CN105078883A - Ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system - Google Patents
Ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system Download PDFInfo
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- CN105078883A CN105078883A CN201510572583.XA CN201510572583A CN105078883A CN 105078883 A CN105078883 A CN 105078883A CN 201510572583 A CN201510572583 A CN 201510572583A CN 105078883 A CN105078883 A CN 105078883A
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- ambroxol hydrochloride
- aqueous injection
- respiratory system
- composition aqueous
- calcium chloride
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Abstract
The invention relates to an ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system, and belongs to the technical field of medicine. The composition aqueous injection is prepared from ambroxol hydrochloride and calcium chloride. The ambroxol hydrochloride, different from that reported in the prior art, is a novel crystalline compound, and x-ray powder diffraction pattern obtained through Cu-K alpha ray measurement is as shown in Figure 1. Tests prove that the ambroxol hydrochloride compound disclosed by the invention is relatively good in solubility and relatively high in stability, and the ambroxol hydrochloride compound can be used for preparing various preparations; and the aqueous injection prepared from the ambroxol hydrochloride crystalline compound provided by the invention is simple in component and good in stability.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease.
Background technology
Ambroxol hydrochloride (AmbroxolHydrochloride) has another name called Ambroxol Hydrochloride, a kind of respiratory tract lubrication expectorant and mucolytic, ambroxol hydrochloride, chemical name is trans-4-[(2-amino-3,5-dibromo-benzyl) amino] cyclohexanol HCI, for white is to micro-yellow crystalline powder; Ambroxol hydrochloride has the characteristic that mucus is got rid of facilitation and dissolved secretions, and it can promote the eliminating of thick secretions in respiratory tract and reduce the delay of mucus, thus significantly promotes expectoration, improves breath state.The secretion of pulmonary surfactant, the secretion of air flue liquid and ciliary movement can be promoted.Ambroxol hydrochloride is widely used in the thick sputum, dys-expectoration etc. that various acute and chronic respiratory tract disease causes clinically.
At present, the polymorphic about ambroxol hydrochloride has disclosed a lot of patent and document.
The pharmaceutical composition that patent ZL201210513123.6 discloses a kind of ambroxol hydrochloride crystal formation and obtained by this crystal formation, described ambroxol hydrochloride crystal formation in the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angle of diffraction at 6.9 °, 7.2 °, 12.8 °, 15.6 °, 17.5 °, 20 °, 21 °, 22 °, 24 ° of places demonstrate characteristic diffraction peak.
Patent ZL201210231927.7 relates to a kind of unformed ambroxol compound and preparation method thereof, and the X-ray powder diffraction pattern of this unformed powder is without obvious characteristic peak.
Patent application 201410071920.2 relates to a kind of ambroxol compound and oral cavity disintegration tablet.The X-ray powder diffraction pattern that ambroxol hydrochloride of the present invention uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.Containing ambroxol hydrochloride 10-30 weight portion, filler 50-80 weight portion, disintegrating agent 10-15 weight portion, fluidizer 0.3-1.6 weight portion, lubricant 0.4-1.6 weight portion, correctives 8-16 weight portion in Orally disintegrating tablet of ambroxol hydrochloride.
Ambroxol hydrochloride is insoluble in water, very large difficulty is brought to the preparation of preparation, the present invention proposes a kind of new hydrochloric acid ammonia bromine compounds, there is good dissolubility and higher stability, facilitate the preparation of various preparation, utilize and the invention provides that the aqueous injection component that ambroxol hydrochloride crystal-form compound makes is simple, good stability.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease, described compositions aqueous injection is made up of ambroxol hydrochloride, calcium chloride; Described ambroxol hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: the weight ratio of ambroxol hydrochloride and calcium chloride is 1:0.3-0.7.
Second optimal technical scheme of the present invention is: the weight ratio of ambroxol hydrochloride and calcium chloride is 1:0.4-0.6.
3rd optimal technical scheme of the present invention is: the weight ratio of ambroxol hydrochloride and calcium chloride is 1:0.5.
4th optimal technical scheme of the present invention is: the preparation method of described compositions aqueous injection comprises the following steps:
Get the ambroxol hydrochloride of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of ambroxol hydrochloride weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
The preparation method of the ambroxol hydrochloride crystal in the present composition comprises the following steps:
(1) be dissolved in by ambroxol hydrochloride in the mixed solvent of methanol, butanone, the solvent load that needs of every gram of ambroxol hydrochloride is 50ml, and the volume ratio of methanol, butanone is 3.5:1;
(2), after being heated to 30 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains ambroxol hydrochloride crystal.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of ambroxol hydrochloride novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this ambroxol hydrochloride crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, the new hydrochloric acid ammonia bromine compounds that the present invention proposes, there is good dissolubility and higher stability, facilitate the preparation of various preparation, utilize and the invention provides that the aqueous injection component that ambroxol hydrochloride crystal-form compound makes is simple, good stability.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the ambroxol hydrochloride crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of ambroxol hydrochloride crystal
(1) be dissolved in by ambroxol hydrochloride in the mixed solvent of methanol, butanone, the solvent load that needs of every gram of ambroxol hydrochloride is 50ml, and the volume ratio of methanol, butanone is 3.5:1;
(2), after being heated to 30 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains ambroxol hydrochloride crystal.
