CN105456187A - Bromhexine hydrochloride solution composition for inhalation and preparation method thereof - Google Patents
Bromhexine hydrochloride solution composition for inhalation and preparation method thereof Download PDFInfo
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- CN105456187A CN105456187A CN201610007945.5A CN201610007945A CN105456187A CN 105456187 A CN105456187 A CN 105456187A CN 201610007945 A CN201610007945 A CN 201610007945A CN 105456187 A CN105456187 A CN 105456187A
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- bisolvon
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- tartaric acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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Abstract
The invention provides a bromhexine hydrochloride solution composition for inhalation and a preparation method thereof. A bromhexine hydrochloride solution for inhalation is prepared from bromhexine hydrochloride, tartaric acid and water for injection. The bromhexine hydrochloride solution for inhalation has the advantages of being simple in prescription composition, high in stability, high in safety of drug application, suitable for industrial production and the like.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of suction Bisolvon liquid composite and preparation method thereof.
Background technology
Bisolvon (BromhexineHydrochloride, 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.Be applicable to the patient that the thick sputum such as chronic bronchitis, asthma not easily brings up.Since 1960s, namely Bisolvon is a kind of mucolytic agent of extensive use, and it also has character and the antibacterial activity in vitro of scavenging free radicals.
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.
Chinese patent application CN104306329A discloses the higher bromhexine hydrochloride in injection of a kind of stability, and its adjuvant comprises tartaric acid and stabilizing agent (mannitol, xylitol and sorbitol) etc.The shortcoming of this technical scheme is that the supplementary product consumption of injection is comparatively large, there is drug safety sex chromosome mosaicism to a certain degree.
Fog inhalation therapy is, with atomising device, medicine (solution or powder) is dispersed into small droplet or microgranule, it is made to be suspended in gas, and enter in respiratory tract and lung, reach the object of topical therapeutic (spasmolytic, antiinflammatory, eliminate the phlegm) and whole body therapeutic.Bisolvon Neulized inhalation liquid is existing procucts listing (the Bisolvon inhalant liquid 0.2% of Japanese Boehringer Ingelheim company) abroad, but containing antiseptic such as methyl hydroxybenzoate.Methyl hydroxybenzoate is as antiseptic, and the cell membrane of energy destroy microorganisms, makes intracellular protein denaturation, and can suppress the respiratory enzyme system of microbial cell and the activity of electron transmission enzyme system, have stronger bacteriostasis, but may work the mischief to human body.In addition, methyl hydroxybenzoate can slowly be hydrolyzed in the solution, and generate material---the P-hydroxybenzoic acid that toxicity is stronger, methyl hydroxybenzoate also has stimulation to skin and respiratory tract, should be noted that protection in production.
Therefore, preparation prescription composition is simple, stability is high, drug safety is high, be applicable to the suction Bisolvon solution of suitability for industrialized production is the technical problem that needs those skilled in the art put forth effort to solve.
Summary of the invention
In long-term research process, applicant is surprised to find, without the need to adding the stabilizing agents such as mannitol as Chinese patent application CN104306329A, also without the need to adding the antiseptic such as methyl hydroxybenzoate as commercialized product, only tartaric consumption need be controlled within the specific limits, and pH value is controlled between 2.5-4.5, its related substances of suction Bisolvon liquid composite can be controlled in extremely low level, and the stability of this solution longer-term storage is also high.
Based on above-mentioned discovery, applicant provide a kind of suction Bisolvon liquid composite, it is made up of Bisolvon, tartaric acid and water for injection.Preferably, the preparation technology of described suction Bisolvon liquid composite comprises the step of subpackage after inflated with nitrogen.
Particularly, the invention provides a kind of suction Bisolvon liquid composite, its pH value is 2.5-4.5, composed as follows:
Bisolvon 0.4-4g,
Tartaric acid 0.1-4g,
Water for injection adds to 1000ml.
As optimal technical scheme, the preparation technology of described suction Bisolvon liquid composite comprises the step of subpackage after inflated with nitrogen.
More specifically, described suction Bisolvon liquid composite is composed as follows:
Scheme (1)
Bisolvon 0.4g,
Tartaric acid 0.1g,
Water for injection adds to 1000ml.
Scheme (2)
Bisolvon 2g,
Tartaric acid 1g,
Water for injection adds to 1000ml.
Scheme (3)
Bisolvon 4g,
Tartaric acid 4g,
Water for injection adds to 1000ml.
Preferably, the pH value of suction Bisolvon liquid composite of the present invention is 3.0-4.0, more preferably pH3.5.
