ~ 4.8, add to the full amount of water for injection again, stir evenly, survey pH and content, get the amyl ethyl quin ether hydrochloride medicinal liquid after the processing;
B, the amyl ethyl quin ether hydrochloride medicinal liquid after processing through embedding behind the membrane filtration in the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize, and get final product.
Described high temperature sterilize is 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 by after taking pH adjusting agent to regulate 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 of pH value rising and content decrease can not appear in long-term placement, thereby make the penehyclidine hydrochloride injection product more stable aspect pH, content, product quality is easier to be guaranteed.
2, the penehyclidine hydrochloride injection that obtains by preparation method of the present invention is placed for a long time its pH value 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 penehyclidine hydrochloride injection that obtains by preparation technology of the present invention, not only safe but also effective through long-term toxicity test for animals and pharmacodynamics test proof.
4, because the present invention takes specific aqueous acid to regulate the pH value mode, and for the characteristic of specific penehyclidine hydrochloride injection, by control pH value scope, thereby realized ensureing the purpose of penehyclidine hydrochloride injection stability.
Below in conjunction with experiment the present invention made and to further specify:
Test determining of 1 penehyclidine 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 the sealing compound sealing is for 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 the sealing compound sealing is for 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 the sealing compound sealing is for 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 the sealing compound sealing is for 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 the sealing compound sealing is for subsequent use.
1., 2., 3., 4., 5. penehyclidine hydrochloride injection was placed 10 days under 100 ℃ of hot conditionss detect pH value and content respectively at sampling in 1 day, 5 days, 10 days with above-mentioned, the results are shown in Table 1
The different pH value of table 1 are on the impact of penehyclidine hydrochloride injection stability
Note: the labelled amount that content refers to, its acceptability limit interval is 90%-110% of labelled amount.
The result: experimentation shows that the penehyclidine 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, penehyclidine hydrochloride injection o'clock has good stability in pH4.5～6.5.
Experiment 2(adopts ampoule bottle that medicinal liquid is carried out fill, medicinal liquid is not carried out pH value and regulates)
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 regularly sampling detects pH value and content, the results are shown in 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 labelled amount.
The result: it is not good 1, not regulate the stability of penehyclidine 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 pH value and the content influence of penehyclidine hydrochloride injection product, and especially the pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more less.
Experiment 3(adopts 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 regularly sampling detects pH value and content, the results are shown in 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 labelled amount.
The result: 1, with bottled similar of ampoule, the stability of penehyclidine 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 pH value and the content influence of penehyclidine hydrochloride injection product, and especially the pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more less.
According to above-mentioned experiment:
Take the preparation technology who does not regulate pH value to carry out further experiment, accelerate experiment study on the stability result show penehyclidine hydrochloride injection ampoule bottle (1ml: 1mg) and cillin bottle (1ml: stability is not good 0.5mg), especially pH value, come-up is (from come-up about 5.6 to about 6.3) obviously, near the acceptability limit upper limit, content also has obvious decline.
When below any a collection of raw material of proof was taked penehyclidine hydrochloride injection not to be regulated the preparation technology of pH value, pH value and content all can change
Experiment 4(different batches raw material)
1. 090201 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
2. 090201 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
3. 090701 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
4. 090701 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
5. 090801 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
6. 090801 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
7. 090901 crowd of ﹠amp; 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 regularly sampling detects pH value and content.
8. 090901 crowd of ﹠amp; 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 regularly sampling detects pH value and content.Investigation the results are shown in 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 labelled amount.
The result: 1, the stability of penehyclidine hydrochloride injection (not regulating pH value) in ampoule bottle and cillin bottle of different batches raw material preparation 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 pH value and the content influence of penehyclidine hydrochloride injection product, and especially the pH value between the product of different sterilising conditions after long-term placement the and content difference are apart from more and more less.
Conclusion: 090201 batch, 090701 batch, 090801 batch, 090901 batch acidity of amyl ethyl quin ether hydrochloride is different, be respectively 5.11,5.78,5.51,5.64, but the penehyclidine hydrochloride injection for preparing, no matter interior packaging material is ampoule bottle or cillin bottle, no matter whether sterilize, pH value and content are all unstable after accelerating to place.This shows that this product pH value and content are unstable little with raw material relation itself.
