CN103690479A - Glycopyrronium bromide injection and preparation method thereof - Google Patents
Glycopyrronium bromide injection and preparation method thereof Download PDFInfo
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- CN103690479A CN103690479A CN201310639006.9A CN201310639006A CN103690479A CN 103690479 A CN103690479 A CN 103690479A CN 201310639006 A CN201310639006 A CN 201310639006A CN 103690479 A CN103690479 A CN 103690479A
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Abstract
The invention discloses glycopyrronium bromide injection and a preparation method thereof. The preparation method disclosed by the invention comprises the following steps of: (1), adding 50-90% of injection water into a preparation tank, adding sodium chloride, adding a pH adjusting agent after dissolving to adjust the pH value to 1.0-4.0, and then, diluting to total weight by adding injection water to obtain solution A; (2), adding glycopyrronium bromide into the solution A at the constant temperature of 30-40 DEG C, stirring till dissolving completely, crudely filtering in a filtrate tank through a milliporous filtration membrane which is 0.45 mu m, and finally filtering through a milliporous filtration membrane which is 0.22 mu m to obtain an intermediate product; (3), filling the filtrate tank into a neutral boron-silicon container, sealing, and sterilizing through steam at 115-121 DEG C for 8-30 min to obtain the glycopyrronium bromide injection. The glycopyrronium bromide injection disclosed by the invention has the characteristics of being good in stability, high in safety and the like.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, be specifically related to a kind of glycopyrronium bromide injection of safety and stability, the invention still further relates to a kind of preparation method of glycopyrronium bromide injection of safety and stability.
Background technology
Glycopyrronium bromide (Glycopyrronium Bromide) is quaternary amines anticholinergic agent, similar to other anticholinergic agents (as muscarine antagonist), can suppress the rear cholinergic nerve of joint and the reaction of smooth muscle to acetylcholine, the receptor of these periphery choline is positioned at smooth muscle autorhythmic cell, cardiac muscle, sinuatrial node, atrioventricular node and exocrine gland, minority is positioned at autonomic ganglion, therefore can reduce free acid and the volume of gastric secretion, control the transition secretion of throat, trachea, bronchus body of gland.Before using anaesthetic, conventionally can use glycopyrronium bromide as premedicate, can reduce like this Cardiac depression, minimizing saliva and TF secretion that vagus reflex causes.
Conventional glycopyrronium bromide injection conventionally first joins active carbon in feed liquid and decolours at present, then by filter, filter to remove active carbon, but the injection for small dimension, this method should not be used, its absorption to drug content is large, can affect the bin stability of injection.Now also have by adding benzyl alcohol to improve the bin stability of injection, yet the interpolation of benzyl alcohol can cause side effect, even can cause the generation of death by accident, especially pediatric patients, when neonate gives to there will be when >99 mg/kg/day or the light neonate of birth weight give benzyl alcohol " syndrome of panting ", wherein with central nervous system, suppress, metabolic acidosis, the symptoms such as panting property breathing are main manifestations feature, also there will be gradual neurasthenia simultaneously, epilepsy, intracranial hemorrhage, hematological abnormality, skin injury, liver and renal damage, hypotension, the symptom such as bradycardia or cardiovascular collapse, premature infant, under-weight neonate and the patient who accepts high dose benzyl alcohol, more easily there is toxic reaction.Therefore, existing glycopyrronium bromide injection unstable properties, and drug risk is higher, is unsuitable for life-time service.
Summary of the invention
The object of the invention is to for overcoming the problem of the deficiencies in the prior art and existence, propose a kind of good stability, safe glycopyrronium bromide injection.The present invention also provides the preparation method of this glycopyrronium bromide injection.
In order to solve prior art problem, the present invention is achieved by the following technical solutions.
A glycopyrronium bromide injection, is comprised of glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, and this each component of glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0 mg/ml
It is 1.0 ~ 4.0 that pH adjusting agent adds to injection pH value
Water for injection adds to 1000ml.
Described pH adjusting agent is hydrochloric acid or sodium hydroxide.
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection that adds sodium chloride and 50 ~ 90% formula ratios in preparing tank, after dissolving, add surplus water for injection and pH adjusting agent to regulate pH value to 1.0 ~ 4.0, obtain solution A;
2) under temperature is the constant temperature of 30 ~ 40 ℃, glycopyrronium bromide is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 ℃ of temperature, obtains glycopyrronium bromide injection.
The present invention carries out endotoxin control to adjuvant, and feed liquid is carried out to essence and filter, thereby reduces the thermal source amount of medicine, increases the drug effect of medicine, improves the stability of medicine; In addition, the adjuvant of use does not have toxicity, has improved the safety of medicine, and the glycopyrronium bromide injection of gained has the features such as good stability, safety height, and its scope of application is wider.
The specific embodiment
The present invention has disclosed a kind of glycopyrronium bromide injection, glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, consists of, and this each component of glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0 mg/ml
It is 1.0 ~ 4.0 that pH adjusting agent adds to injection pH value
Water for injection adds to 1000ml.
