CN103690479B - A kind of Glycopyrronium bromide injection and preparation method thereof - Google Patents
A kind of Glycopyrronium bromide injection and preparation method thereof Download PDFInfo
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- CN103690479B CN103690479B CN201310639006.9A CN201310639006A CN103690479B CN 103690479 B CN103690479 B CN 103690479B CN 201310639006 A CN201310639006 A CN 201310639006A CN 103690479 B CN103690479 B CN 103690479B
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Abstract
The invention discloses a kind of Glycopyrronium bromide injection and preparation method thereof, this preparation method comprises the following steps: the water for injection 1) adding 50 ~ 90% amounts in preparing tank, add sodium chloride, pH adjusting agent adjust ph to 1.0 ~ 4.0 are added after dissolving, add water for injection again and be diluted to full dose, obtain solution A; 2) be under the constant temperature of 30 ~ 40 DEG C in temperature, glycopyrronium bromide thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products; 3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 DEG C of temperature, obtains Glycopyrronium bromide injection.Glycopyrronium bromide injection of the present invention has good stability, safety high.
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 (GlycopyrroniumBromide) is quaternary amines anticholinergic agent, similar to other anticholinergic agents (as muscarine antagonist), the rear cholinergic nerve of joint and smooth muscle can be suppressed the reaction of 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 excessive secretion of throat, trachea-bronchial epithelial cell body of gland.Before use anaesthetic, glycopyrronium bromide usually can be used as premedicate, Cardiac depression that vagus reflex causes can be reduced like this, reduce saliva and TF secretion.
Active carbon first joins in feed liquid by Glycopyrronium bromide injection usually conventional at present to decolour, then undertaken filtering to remove active carbon by filter, but for the injection of small dimension, this method should not use, it is large to the absorption of drug content, can affect the bin stability of injection.Also there is the bin stability improving injection by adding benzyl alcohol now, but the interpolation of benzyl alcohol can cause side effect, even can cause the generation of death by accident, especially pediatric patients, there will be " syndrome of panting " when neonate gives >99mg/kg/day or the light neonate of birth weight gives benzyl alcohol, wherein with central nervous system impression, metabolic acidosis, the symptoms such as asthmatic breathing are main manifestations feature, also there will be gradual nervous weak 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 accepting 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 deficiencies in the prior art and Problems existing, proposing the Glycopyrronium bromide injection that a kind of good stability, safety are high.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 kind of Glycopyrronium bromide injection, be made up of glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, each component of this Glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0mg/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) in preparing tank, add the water for injection of sodium chloride and 50 ~ 90% formula ratios, add surplus water for injection and pH adjusting agent adjust ph to 1.0 ~ 4.0 after dissolving, obtain solution A;
2) be under the constant temperature of 30 ~ 40 DEG C in temperature, glycopyrronium bromide thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 DEG C of temperature, obtains Glycopyrronium bromide injection.
The present invention carries out endotoxin control to adjuvant, and carries out essence filtration to feed liquid, thus 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, improves the safety of medicine, and the Glycopyrronium bromide injection of gained has good stability, safety high, and its scope of application is wider.
Detailed description of the invention
Present invention is disclosed a kind of Glycopyrronium bromide injection, be made up of glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, each component of this Glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0mg/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) in preparing tank, add the water for injection of sodium chloride and 50 ~ 90% formula ratios, add surplus water for injection and pH adjusting agent adjust ph to 1.0 ~ 4.0 after dissolving, obtain solution A;
2) be under the constant temperature of 30 ~ 40 DEG C in temperature, glycopyrronium bromide thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 DEG C of temperature, obtains Glycopyrronium bromide injection.
The present invention carries out endotoxin control to adjuvant, and carries out essence filtration to feed liquid, thus reduces the thermal source amount of medicine, increases the drug effect of medicine, improves the stability of medicine; Improved the stability of injection further by the control of the order of addition of the order of addition to adjuvant quality, adjuvant, pH adjusting agent content and pH adjusting agent etc. simultaneously, in addition, the adjuvant used does not have toxicity, while ensure that injection is stable, also improve the safety of injection, the Glycopyrronium bromide injection of gained has good stability, safety high, and its scope of application is wider.
In order to the understanding of those skilled in the art, below by way of specific embodiment, further detailed description is done to the present invention.