In addition, the invention still further relates to the preparation method of above-mentioned suction Bisolvon liquid composite, comprise the steps:
(1) in the water for injection of recipe quantity 60-80%, add Bisolvon, tartaric acid, stirring and dissolving, adjustment pH is 2.5-4.5, adds water to full dose;
(2) 0.22 μm of filtering with microporous membranes are degerming, and inflated with nitrogen is aseptic subpackaged, to obtain final product; Or inflated with nitrogen, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
The using dosage of the described suction Bisolvon solution that the present invention relates to can be determined according to the judgement of clinician.Such as, every day 1 ~ 3 time, each 4mg.
Suction Bisolvon liquid composite of the present invention achieves following technique effect:
1) its related substances of suction Bisolvon liquid composite of the present invention can control in extremely low level, and the stability of long term storage is also high.
2) need with prior art to add compared with the adjuvants such as mannitol, xylitol, sorbitol or methyl hydroxybenzoate, suction Bisolvon solution prescription of the present invention is simpler, and cost is lower, and drug safety is higher, is more suitable for suitability for industrialized production.
In addition, Chinese patent application CN104306329A points out, when the stabilizing agents such as mannitol and tartaric content ratio being down to 5:1 (embodiment 4 of this application), the stability of obtained bromhexine hydrochloride in injection just obviously reduces.But applicant shows through large quantifier elimination, after removing the so-called stabilizing agents such as mannitol completely, not only its related substances of suction Bisolvon liquid composite that the present invention obtains does not increase, and stability is also still good.Therefore, technical scheme of the present invention achieves unforeseeable technique effect.
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.
In embodiment, supplementary material used is commercial.
Embodiment 1 suction Bisolvon of the present invention solution
Prescription:
Bisolvon 0.4g,
Tartaric acid 0.1g,
Water for injection adds to 1000ml.
Preparation method:
(1) water for injection of recipe quantity 60-80% is heated to 60-80 DEG C, adds Bisolvon, tartaric acid, stirring and dissolving, regulate pH to be 4.5 with sodium hydroxide, add water to full dose;
(2) 0.22 μm of filtering with microporous membranes are degerming, and inflated with nitrogen is aseptic subpackaged, to obtain final product.
Embodiment 2 suction Bisolvon of the present invention solution
Prescription:
Bisolvon 2g,
Tartaric acid 1g,
Water for injection adds to 1000ml.
Preparation method:
(1) water for injection of recipe quantity 60-80% is heated to 60-80 DEG C, adds Bisolvon, tartaric acid, stirring and dissolving, regulate pH to be 3.5 with sodium hydroxide, add water to full dose;
(2) inflated with nitrogen, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
Embodiment 3 suction Bisolvon of the present invention solution
Prescription:
Bisolvon 4g,
Tartaric acid 4g,
Water for injection adds to 1000ml.
Preparation method:
(1) in the water for injection of recipe quantity 60-80%, add Bisolvon, tartaric acid, stirring and dissolving, regulate pH to be 2.5 with sodium hydroxide, add water to full dose;
(2) inflated with nitrogen, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
Reference examples 1 is with reference to Chinese patent application CN104306329A embodiment 1
Prescription:
Preparation method:
60-80% water for injection 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.
Experimental example sucks the quality and stability study of using Bisolvon solution
Suction Bisolvon solution prepared by Example 1-3 and bromhexine hydrochloride in injection prepared by reference examples 1, according to the requirement of Chinese Pharmacopoeia 2010 editions two annex XIXC stability test guidelines, investigate stability, and utilize high performance liquid chromatography to detect the content of related substance, result is as follows:
The testing result of table 10 day
Table 2 accelerated test result
(simulation commercially available back, temperature 60 C, places 10 days)
Visible, compared with Chinese patent application CN104306329A embodiment 1 (reference examples 1), suction Bisolvon solution (embodiment 1-3) prepared by the present invention in product quality and storage stability, equal no significant difference.
Claims (9)
1. suck and use a Bisolvon liquid composite, it is made up of Bisolvon, tartaric acid and water for injection.
2. suction Bisolvon liquid composite according to claim 1, its preparation technology comprises the step of subpackage after inflated with nitrogen.
3. suction Bisolvon liquid composite according to claim 1 and 2, its pH value is 2.5-4.5, composed as follows:
Bisolvon 0.4-4g,
Tartaric acid 0.1-4g,
Water for injection adds to 1000ml.
4. suction Bisolvon liquid composite according to claim 3, it is composed as follows:
Bisolvon 0.4g,
Tartaric acid 0.1g,
Water for injection adds to 1000ml.
5. suction Bisolvon liquid composite according to claim 3, it is composed as follows:
Bisolvon 2g,
Tartaric acid 1g,
Water for injection adds to 1000ml.