Described pH adjusting agent is hydrochloric acid or sodium hydroxide.
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection that adds sodium chloride and 50 ~ 90% formula ratios in preparing tank, after dissolving, add surplus water for injection and pH adjusting agent to regulate pH value to 1.0 ~ 4.0, obtain solution A;
2) under temperature is the constant temperature of 30 ~ 40 ℃, glycopyrronium bromide is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 ℃ of temperature, obtains glycopyrronium bromide injection.
The present invention carries out endotoxin control to adjuvant, and feed liquid is carried out to essence and filter, thereby reduces the thermal source amount of medicine, increases the drug effect of medicine, improves the stability of medicine; Simultaneously by the control of order of addition of the order of addition of adjuvant quality, adjuvant, pH adjusting agent content and pH adjusting agent etc. further being improved to the stability of injection, in addition, the adjuvant using does not have toxicity, when having guaranteed that injection is stable, also improved the safety of injection, the glycopyrronium bromide injection of gained has the features such as good stability, safety height, and its scope of application is wider.
For those skilled in the art's understanding, below by specific embodiment, the present invention is done to further detailed description.
Embodiment 1
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection and the sodium chloride 7.0g that add 50% volume in preparing tank, after dissolving, add the water for injection of surplus, add again sodium hydroxide 0.01g after adding hydrochloric acid 0.1ml, pH value is adjusted to 2.5, obtains solution A;
2) under temperature is the constant temperature of 35 ℃, glycopyrronium bromide 0.1g is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 15min at 121 ℃ of temperature, obtains glycopyrronium bromide injection.
The present embodiment glycopyrronium bromide injection is made into 1000 injection, and the pH value of glycopyrronium bromide injection is 2.5.
Embodiment 2
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection and the sodium chloride 9.0g that add 80% volume in preparing tank, after dissolving, add the water for injection of surplus, then add hydrochloric acid 0.1ml, regulate pH value to 3.0, obtain solution A;
2) under temperature is the constant temperature of 30 ℃, glycopyrronium bromide 0.2g is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 30min at 115 ℃ of temperature, obtains glycopyrronium bromide injection.
The present embodiment glycopyrronium bromide injection is made into 1000 injection, and the pH value of glycopyrronium bromide injection is 3.
Embodiment 3
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection and the sodium chloride 10.0g that add 70% volume in preparing tank, after dissolving, add the water for injection of surplus, then add hydrochloric acid 0.22ml, regulate pH value to 1.0, obtain solution A;
2) under temperature is the constant temperature of 35 ℃, glycopyrronium bromide 0.1g is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 15min at 121 ℃ of temperature, obtains glycopyrronium bromide injection.
The present embodiment glycopyrronium bromide injection is made into 1000 injection, and the pH value of glycopyrronium bromide injection is 1.
Embodiment 4
A preparation method for glycopyrronium bromide injection, comprises the following steps:
1) to the water for injection and the sodium chloride 10.0g that add 90% volume in preparing tank, after dissolving, add the water for injection of surplus, then add sodium hydroxide 0.12g, regulate pH value to 4.0, obtain solution A;
2) under temperature is the constant temperature of 40 ℃, glycopyrronium bromide 0.5g is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8min at 121 ℃ of temperature, obtains glycopyrronium bromide injection.
The present embodiment glycopyrronium bromide injection is made into 1000 injection, and the pH value of glycopyrronium bromide injection is 4.
Test example 1: activated carbon dosage is on medicament contg and endotoxic impact
Test method: the glycopyrronium bromide injection that adopts respectively medicinal charcoal Processing Example 2 formulas of different amounts, after stirring, get 4 parts of solution, be numbered solution 1,2,3, No. 4, every part of 200ml, respectively 2,3, No. 4 solution are added to needle-use activated carbon 0.04g(0.02%), 0.10g(0.05%), 0.16g (0.08%), stir 30min, use titanium filter stick filtering decarbonization, filtrate is compared and measured.Measure absorption front and back endotoxin content simultaneously.Experimental result is as shown in table 1:
| Numbering | Solution colour | Clarity | Content (%) | Endotoxin measurement value |
| 1 | Colourless | Clear and bright | 102.95 | ＜40Eu/ml |
| 2 | Colourless | Clear and bright | 89.60 | ＜40Eu/ml |
| 3 | Colourless | Clear and bright | 81.35 | ＜40Eu/ml |
| 4 | Colourless | Clear and bright | 68.89 | ＜40Eu/ml |
Table 1: glycopyrronium bromide injection charcoal test.
As seen from the experiment, the difference of the consumption of active carbon, there is significant change in the medicament contg in injection, and absorption front and back endotoxin is all significantly less than the endotoxin control criterion of USP standard.Can draw the following conclusions accordingly: by controlling the level of endotoxin in stock and adjunct, the preparation of preparing can reach endotoxin limit standard, and charcoal adsorption process can be introduced pollution.