Experiment 5(regulates pHZhi ﹠amp; 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.88, 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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.96, 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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.16, 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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.31, content=98.9%.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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.49, content=100.5%.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 is placed investigation under acceleration environment, regularly sampling detects pH value and content.Investigation the results are shown in 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 labelled amount.Visible foreign matters checks according to pharmacopeia appendix visible foreign matters inspection technique.
Result: the optimal stability of regulating the penehyclidine hydrochloride injection (ampoule bottle) of pH value to 4.6～4.8 during preparation.
Experiment 6(regulates pHZhi ﹠amp; 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.86, content=100.1%.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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.99, 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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.18, content=98.7%.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 placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.32, 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 is placed investigation under acceleration environment, regularly sampling 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=5.46, content=100.7%.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 placed investigation under acceleration environment, regularly sampling detects pH value and content.Investigation the results are shown in 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 labelled amount.Visible foreign matters checks according to pharmacopeia appendix visible foreign matters inspection technique.
Result: the optimal stability of regulating the penehyclidine hydrochloride injection (cillin bottle) of pH value to 4.6～4.8 during preparation.
Be described further below in conjunction with specific embodiments of the invention
Embodiment 1(regulates pH﹠amp; 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 with the 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.88, content=101.5%.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 namely get embodiment 1 sample.
Embodiment 2(regulates pH﹠amp; 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 with the 0.5mol/L aqueous hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.87, content=100.7%.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 namely get embodiment 2 samples.
Embodiment 3(regulates pH﹠amp; 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 with the 0.3mol/L aqueous hydrochloric acid solution, add to the full amount of water for injection again, survey pH=4.87, content=100.7%.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 namely get embodiment 2 samples.
Embodiment 4
As aforementioned, as a same reason and step, described pH adjusting 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 purpose of the present invention equally.
Embodiment 5
As aforementioned, as a same reason and step, when described pH adjusting agent concentration is 0.2mol/L or 0.4mol/L, can realize purpose of the present 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 adjusting agent, can realize purpose of the present invention equally.
Embodiment 7
As aforementioned, as a same reason and step, the temperature of described high temperature sterilization drying is 100 ℃, 118 ℃ or 121 ℃, when at once being 30 minutes, 21 minutes, 12 minutes, can realize purpose of the present invention equally.
The invention will be further described below in conjunction with pharmacodynamics test and long-term toxicity test for animals
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 clean dry volumetric flask for subsequent use.Be up to the standards and namely get the contrast medicine.
Each embodiment sample pharmacodynamics test---to the spasmolysis of Anaesthetic Rabbits stomach, small intestinal, colon, gallbladder, bladder
1, experiment material
1.1 tested medicine
Blank: 0.9% sodium chloride injection, commercially available, produced by Kelun Pharm Ind Co., Ltd., Sichuan.
The contrast medicine: the self-control penehyclidine hydrochloride injection, be loaded in the volumetric flask, be diluted to desired concn with water for injection before use.
Test specimen: self-control embodiment 1, embodiment 2 samples, be colourless liquid, be diluted to desired concn with water for injection before use.
1.2 laboratory animal
The large ear rabbit of healthy adult Japan, about body weight 2kg, male and female all have, and one grade, are purchased from Sichuan University's Experimental Animal Center.
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 5 conduits with sacculus respectively, full with normal saline, the conduit other end links by pressure transducer and channel polygraph or two road physiology monitors, changes with record organ internal pressure.Stablized 15～20 minutes, record each organ normal contraction, with contractive amplitude (mmHg) as the normal pressure index, then intramuscular injection gives penehyclidine hydrochloride injection test specimen 0.02mg/kg, penehyclidine 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), 0.05%Ach(colon, stomach, gallbladder at each organ surface respectively in 60 minutes), 0.5ml, stomach are 1ml, measure immediately each organ internal pressure and change, and with test of significance between T check work group.