6. suction Bisolvon liquid composite according to claim 3, it is composed as follows:
Bisolvon 4g,
Tartaric acid 4g,
Water for injection adds to 1000ml.
7., according to the arbitrary described suction Bisolvon liquid composite of claim 1-6, also comprise the sodium chloride as isoosmotic adjusting agent.
8. the preparation method of the arbitrary described suction Bisolvon liquid composite of claim 1-6, comprises the steps:
(1) in the water for injection of recipe quantity 60-80%, add Bisolvon, tartaric acid, stirring and dissolving, adjustment pH is 2.5-4.5, adds water to full dose;
(2) 0.22 μm of filtering with microporous membranes are degerming, and inflated with nitrogen is aseptic subpackaged, to obtain final product; Or inflated with nitrogen, subpackage, 121 DEG C of sterilizings 15 minutes, packaging, to obtain final product.
9. the preparation method of suction Bisolvon liquid composite according to claim 8, wherein said pH is 3.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610007945.5A CN105456187A (en) | 2016-01-07 | 2016-01-07 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610007945.5A CN105456187A (en) | 2016-01-07 | 2016-01-07 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
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| CN105456187A true CN105456187A (en) | 2016-04-06 |
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| CN201610007945.5A Pending CN105456187A (en) | 2016-01-07 | 2016-01-07 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176615A (en) * | 2016-08-30 | 2016-12-07 | 天津市中升挑战生物科技有限公司 | A kind of Bisolvon soluble powder and preparation method and application |
| 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 |
| CN110898041A (en) * | 2018-09-18 | 2020-03-24 | 北京盈科瑞创新药物研究有限公司 | Bromhexine hydrochloride solution preparation for inhalation and preparation method thereof |
| CN114557983A (en) * | 2022-03-18 | 2022-05-31 | 北京诺和德美医药科技有限公司 | Stable bromhexine hydrochloride solution for inhalation 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 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63275521A (en) * | 1987-05-07 | 1988-11-14 | Taisho Pharmaceut Co Ltd | Solid preparation of bromhexine hydrochloride |
| 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 |
| CN103893116A (en) * | 2014-04-17 | 2014-07-02 | 河北仁合益康药业有限公司 | Oral liquid composition of bromhexine hydrochloride |
| CN104306329A (en) * | 2014-11-07 | 2015-01-28 | 石家庄科仁医药科技有限公司 | Bromhexine hydrochloride injection and preparation method and application thereof |
| CN104434786A (en) * | 2014-12-09 | 2015-03-25 | 石家庄科仁医药科技有限公司 | Stable bromhexine hydrochloride sodium chloride injection composition |
-
2016
- 2016-01-07 CN CN201610007945.5A patent/CN105456187A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63275521A (en) * | 1987-05-07 | 1988-11-14 | Taisho Pharmaceut Co Ltd | Solid preparation of bromhexine hydrochloride |
| 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 |
| CN103893116A (en) * | 2014-04-17 | 2014-07-02 | 河北仁合益康药业有限公司 | Oral liquid composition of bromhexine hydrochloride |
| CN104306329A (en) * | 2014-11-07 | 2015-01-28 | 石家庄科仁医药科技有限公司 | Bromhexine hydrochloride injection and preparation method and application thereof |
| CN104434786A (en) * | 2014-12-09 | 2015-03-25 | 石家庄科仁医药科技有限公司 | Stable bromhexine hydrochloride sodium chloride injection composition |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176615A (en) * | 2016-08-30 | 2016-12-07 | 天津市中升挑战生物科技有限公司 | A kind of Bisolvon soluble powder and preparation method and application |
| CN110898041A (en) * | 2018-09-18 | 2020-03-24 | 北京盈科瑞创新药物研究有限公司 | Bromhexine hydrochloride solution preparation for inhalation and preparation method thereof |
| CN110898041B (en) * | 2018-09-18 | 2023-04-14 | 北京盈科瑞创新药物研究有限公司 | Bromhexine hydrochloride solution preparation for inhalation 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 |
| CN114557983A (en) * | 2022-03-18 | 2022-05-31 | 北京诺和德美医药科技有限公司 | Stable bromhexine hydrochloride solution for inhalation and preparation method thereof |
| CN114557983B (en) * | 2022-03-18 | 2022-12-27 | 北京诺和德美医药科技有限公司 | Stable bromhexine hydrochloride solution for inhalation 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 |
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Address after: 051500 Haixing Road, Zhaoxian County Industrial Park, Shijiazhuang, Hebei Applicant after: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. Address before: 053411 Hengshui City, Hebei, Wuyi County, Qing Liang store town Applicant before: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. |
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Application publication date: 20160406 |