Embodiment 1
A preparation method for Glycopyrronium bromide injection, comprises the following steps:
1) in preparing tank, add water for injection and the sodium chloride 7.0g of 50% volume, add the water for injection of surplus after dissolving, add sodium hydroxide 0.01g again after adding hydrochloric acid 0.1ml, pH value is adjusted to 2.5, obtains solution A;
2) be under the constant temperature of 35 DEG C in temperature, glycopyrronium bromide 0.1g thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 15min at 121 DEG C 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) in preparing tank, add water for injection and the sodium chloride 9.0g of 80% volume, add the water for injection of surplus after dissolving, then add hydrochloric acid 0.1ml, adjust ph to 3.0, obtain solution A;
2) be under the constant temperature of 30 DEG C in temperature, glycopyrronium bromide 0.2g thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 30min at 115 DEG C 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) in preparing tank, add water for injection and the sodium chloride 10.0g of 70% volume, add the water for injection of surplus after dissolving, then add hydrochloric acid 0.22ml, adjust ph to 1.0, obtain solution A;
2) be under the constant temperature of 35 DEG C in temperature, glycopyrronium bromide 0.1g thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 15min at 121 DEG C 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) in preparing tank, add water for injection and the sodium chloride 10.0g of 90% volume, add the water for injection of surplus after dissolving, then add sodium hydroxide 0.12g, adjust ph to 4.0, obtain solution A;
2) be under the constant temperature of 40 DEG C in temperature, glycopyrronium bromide 0.5g thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8min at 121 DEG C 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 adopting medicinal charcoal Processing Example 2 formula of different amounts respectively, solution 4 parts is got after stirring, be numbered 1,2,3, No. 4 solution, every part of 200ml, respectively 2,3, No. 4 solution are added 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 measures.Endotoxin content before and after Simultaneously test absorption.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 before and after absorption, 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 prepared can reach endotoxin limit standard, and charcoal adsorption process can introduce pollution.
Test example 2:pH regulator is on the impact of injection stability
Research method: take 5 parts of sodium chloride respectively and be about 8g, respectively add 800ml water for injection and make dissolving, add appropriate 1mol/L hydrochloric acid, pH value is adjusted to about 1.0,2.0,2.5,3.0,4.0 respectively, then injects water to 1000ml; Separately get 1 part of sodium chloride and be about 8g, inject water to 1000ml.Get above-mentioned solution 900ml after filtration, add glycopyrronium bromide 180mg respectively, fine straining after stirring and dissolving, get filtrate and load in ampoule bottle that to melt envelope for subsequent use by often propping up 1ml.
Get each 100 of above prescription preparation, sterilizing 15min at 121 ~ 125 DEG C of temperature;
Get each 100 of above prescription preparation, sterilizing 30min at 121 ~ 125 DEG C 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, when pH value is 1 ~ 4, related substance in sterilizing 15min injection does not increase substantially, principal agent stability is better, relatively unstable when the pH value in sterilizing 30min injection is 4, and when not adding pH adjusting agent, injection is unstable.If adjust ph again after adjuvant is miscible, then principal agent has started degraded when non-adjust ph.Above result confirms, must first adjust ph, then adds principal agent, and select pH value to be 1 ~ 4, sterilizing 15min, 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 in 40 DEG C, carry out temperatures involved factorial experiments under relative humidity 75% condition, detected the character of Glycopyrronium bromide injection, content, pH value, outward appearance and related substance respectively at 5,10 days, result is as shown in table 3:
Table 3: high temperature is on the impact of long-time stability.
From above-mentioned test data, Glycopyrronium bromide injection is under high temperature 40 DEG C of conditions, and each index has no significant change, steady quality.
2, accelerated test
Test method: the Glycopyrronium bromide injection of embodiment 2 is pressed commercially available back, be placed in 30 DEG C, carry out accelerated test under relative humidity 75% condition, respectively at the 0th month, January, February, March, June sampling once, detect the character of Glycopyrronium bromide injection, content, pH value, outward appearance and related substance etc., result is as shown in table 4:
Table 4: accelerate to leave standstill the impact on long-time stability.
Result shows, under acceleration conditions, test specimen, except related substance, shows a rising trend, and other changes are little, still meet medicine shelf life standard, therefore the steady quality of sample.
The content mentioned in above-described embodiment is not limitation of the invention, and under the prerequisite not departing from inventive concept of the present invention, any apparent replacement is all within protection scope of the present invention.
Claims (1)
1. a Glycopyrronium bromide injection, is made up of glycopyrronium bromide, sodium chloride, pH adjusting agent and water for injection, and each component of this Glycopyrronium bromide injection is composed as follows:
Glycopyrronium bromide 0.1 ~ 0.5mg/ml
Sodium chloride 7.0 ~ 10.0mg/ml
It is 1.0 ~ 4.0 that pH adjusting agent adds to injection pH value
Water for injection adds to 1000ml;
Wherein, described pH adjusting agent is hydrochloric acid or sodium hydroxide;
Described Glycopyrronium bromide injection is prepared by following steps:
1) in preparing tank, add the water for injection of sodium chloride and 50 ~ 90% formula ratios, add surplus water for injection and pH adjusting agent adjust ph to 1.0 ~ 4.0 after dissolving, obtain solution A;
2) be under the constant temperature of 30 ~ 40 DEG C in temperature, glycopyrronium bromide thrown in solution A, is stirred to and dissolves completely, in filtrate tank, carry out coarse filtration through the microporous filter membrane of 0.45 μm, then carry out end-filtration through the microporous filter membrane of 0.22 μm, obtain intermediate products;
3) filtrate tank be loaded in the container of neutral borosilicate material, sealing, then steam sterilization 8 ~ 30min at 115 ~ 121 DEG C of temperature, obtains Glycopyrronium bromide injection.
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| 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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| 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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| 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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| Title |
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| "Glycopyrrolate 0.2mg/mL Intravenous Injection (Solution, 10 mL)";MEDISCA NETWORK INC;《www.medisca.net/cen/F005006va.pdf》;20120319;第1-4页 * |
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