3, result
Table 7 intramuscular injection penehyclidine hydrochloride injection to Anaesthetic Rabbits gastrointestinal smooth muscle spasmolysis (
, n=8)
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with the NS group
Compare Δ P＜0.05 with contrast medicine group, Δ Δ P＜0.01, as follows.
Table 8 intramuscular injection amyl ethyl quin ether hydrochloride to the spasmolysis of Anaesthetic Rabbits gallbladder, bladder (
, n=8)
4, conclusion
By table 7, as seen from Table 8, penehyclidine hydrochloride injection intramuscular injection prepared according to the methods of the invention all has obvious relexation to the spastic contraction of stomach, small intestinal, colon, gallbladder, bladder due to the Anaesthetic Rabbits Ach.Compare with sodium chloride injection blank group and to have significant difference, compare zero difference with the penehyclidine hydrochloride injection contrast medicine group that capacity is bottled.Show that the bottled penehyclidine hydrochloride injection of penehyclidine 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, tested medicine
Blank: 0.9% sodium chloride injection, commercially available, produced by Kelun Pharm Ind Co., Ltd., Sichuan.
The contrast medicine: the self-control penehyclidine hydrochloride injection, be loaded in the volumetric flask, be condensed into desired concn through 100 ℃ before use.
Test specimen: self-control embodiment 1, embodiment 2 samples, be colourless liquid, be condensed into desired concn through 100 ℃ before use.
2, experimental animal
Beasle dog, about body weight 10Kg, male and female half and half are purchased from Sichuan University's Experimental Animal Center.
3, dosage
Go out the dose,equivalent of Canis familiaris L. according to the conversion method that provides in the document " in the pharmacological testing between animal and the dose,equivalent between the animals and human beings body convert ", amplify on this basis 50 times and carry out long term toxicity test.
The dose,equivalent conversion coefficient (1.85) of the dosage of Canis familiaris L. (the intramuscular injection)=every consumption per day of people (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 for the treatment of organophosphorus poison poisoning and premedication clinically, and periodically the administration phase for the treatment of is generally within 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, 2 groups of 1 group of embodiment, embodiment and blank group, and except 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 the 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.From front 7 days of administration to the last administration 1 week, every day, observed and recorded was 1 time; Wherein heart rate and pupil were measured 1 time in per 2 days, and body weight claims 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 front 7 days, and per 3 weeks are traced 1 time after the administration.
The blood blood examination is looked into: extracting vein blood, with Couter blood count (Britain's products) red, the leukocyte of counting and quantitative hemoglobin; With general microscopic counting platelet and leukocyte differential count.Front 2 weeks of administration, every weekly check 1 time; Per 3 weekly checks are 1 time after the administration.
Blood biochemistry checking: venous blood sampling, 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: the urine test paper of producing with the Beijing Chemical Plant checks the red matter of urine pH, albumen, glucose, ketoboidies, urobilinogen, gallbladder of Canis familiaris L. 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, every batch every group each 3 check (time homologous ray postmortem).The scope of examination comprises brain, the heart, lung, liver, kidney, adrenal gland, spleen, stomach, jejunum, pancreas and testis.
Convalescent period checks: convalescent period, its Detection of content was identical with the administration phase except not being subjected to the reagent.
6, result of the test
6.1 overview
Contrast after administration 2-3 week that 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 reduces); But movable and behavior and feces character are had no significant effect.Above-mentioned symptom or sign obviously alleviated to administration in the 9th week, all disappeared all animals survived after 1 week of drug withdrawal.The blank group is without above-mentioned unusual.
6.2 body weight
Contrast medicine group, each embodiment treated animal medicine front and back body weight without obvious change, and as if be subject to inhibition with the blank group than its body weight gain, process all without obvious but learn by statistics.
6.3 pupil
Contrast medicine group, each embodiment treated animal have obvious platycoria phenomenon, no matter be with administration before relatively or and the blank group notable difference (p＜0.05 or p＜0.01) is more all arranged.
