CN104306329B - A kind of bromhexine hydrochloride in injection and its production and use - Google Patents
A kind of bromhexine hydrochloride in injection and its production and use Download PDFInfo
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- CN104306329B CN104306329B CN201410624129.XA CN201410624129A CN104306329B CN 104306329 B CN104306329 B CN 104306329B CN 201410624129 A CN201410624129 A CN 201410624129A CN 104306329 B CN104306329 B CN 104306329B
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Abstract
The invention provides a kind of bromhexine hydrochloride in injection and preparation method thereof.The bromhexine hydrochloride in injection of the present invention is made up of active ingredient hydrochloric acid bromhexine and tartaric acid, stabilizer, sodium hydroxide, water for injection.The bromhexine hydrochloride in injection of the present invention has the advantages that relevant content of material is low, stability is high.
Description
Technical field
The present invention relates to pharmaceutical field, and in particular to a kind of bromhexine hydrochloride in injection composition, its preparation method and its
Purposes in expelling phlegm drugses are prepared.
Background technology
Bromhexine hydrochloride (Bromhexine Hydrochloride, BRH), i.e. N- methyl-N-cyclohexyls -2- amino -3,
5- dibromobenzene methylamine hydrochlorides, are the semi-synthetics that duck nozzle flower alkali (Vasicine) is obtained through structure of modification, there is stronger dissolving
Viscous phlegm effect, can make the mucopolysaccharide cellulose in phlegm or mucoprotein cracking, reduce sputum viscosity.Bromhexine hydrochloride is applied to treatment
The thick sputums such as chronic bronchitis, asthma are difficult the patient brought up.
Bromhexine hydrochloride soluble,very slightly in water, although dissolubility is preferable in acid condition, but less stable.Europe
Pharmacopeia 7.0 editions has recorded 5 kinds of impurity (A, B, C, D, E).Prior art using addition stabilizer etc. means improve hydrochloric acid bromine oneself
The stability of novel formulation, but organic solvent or the macromolecule material such as stabilizer alcohol, propane diols, polyethylene glycol, tween or PVP
Although material can improve the dissolving situation of bromhexine hydrochloride and increase its stability, disulfiram reaction, haemolysis etc. may be brought
Safety risks.Therefore, the bromhexine hydrochloride in injection composition of prior art still have that security is relatively low, relevant material compared with
High, unstable the shortcomings of.For example：
Cosolvent ethanol and stabilizer poloxamer, hydroxyl are added in bromhexine hydrochloride in injection disclosed in CN100409835C
Propyl cellulose etc., and poloxamer, hydroxypropyl cellulose are high polymer material, there are certain security risks.
CN1184963C dissolves bromhexine hydrochloride using hot absolute ethyl alcohol, but is used as expectorant, bromhexine hydrochloride Chang Yukang
Raw element drug combination, this raises the incidence for reacting disulfiram.
CN102293741B discloses a kind of prescription of the bromhexine hydrochloride high-capacity injection without ethanol, by ultrasound
Handling process prepares settled solution, but it is higher (＞ 0.5%) about material.
Nearly 1% is up to comprising citric acid or phosphoric acid, the relevant material of the lyophilized formulations of mannitol in CN101502494B, i.e.,
The invention is set further to add meglumine, the relevant material of its lyophilized formulations only has a little reduction, and in storage process substantially
Increase.CN101502494B also indicates that " (bromhexine hydrochloride) lyophilized formulations for not adding meglumine change filler or pH regulations
The species of agent is little to its stability improvement action effect ".
The bromhexine hydrochloride in injection product that Boehringer Ingelheim lists a companyEqually exist relevant material
Content is high, the shortcoming of stability difference.
Therefore, there is the shortcomings of relevant material is higher, stability is poor in existing bromhexine hydrochloride injection, or there is safety
Property risk, prepare that a kind of relevant content of material is low, stability is high, the simple bromhexine hydrochloride in injection of safe, technique is
Those skilled in the art are needed to put forth effort the technical problem solved.
The content of the invention
By lot of experiments, it has been found that the tartaric acid as cosolvent and mannitol, the wood as stabilizer
When sugar alcohol or sorbierite are shared, the bromhexine hydrochloride in injection relevant content of material of the invention prepared is low, stability is high.Especially
It is, when tartaric acid with mannitol with special ratios 1:When 10-50 is shared, the present invention prepare bromhexine hydrochloride in injection it is relevant
Material is lower, stability is higher.More particularly, when tartaric acid and mannitol are with special ratios 1:30 when sharing, present invention system
The relevant material of standby bromhexine hydrochloride in injection is extremely low, stability is high, achieves unexpected technique effect.Based on upper
State discovery, applicant be prepared for technique it is simple, about material is low, stability is high, safe bromhexine hydrochloride in injection, enter
And complete the present invention.
Specifically, the invention provides a kind of bromhexine hydrochloride in injection, based on 1000ml, constitute as follows：
Wherein, stabilizer is selected from one of mannitol, xylitol, sorbierite or its mixture, preferably mannitol.
