CN104306329A - Bromhexine hydrochloride injection and preparation method and application thereof - Google Patents
Bromhexine hydrochloride injection and preparation method and application thereof Download PDFInfo
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- CN104306329A CN104306329A CN201410624129.XA CN201410624129A CN104306329A CN 104306329 A CN104306329 A CN 104306329A CN 201410624129 A CN201410624129 A CN 201410624129A CN 104306329 A CN104306329 A CN 104306329A
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Abstract
The invention provides bromhexine hydrochloride injection and a preparation method thereof. The bromhexine hydrochloride injection comprises an active component bromhexine hydrochloride, and tartaric acid, a stabilizing agent, sodium hydroxide and water for injection. The bromhexine hydrochloride injection has the advantages of low contents of relevant materials, high stability and the like.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a kind of bromhexine hydrochloride in injection compositions, its preparation method and preparing the purposes in expelling phlegm drugs.
Background technology
Bisolvon (Bromhexine Hydrochloride, BRH), i.e. N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzene methylamine hydrochloride, it is the semi-synthetic that duck chews colored alkali (Vasicine) and obtains through structure of modification, there is stronger dissolving to glue expectorant effect, mucopolysaccharide cellulose or the mucin cracking of apoplexy due to phlegm can be made, reduce sputum viscosity.Bisolvon is applicable to the patient that thick sputum such as treatment chronic bronchitis, asthma etc. not easily brings up.
Bisolvon is soluble,very slightly in water, although dissolubility is better in acid condition, and less stable.European Pharmacopoeia 7.0 editions has recorded 5 kinds of impurity (A, B, C, D, E).Prior art all adopts means such as adding stabilizing agent to improve the stability of Bisolvon preparation, but although the organic solvents such as stabilizer alcohol, propylene glycol, Polyethylene Glycol, tween or polyvidone or macromolecular material can improve the dissolving situation of Bisolvon and increase its stability, the safety risks such as disulfiram reaction, haemolysis may be brought.Therefore, still there is the shortcomings such as safety is lower, related substance is higher, unstable in the bromhexine hydrochloride in injection compositions of prior art.Such as:
Add cosolvent ethanol and stabilizing agent poloxamer, hydroxypropyl cellulose etc. in bromhexine hydrochloride in injection disclosed in CN100409835C, and poloxamer, hydroxypropyl cellulose are macromolecular material, there is certain security risks.
CN1184963C adopts hot anhydrous alcohol solution Bisolvon, but as expectorant, and Bisolvon is normal with antibiotic drug combination, incidence rate rising that this will make disulfiram react.
CN102293741B discloses a kind of prescription not containing the Bisolvon high-capacity injection of ethanol, prepares settled solution through ultrasonic processing technique, but its related substance higher (> 0.5%).
Comprise in CN101502494B citric acid or phosphoric acid, mannitol the related substance of lyophilized formulations up to nearly 1%, even if this invention adds meglumine further, the related substance of its lyophilized formulations only has a little minimizing, and obviously increases in storage process.CN101502494B also points out, " kind that (Bisolvon) lyophilized formulations not adding meglumine changes filler or pH adjusting agent is very micro-to its stability improvement action effect ".
The bromhexine hydrochloride in injection product that Boehringer Ingelheim lists a company
have that its related substances is high, the shortcoming of poor stability equally.
Therefore, existing Bisolvon injection has the shortcomings such as related substance is higher, poor stability, or there is security risks, prepare that a kind of its related substances is low, stability is high, safety is high, the simple bromhexine hydrochloride in injection of technique needs those skilled in the art to put forth effort the technical problem solved.
Summary of the invention
Through lot of experiments, applicant finds, when the tartaric acid as cosolvent share with mannitol, xylitol or the sorbitol as stabilizing agent, bromhexine hydrochloride in injection its related substances prepared by the present invention is low, stability is high.Particularly, when tartaric acid and mannitol share with special ratios 1:10-50, the related substance of bromhexine hydrochloride in injection prepared by the present invention is lower, stability is higher.More particularly, when tartaric acid and mannitol share with special ratios 1:30, the related substance of bromhexine hydrochloride in injection prepared by the present invention is extremely low, stability is high, achieves unforeseeable technique effect.Based on above-mentioned discovery, applicant has prepared the bromhexine hydrochloride in injection that technique is simple, related substance is low, stability is high, safety is high, and then completes the present invention.
Particularly, the invention provides a kind of bromhexine hydrochloride in injection, by 1000ml, composed as follows:
Wherein, stabilizing agent is selected from one of mannitol, xylitol, sorbitol or its mixture, is preferably mannitol.
Wherein, the weight content ratio of tartaric acid and stabilizing agent is preferably 1:10-50.
More specifically, the invention provides following three kinds of bromhexine hydrochloride in injection:
1) bromhexine hydrochloride in injection, by 1000ml, composed as follows:
2) bromhexine hydrochloride in injection, by 1000ml, composed as follows:
3) bromhexine hydrochloride in injection, by 1000ml, composed as follows:
On the other hand, the invention still further relates to the preparation method of above-mentioned bromhexine hydrochloride in injection, step is as follows: 60-80% injection water is heated to 60 DEG C, add supplementary material by prescription, stirring and dissolving, be cooled to room temperature, regulate pH to be 2.0-5.0 with sodium hydroxide, add water to full dose, add activated carbon adsorption bacterial endotoxin, filter carbon removal, fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
In addition, the invention still further relates to described bromhexine hydrochloride in injection and prepare the purposes in expelling phlegm drugs.
The dosage of bromhexine hydrochloride in injection of the present invention needs the judgement according to clinician and determines, and such as, daily dose can be 8-12mg.