The impact of test example 2:pH regulator on injection stability
Research method: take respectively 5 parts of about 8g of sodium chloride, respectively add 800ml water for injection to make to dissolve, add appropriate 1mol/L hydrochloric acid, pH value is adjusted to approximately 1.0,2.0,2.5,3.0,4.0 respectively, then inject water to 1000ml; Separately get 1 part of about 8g of sodium chloride, inject water to 1000ml.After filtration, get above-mentioned solution 900ml, add respectively glycopyrronium bromide 180mg, fine straining after stirring and dissolving, gets filtrate and by every 1ml, packs that in ampoule bottle, to melt envelope standby into.
Get each 100, above prescription preparation, sterilizing 15min at 121 ~ 125 ℃ of temperature;
Get each 100, above prescription preparation, sterilizing 30min at 121 ~ 125 ℃ of temperature;
Measure before sterilizing, sterilizing 15min and 30min sample size and related substance, test result is as shown in table 2:
Table 2: different pH value, different sterilization time sample size and determination of related substances result.
As shown in Table 2, along with the prolongation of sterilization time, at pH value, it is 1 ~ 4 o'clock, related substance in sterilizing 15min injection does not increase substantially, principal agent stability is better, the pH value in sterilizing 30min injection be 4 o'clock relatively unstable, and injection is not unstable while not adding pH adjusting agent.If regulate pH value after adjuvant is miscible, principal agent has started degraded when not regulating pH value again.Above result confirms, must first regulate pH value, then add principal agent, and select that pH value is 1 ~ 4, sterilizing 15min, and principal agent is more stable.
Test example 3: stability study
1, hot test
Test method: by the glycopyrronium bromide injection fill of embodiment 2 in flint glass ampoule bottle, be placed under 40 ℃, relative humidity 75% condition and carry out temperatures involved factorial experiments, at 5,10 days, detect respectively character, content, pH value, outward appearance and the related substance of glycopyrronium bromide injection, result is as shown in table 3:
Table 3: the impact of high temperature on long-time stability.
From above-mentioned test data, glycopyrronium bromide injection is under 40 ℃ of conditions of high temperature, and each index has no significant change, steady quality.
2, accelerated test
Test method: the glycopyrronium bromide injection of embodiment 2 is pressed to commercially available back, be placed under 30 ℃, relative humidity 75% condition and carry out accelerated test, respectively at the 0th month, January, February, March, June, sample once, character, content, pH value, outward appearance and the related substance etc. that detect glycopyrronium bromide injection, result is as shown in table 4:
Table 4: accelerate the standing impact on long-time stability.
Result shows, under acceleration environment, test specimen, except related substance, shows a rising trend, and other change little, still meet medicine shelf life standard, so the steady quality of sample.
The content of mentioning in above-described embodiment is not limitation of the invention, is not departing under the prerequisite of inventive concept of the present invention, and any apparent replacement is all within protection scope of the present invention.
Claims (3)
1. a glycopyrronium bromide injection, is comprised of glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, and this each component of glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0 mg/ml
It is 1.0 ~ 4.0 that pH adjusting agent adds to injection pH value
Water for injection adds to 1000ml.
2. glycopyrronium bromide injection according to claim 1, is characterized in that: described pH adjusting agent is hydrochloric acid or sodium hydroxide.
3. a preparation method for glycopyrronium bromide injection according to claim 1 and 2, comprises the following steps:
1) to the water for injection that adds sodium chloride and 50 ~ 90% formula ratios in preparing tank, after dissolving, add surplus water for injection and pH adjusting agent to regulate pH value to 1.0 ~ 4.0, obtain solution A;
2) under temperature is the constant temperature of 30 ~ 40 ℃, glycopyrronium bromide is thrown to solution A, be stirred to completely and dissolve, the microporous filter membrane through 0.45 μ m in filtrate tank carries out coarse filtration, then carries out end-filtration through the microporous filter membrane of 0.22 μ m, obtains intermediate products;
3) filtrate tank is loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 ℃ of temperature, obtains glycopyrronium bromide injection.
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Cited By (3)
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| CN105362218A (en) * | 2015-12-17 | 2016-03-02 | 浙江华海药业股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN111166715A (en) * | 2018-11-11 | 2020-05-19 | 北京凯因科技股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN113018280A (en) * | 2021-03-01 | 2021-06-25 | 石家庄四药有限公司 | Solution preparation for ipratropium bromide inhalation and preparation method thereof |
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| US20080317832A1 (en) * | 2007-06-22 | 2008-12-25 | Sciele Pharma, Inc. | Transdermal delivery system comprising glycopyrrolate to treat sialorrhea |
| CN102552126A (en) * | 2012-01-20 | 2012-07-11 | 清远嘉博制药有限公司 | High-safety ropivacaine hydrochloride injection and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105362218A (en) * | 2015-12-17 | 2016-03-02 | 浙江华海药业股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN111166715A (en) * | 2018-11-11 | 2020-05-19 | 北京凯因科技股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN113018280A (en) * | 2021-03-01 | 2021-06-25 | 石家庄四药有限公司 | Solution preparation for ipratropium bromide inhalation and preparation method thereof |
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