The X-ray powder diffraction pattern that the ambroxol hydrochloride crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of ambroxol hydrochloride aqueous injection
Get 1g ambroxol hydrochloride, 0.3g calcium chloride, be dissolved in water for injection, add 0.01g active carbon stirring at room temperature 30 minutes, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
embodiment 3:the preparation of ambroxol hydrochloride aqueous injection
Get 1g ambroxol hydrochloride, 0.4g calcium chloride, be dissolved in water for injection, add 0.01g active carbon stirring at room temperature 30 minutes, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
embodiment 4:the preparation of ambroxol hydrochloride aqueous injection
Get 1g ambroxol hydrochloride, 0.5g calcium chloride, be dissolved in water for injection, add 0.01g active carbon stirring at room temperature 30 minutes, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
embodiment 5:the preparation of ambroxol hydrochloride aqueous injection
Get 1g ambroxol hydrochloride, 0.6g calcium chloride, be dissolved in water for injection, add 0.01g active carbon stirring at room temperature 30 minutes, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
embodiment 6:the preparation of ambroxol hydrochloride aqueous injection
Get 1g ambroxol hydrochloride, 0.7g calcium chloride, be dissolved in water for injection, add 0.01g active carbon stirring at room temperature 30 minutes, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
experimental example 1:mobility is tested
The mobility of this experimental example to the ambroxol compound of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, ambroxol compound is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of ambroxol compound accumulation horizon.Experimental result is as shown in table 1.
Table 1 mobility experimental result
From the interpretation of table 1, the mobility of the ambroxol compound that the embodiment of the present invention 1 prepares is fine.
experimental example 2: dissolubility contrast test
The dissolubility of following ambroxol hydrochloride is detected,
Comparative example 1: commercially available ambroxol hydrochloride (Wuhan English and pharmaceutical Co. Ltd);
Comparative example 2: prepare according to the embodiment 1 of patent ZL201210513123.6;
Comparative example 3: prepare according to the embodiment 1 of patent ZL201210231927.7;
Comparative example 4: prepare according to the embodiment 1 of patent application 201410071920.2;
1. be determined at the quality of ambroxol hydrochloride in 100g water saturation solution under 20 DEG C of conditions; Experimental result is as shown in table 2.
Table 2 dissolubility comparative test result
As can be seen from Table 2, the water solublity of ambroxol hydrochloride of the present invention greatly improves compared with comparative example, brings conveniently to preparation preparation.
experimental example 3:influence factor tests
1. hot test
The aqueous injection that Example 2 prepares, simulation listing packaging, puts in sealing clean container, places 10 days at 40 ± 2 DEG C of temperature, and in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
2. high humility test
The aqueous injection that Example 2 prepares, simulation listing packaging, puts in sealing clean container, place 10 days under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
3. strong illumination test
The aqueous injection that Example 4 prepares, simulation listing packaging, puts in sealing clean container, and being placed in illumination is place 10 days under the condition of 4500lx, and in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result compared with 0 day.The results are shown in Table 3:
Table 3 influence factor result of the test
Result shows: the ambroxol hydrochloride aqueous injection that the present invention prepares, and its stability is good, and under high temperature, high humidity, high light conditions, equal retention is stablized.Influence factor's experiment is carried out to the ambroxol hydrochloride aqueous injection that other embodiments of the invention prepare, obtains similar experimental result.
Claims (6)
1. treat a medicine ambroxol hydrochloride composition aqueous injection for respiratory system disease, it is characterized in that: described compositions aqueous injection is made up of ambroxol hydrochloride, calcium chloride; Described ambroxol hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease according to claim 1, is characterized in that: the weight ratio of described ambroxol hydrochloride and calcium chloride is 1:0.3-0.7.
3. the medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease according to claim 2, is characterized in that: the weight ratio of described ambroxol hydrochloride and calcium chloride is 1:0.4-0.6.
4. the medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease according to claim 3, is characterized in that: the weight ratio of described ambroxol hydrochloride and calcium chloride is 1:0.5.
5. prepare the method for the medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease as claimed in claim 1 for one kind, it is characterized in that comprising the following steps: get the ambroxol hydrochloride of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of ambroxol hydrochloride weight, filter carbon removal, filtrate injects water to 2000ml, cross 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains ambroxol hydrochloride aqueous injection.
6. the medicine ambroxol hydrochloride composition aqueous injection for the treatment of respiratory system disease according to claim 1, it is characterized in that, the preparation method of the crystal of described ambroxol hydrochloride comprises the following steps:
(1) be dissolved in by ambroxol hydrochloride in the mixed solvent of methanol, butanone, the solvent load that needs of every gram of ambroxol hydrochloride is 50ml, and the volume ratio of methanol, butanone is 3.5:1;
(2), after being heated to 30 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains ambroxol hydrochloride crystal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510572583.XA CN105078883A (en) | 2015-09-10 | 2015-09-10 | Ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system |
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| CN201510572583.XA CN105078883A (en) | 2015-09-10 | 2015-09-10 | Ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050014847A1 (en) * | 2003-07-16 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Ambroxol for the treatment of chronic nociceptive pain |
| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104788327A (en) * | 2015-05-15 | 2015-07-22 | 苗怡文 | Ambroxol hydrochloride compound for treating respiratory system disease and preparation method of ambroxol hydrochloride compound |
| CN104840417A (en) * | 2015-04-30 | 2015-08-19 | 济南康和医药科技有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
-
2015
- 2015-09-10 CN CN201510572583.XA patent/CN105078883A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050014847A1 (en) * | 2003-07-16 | 2005-01-20 | Boehringer Ingelheim International Gmbh | Ambroxol for the treatment of chronic nociceptive pain |
| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104840417A (en) * | 2015-04-30 | 2015-08-19 | 济南康和医药科技有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
| CN104788327A (en) * | 2015-05-15 | 2015-07-22 | 苗怡文 | Ambroxol hydrochloride compound for treating respiratory system disease and preparation method of ambroxol hydrochloride compound |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
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Application publication date: 20151125 |
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