6.4 heart rate
Heart rate appears in contrast medicine group, each embodiment treated animal in early days to be accelerated, and fluctuation is larger; After the 5th week, heart rate slows down gradually, and further slows down after the drug withdrawal.In above-mentioned alteration in heart rate, and heart rate compares before the administration, except the 3rd all hearts rate after the administration are obviously accelerated (p＜0.05); Obviously slow down outside (p＜0.01) the equal no significant difference of variation At All Other Times (p＜0.05) with heart beating after the drug withdrawal; Compare such as the alteration in heart rate with the corresponding time of blank group, 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 is except having in early days the quickening of the property of stopping up heart rate, without other obvious changes.
6.6 blood biochemical
GPT after each treated animal administration, BSP retention rate, blood urea nitrogen (BUN) and creatinine all without obviously changing, show hepatic and renal function is had no significant effect.
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
The red matter of urine pH, albumen, glucose, ketoboidies, gallbladder after each treated animal administration and occult blood and microscopy finding, and administration is front and the blank group is compared, all without obviously changing.
6.9 system's postmortem
The blank group and contrast medicine group, each embodiment treated animal of after administration, living after 12 weeks and drug withdrawal 1 week 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 the pathological change relevant with drug toxicity and blank group no significant difference at 11 kinds of internal organs such as brains after each treated animal administration.
7, conclusion
The result shows the penehyclidine hydrochloride injection that gives simultaneously identical high dose (50 times) penehyclidine hydrochloride injection that capacity is bottled (contrast medicine group) and the inventive method preparation, obvious anticholinergic agent Common drugs reaction appears in each treated animal,, but behavioral activity, body weight and feces state are had no significant effect; The drug reaction that occurs alleviated in the 9th week of administration, and drug withdrawal disappeared after 1 week.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 penehyclidine hydrochloride injection safety that shows the inventive method preparation is credible.
Claims (4)
1. the preparation method of a penehyclidine hydrochloride injection, it is characterized in that: penehyclidine hydrochloride injection produce take pH adjusting 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, high temperature sterilize, and get final product;
Described pH adjusting agent is aqueous hydrochloric acid solution, and its concentration is 0.1mol/L;
The pH value of described amyl ethyl quin ether hydrochloride medicinal liquid is 4.6 ~ 4.8.
2. the preparation method of penehyclidine hydrochloride injection according to claim 1, it is characterized in that: the concrete step of preparation process of described penehyclidine hydrochloride injection is as follows:
A, take by weighing amyl ethyl quin ether hydrochloride, be dissolved in water for injection, regulate pH to 4.6 ~ 4.8 with the 0.1mol/L aqueous hydrochloric acid solution, add to the full amount of water for injection again, stir evenly, survey pH and content, get the amyl ethyl quin ether hydrochloride medicinal liquid after the processing;
B, the amyl ethyl quin ether hydrochloride medicinal liquid after processing through embedding behind the membrane filtration in the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize, and get final product.
3. the preparation method of penehyclidine hydrochloride injection according to claim 1, it is characterized in that: the temperature of described high temperature sterilize is 100 ~ 121 ℃, the time is 12 ~ 30 minutes.
4. the preparation method of penehyclidine hydrochloride injection according to claim 1 and 2, it is characterized in that: the concrete step of preparation process of described penehyclidine hydrochloride injection is as follows:
A, take by weighing amyl ethyl quin ether hydrochloride, be dissolved in water for injection, regulate pH to 4.6 ~ 4.8 with the 0.1mol/L aqueous hydrochloric acid solution, add to the full amount of water for injection again, stir evenly, survey pH and content, get the amyl ethyl quin ether hydrochloride medicinal liquid after the processing;
B, the amyl ethyl quin ether hydrochloride medicinal liquid after processing through embedding behind the membrane filtration in the ampoule bottle or cillin bottle of cleaning sterilizing-drying, high temperature sterilize, and get final product;
The temperature of described high temperature sterilize is 100 ~ 121 ℃, and the time is 12 ~ 30 minutes.
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| CN107638383A (en) * | 2016-07-21 | 2018-01-30 | 王琴 | The preparation technology of penehyclidine hydrochloride injection |
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| CN101474178A (en) * | 2009-01-15 | 2009-07-08 | 成都力思特制药股份有限公司 | Application of penehyclidine hydrochloride in preparing medicament for treating cardiogenic shock |
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