Based on the scientific and rational prescription proportioning of bromhexine hydrochloride in injection of the present invention, not only provide the bromhexine hydrochloride in injection prescription comprising tartaric acid and specified stabiliser (mannitol, xylitol, sorbitol), but also the weight content ratio finding tartaric acid and stabilizing agent is when being 1:10-50, the stability of injection of the present invention is high, obviously be better than the prescription outside above-mentioned content range, achieve unforeseeable technique effect.Particularly, tartaric acid is higher than the stability of the injection of the present invention for 1:30 with the content of mannitol.
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 present invention drastically increases stability.2) bromhexine hydrochloride in injection of the present invention is not containing organic solvent and macromolecular material, reduces potential safety hazard.3) bromhexine hydrochloride in injection preparation technology of the present invention is simple, with low cost.
Detailed description of the invention
Detailed description of the invention is only and further explains and describes the present invention, should not be interpreted as any limitation of the invention.The supplementary material used in the specific embodiment of the invention is commercial.
The preparation of embodiment 1 ~ 6 bromhexine hydrochloride in injection
Prescription:
Wherein, the weight content ratio of embodiment 1-3 tartaric acid and stabilizing agent is 1:10-50, and the corresponding content of reference examples compares in above-mentioned scope, i.e. 1:5 and 1:80.
Preparation technology:
60-80% injection water is heated to 60 DEG C, adds supplementary material by prescription, stirring and dissolving, be cooled to room temperature, regulate pH to be 2.0-5.0 with sodium hydroxide, add water to full dose, add activated carbon adsorption bacterial endotoxin, filter carbon removal, fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
In preparation process, the above embodiment of the present invention can also be filled with nitrogen, to strengthen the stability of preparation further.
The stability study of experimental example bromhexine hydrochloride in injection
According to the requirement of Chinese Pharmacopoeia 2010 editions two annex XIX C stability test guidelines, investigate the obtained Bisolvon oral liquid of embodiment 1 ~ 5 and
stability, related substance and content adopt high performance liquid chromatography, the results are shown in Table 1-3.
Table 1 bromhexine hydrochloride in injection 0 day testing result
Table 2 bromhexine hydrochloride in injection accelerated test result
(simulation commercially available back, temperature 60 C, places 10 days)
Accelerated test shows, the stability of bromhexine hydrochloride in injection of the present invention (embodiment 1-3) is obviously better than reference examples (embodiment 4-5).Particularly, the stability of embodiment 1 is the highest.
Table 3 Bisolvon oral liquid long-term stable experiment result
(relative humidity 60% ± 10%, places 24 months for simulation commercially available back, temperature 25 DEG C ± 2 DEG C)
Journal of Sex Research steady in a long-term shows, the stability of bromhexine hydrochloride in injection of the present invention (embodiment 1-3) is obviously better than reference examples (embodiment 4-5), is also better than commercial preparation
particularly, the stability of embodiment 1 is the highest.
Claims (9)
1. a bromhexine hydrochloride in injection, by 1000ml, composed as follows:
2. bromhexine hydrochloride in injection according to claim 1, wherein stabilizing agent is selected from one of mannitol, xylitol, sorbitol or its mixture.
3. bromhexine hydrochloride in injection according to claim 1, the weight content ratio of its mesotartaric acid and stabilizing agent is 1:10-50.
4. bromhexine hydrochloride in injection according to claim 1, wherein stabilizing agent is mannitol.
5. bromhexine hydrochloride in injection according to claim 1, by 1000ml, composed as follows:
6. bromhexine hydrochloride in injection according to claim 1, by 1000ml, composed as follows:
7. bromhexine hydrochloride in injection according to claim 1, by 1000ml, composed as follows:
8. the preparation method of the arbitrary described bromhexine hydrochloride in injection of claim 1-7, step is as follows: 60-80% injection water is heated to 60 DEG C, adds supplementary material by prescription, stirring and dissolving, is cooled to room temperature, regulates pH to be 2.0-5.0 with sodium hydroxide, add water to full dose, add activated carbon adsorption bacterial endotoxin, filter carbon removal, fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
9. the arbitrary described bromhexine hydrochloride in injection of claim 1-8 is preparing the purposes in expelling phlegm drugs.
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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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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105496952A (en) * | 2016-01-07 | 2016-04-20 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
| CN105534889A (en) * | 2016-01-07 | 2016-05-04 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for suction and preparation method thereof |
| CN105596318A (en) * | 2016-01-07 | 2016-05-25 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride new solution composition used for inhalation and preparing method thereof |
| CN109620799A (en) * | 2019-01-24 | 2019-04-16 | 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 |
| CN114699369A (en) * | 2022-05-19 | 2022-07-05 | 青岛农业大学 | Bromhexine hydrochloride injection and preparation method and application thereof |
| CN114788809A (en) * | 2022-01-25 | 2022-07-26 | 江苏广承药业有限公司 | Loratadine liquid preparation |
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| 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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2014
- 2014-11-07 CN CN201410624129.XA patent/CN104306329B/en active Active
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| 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 |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105496952A (en) * | 2016-01-07 | 2016-04-20 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
| CN105534889A (en) * | 2016-01-07 | 2016-05-04 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for suction and preparation method thereof |
| CN105596318A (en) * | 2016-01-07 | 2016-05-25 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride new solution composition used for inhalation and preparing 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 |
| 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 |
| CN109620799A (en) * | 2019-01-24 | 2019-04-16 | 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 |
| 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 |
| CN114788809A (en) * | 2022-01-25 | 2022-07-26 | 江苏广承药业有限公司 | Loratadine liquid preparation |
| 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 |
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| CN104306329B (en) | 2017-07-28 |
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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. |
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