Wherein, the weight content ratio of tartaric acid and stabilizer is preferably 1:10-50.
More specifically, the invention provides following three kinds of bromhexine hydrochloride in injection：
1) a kind of bromhexine hydrochloride in injection, based on 1000ml, is constituted as follows：
2) a kind of bromhexine hydrochloride in injection, based on 1000ml, is constituted as follows：
3) a kind of bromhexine hydrochloride in injection, based on 1000ml, is constituted as follows：
On the other hand, the invention further relates to the preparation method of above-mentioned bromhexine hydrochloride in injection, step is as follows：By 60-
80% parenteral solution is heated to 60 DEG C with water, and supplementary material is added by prescription, and stirring and dissolving is cooled to room temperature, adjusted with sodium hydroxide
PH is 2.0-5.0, adds water to full dose, plus charcoal absorption bacterial endotoxin, filters carbon removal, refined filtration, packing, 121 DEG C of sterilizings 15
Minute, packaging is produced.
In addition, the purposes the invention further relates to the bromhexine hydrochloride in injection in expelling phlegm drugses are prepared.
The dosage of bromhexine hydrochloride in injection of the present invention is needed depending on the judgement according to clinician, for example, day agent
Amount can be 8-12mg.
Based on bromhexine hydrochloride in injection of the present invention scientific and rational prescription proportioning, not only there is provided comprising tartaric acid and
The bromhexine hydrochloride in injection prescription of specified stabiliser (mannitol, xylitol, sorbierite), and also found tartaric acid with stably
The weight content ratio of agent is 1:During 10-50, the stability of parenteral solution of the present invention is high, hence it is evident that outside above-mentioned content range
Prescription, achieves unexpected technique effect.Particularly, the content ratio of tartaric acid and mannitol is 1:30 present invention injection
The stability highest of liquid.
To sum up, the present invention achieves following technological progress：
1) compared with commercially available bromhexine hydrochloride in injection, bromhexine hydrochloride in injection of the invention is drastically increased surely
It is qualitative.2) bromhexine hydrochloride in injection of the invention is free of organic solvent and high polymer material, reduces potential safety hazard.3) this hair
Bright bromhexine hydrochloride in injection preparation technology is simple, with low cost.
Embodiment
Embodiment is only that the present invention is further explained and described, and is not necessarily to be construed as any limit to the present invention
System.The supplementary material used in the specific embodiment of the invention is purchased in market.
The preparation of the bromhexine hydrochloride in injection of embodiment 1~6
Prescription：
Wherein, the weight content ratio of embodiment 1-3 tartaric acid and stabilizer is 1:10-50, the corresponding content ratio of reference examples
In above range, i.e., 1:5 and 1:80.
Preparation technology：
60-80% parenteral solutions are heated to 60 DEG C with water, supplementary material is added by prescription, stirring and dissolving is cooled to room temperature, are used
Sodium hydroxide regulation pH is 2.0-5.0, adds water to full dose, plus charcoal absorption bacterial endotoxin, filters carbon removal, and refined filtration is dispensed,
121 DEG C are sterilized 15 minutes, and packaging is produced.
In preparation process, the above embodiment of the present invention can also be filled with nitrogen, to further enhance the stabilization of preparation
Property.
The stability study of experimental example bromhexine hydrochloride in injection
According to two annex XIX C stability tests guideline requirements of Chinese Pharmacopoeia 2010 edition, embodiment 1~5 is investigated
Obtained bromhexine hydrochloride oral liquid andStability, use high performance liquid chromatography about material and content,
It the results are shown in Table 1-3.
Table 1 bromhexine hydrochloride in injection, 0 day testing result
The bromhexine hydrochloride in injection accelerated test result of table 2
(simulation commercially available back, temperature 60 C, place 10 days)
Accelerated test shows that the stability of bromhexine hydrochloride in injection (embodiment 1-3) of the present invention is substantially better than reference examples
(embodiment 4-5).Particularly, the stability highest of embodiment 1.
The bromhexine hydrochloride oral liquid long-term stable experiment result of table 3
(simulation commercially available back, 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10%, place 24 months)
Journal of Sex Research steady in a long-term shows that the stability of bromhexine hydrochloride in injection (embodiment 1-3) of the present invention is substantially better than
Reference examples (embodiment 4-5), also superior to commercial preparationParticularly, the stability highest of embodiment 1.
Claims (7)
1. a kind of bromhexine hydrochloride in injection, based on 1000ml, is constituted as follows：
Wherein, stabilizer is selected from one of mannitol, xylitol, sorbierite or its mixture；
Wherein, the weight content ratio of tartaric acid and stabilizer is 1:10-50；
Wherein, the preparation method of the bromhexine hydrochloride in injection is as follows：60-80% parenteral solutions are heated to 60 DEG C with water, pressed
Prescription adds supplementary material, and stirring and dissolving is cooled to room temperature, and it is 2.0-5.0 to adjust pH with sodium hydroxide, adds water to full dose, plus living
Property charcoal absorption bacterial endotoxin, filter carbon removal, refined filtration, packing, 121 DEG C sterilize 15 minutes, packaging, produce.
2. bromhexine hydrochloride in injection according to claim 1, wherein stabilizer are mannitol.
3. bromhexine hydrochloride in injection according to claim 1, based on 1000ml, is constituted as follows：
4. bromhexine hydrochloride in injection according to claim 1, based on 1000ml, is constituted as follows：
5. bromhexine hydrochloride in injection according to claim 1, based on 1000ml, is constituted as follows：
6. the preparation method of any bromhexine hydrochloride in injection of claim 1-5, step is as follows：By 60-80% parenteral solutions
60 DEG C are heated to water, supplementary material is added by prescription, stirring and dissolving is cooled to room temperature, it is 2.0- to adjust pH with sodium hydroxide
5.0, full dose, plus charcoal absorption bacterial endotoxin are added water to, carbon removal is filtered, refined filtration is dispensed, and 121 DEG C sterilize 15 minutes, bag
Dress, is produced.
7. purposes of any described bromhexine hydrochloride in injection of claim 1-5 in expelling phlegm drugses are prepared, wherein the salt
The preparation method of sour bromhexine parenteral solution is as follows：60-80% parenteral solutions are heated to 60 DEG C with water, supplementary material is added by prescription,
Stirring and dissolving, is cooled to room temperature, and it is 2.0-5.0 to adjust pH with sodium hydroxide, adds water to full dose, plus charcoal absorption bacterium endogenous toxic material
Element, filters carbon removal, and refined filtration is dispensed, and 121 DEG C sterilize 15 minutes, and packaging is produced.
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| CN201410624129.XA CN104306329B (en) | 2014-11-07 | 2014-11-07 | A kind of bromhexine hydrochloride in injection and its production and use |
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| CN201410624129.XA CN104306329B (en) | 2014-11-07 | 2014-11-07 | A kind of bromhexine hydrochloride in injection and its production and use |
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| CN104306329B true CN104306329B (en) | 2017-07-28 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105496952B (en) * | 2016-01-07 | 2018-11-02 | 河北仁合益康药业有限公司 | A kind of sucking bromhexine hydrochloride liquid composite and preparation method thereof |
| CN105456187A (en) * | 2016-01-07 | 2016-04-06 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
| CN105596318B (en) * | 2016-01-07 | 2018-11-23 | 河北仁合益康药业有限公司 | A kind of sucking bromhexine hydrochloride liquid composite and preparation method thereof |
| CN105534889B (en) * | 2016-01-07 | 2018-11-02 | 河北仁合益康药业有限公司 | A kind of sucking bromhexine hydrochloride liquid composite and preparation method thereof |
| CN109620799B (en) * | 2019-01-24 | 2021-09-24 | 成都欣捷高新技术开发股份有限公司 | Stable bromhexine hydrochloride liquid preparation composition and preparation method thereof |
| CN110251491A (en) * | 2019-06-21 | 2019-09-20 | 上海禾丰制药有限公司 | A kind of sucking bromhexine hydrochloride solution and preparation method thereof |
| CN114788809B (en) * | 2022-01-25 | 2023-04-14 | 江苏广承药业有限公司 | Loratadine liquid preparation |
| CN114699369A (en) * | 2022-05-19 | 2022-07-05 | 青岛农业大学 | Bromhexine hydrochloride injection and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2564822B2 (en) * | 1987-05-07 | 1996-12-18 | 大正製薬株式会社 | Bromhexine hydrochloride solid preparation |
| CN103145564A (en) * | 2013-03-15 | 2013-06-12 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
| CN103435496A (en) * | 2013-07-19 | 2013-12-11 | 江西博意特科技有限公司 | Bromhexine hydrochloride compound, and preparation method, medicinal composition and preparation thereof |
-
2014
- 2014-11-07 CN CN201410624129.XA patent/CN104306329B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2564822B2 (en) * | 1987-05-07 | 1996-12-18 | 大正製薬株式会社 | Bromhexine hydrochloride solid preparation |
| CN103145564A (en) * | 2013-03-15 | 2013-06-12 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
| CN103435496A (en) * | 2013-07-19 | 2013-12-11 | 江西博意特科技有限公司 | Bromhexine hydrochloride compound, and preparation method, medicinal composition and preparation thereof |
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Effective date of registration: 20170621 Address after: Hengshui City, Hebei province 053411 cool Zhen Wuyi County Applicant after: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. Address before: 050000, Shijiazhuang Province, Shijiazhuang hi tech Zone, Heping East Road, No. 619, building, floor, room three, room 353 Applicant before: Shijiazhuang Ke Ren Pharmaceutical Technology Co., Ltd |
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Address after: 051500 Haixing Road, Zhaoxian County Industrial Park, Shijiazhuang, Hebei Patentee after: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. Address before: 053411 Hengshui City, Hebei, Wuyi County, Qing Liang store town Patentee before: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. |