CN102293741B - Bromhexine hydrochlorie injection, its preparation method and application - Google Patents

Bromhexine hydrochlorie injection, its preparation method and application Download PDF

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CN102293741B
CN102293741B CN 201110246847 CN201110246847A CN102293741B CN 102293741 B CN102293741 B CN 102293741B CN 201110246847 CN201110246847 CN 201110246847 CN 201110246847 A CN201110246847 A CN 201110246847A CN 102293741 B CN102293741 B CN 102293741B
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bisolvon
injection
preparation
glucose
aqueous solution
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CN102293741A (en
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张凯
杜玉民
薛娜
韩丰年
马旭伟
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Shijiazhuang Hankang Biology Chemistry Medicine Co., Ltd.
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SHIJIAZHUANG DONGFANG PHARMACEUTICAL CO Ltd
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Abstract

The invention provides a bromhexine hydrochlorie injection, which contains bromhexine hydrochlorie and glucose and does not contain ethanol. Without ethanol, the injection can be used together with antibiotic drugs and has good stability. In accord with national regulations for pharmaceutical preparations, the injection has stable and reliable quality, and therefore can be used safely. The invention also provides a preparation method of the bromhexine hydrochlorie injection, comprising the steps of: preparing an isotonic water solution of glucose, then predissolving the bromhexine hydrochlorie in the isotonic water solution, and conducting an ultrasonic treatment. According to the method of the invention, the use of ethanol in the process of preparing a liquid preparation of bromhexine hydrochlorie can be avoided successfully, and possible adverse reactions during clinical application are avoided. With a process simple for operation, the method provided in the invention improves the stability of the injection.

Description

A kind of bromhexine hydrochloride injection And its preparation method and purposes
Technical field
The invention belongs to the pharmaceutical technology field.Particularly, the present invention relates to a kind of bromhexine hydrochloride injection And its preparation method.
Background technology
Bisolvon (Bromhexine Hydrochloride, (2-amino-3 for N-, the 5-dibromo-benzyl)-and the N-methylcyclohexylamine hydrochlorate) be the hydrochlorate of semisynthetic peganine. derivant, be the effective ingredient in India's expelling phlegm for arresting cough medicine among the people Adhatoda vasica Nees the earliest, 1963 at first synthetic by Keck, the nineteen sixty-five listing.1973 at Discussion on Chinese Listed, for acute and chronic bronchitis, asthma, bronchiectasis, emphysema, especially being applicable to the sticking productive cough of white goes out difficult person and extensively blocks critical emergency case that bronchia causes etc. because of sputum, belong to mucolytic drugs, this medicine can change the viscosity composition of sticking expectorant, reduce the viscosity of expectorant, make expectorant be easy to expectoration.This medicine has become the expectorant of domestic and international clinical first-selection.
Bisolvon is slightly molten in ethanol or chloroform, soluble,very slightly in water, and therefore preparing liquid preparation exists many technical difficulties.The existing method for preparing the Bisolvon liquid preparation mainly uses ethanol to prepare the Bisolvon concentrated solution as solvent, mix with pharmaceutical carrier (sodium chloride, magnesium chloride, lactose sodium, glucose etc.) concentrated solution afterwards, the dilute with water rear decoloring filters, and obtains corresponding Bisolvon liquid preparation.
There is very large defective in application facet at Bisolvon liquid preparation, particularly injection at present, is mainly reflected in the following aspects:
First, Bisolvon is as classical expectorant, often be used for the treatment of clinically respiratory tract disease, even behind surgical operation, also be used for conventional expectoration keeping respiratory smooth, these two kinds of purposes all determined its will inevitably with antibiotic (such as cephalo-type, imidazoles antibiotic) use in conjunction.Yet, find clinically, during the antibiotics medication, contact ethanol or a period of time contact ethanol after drug withdrawal, disulfiram-like reaction appears in patient possibly, show as uncomfortable in chest, breathe hard, laryngeal edema, die Blausucht, dyspnea, increased heart rate, blood pressure drops, limbs fatigue, flush, hyperhidrosis, insomnia, headache, feel sick, vomiting, dim eyesight, drowsiness, hallucination, in a trance even anaphylactic shock occurs, blood pressure drops to 60~70/30~40mmHg, and with loss of consciousness; Even mistaken diagnosis is acute coronary syndrome, heart failure etc.These antibiotics mainly comprise cephalo-type and imdazole derivatives, such as ceftriaxone sodium, cefoperazone, cefotaxime etc.; Metronidazole, tinidazole, ketoconazole, furazolidone, chloromycetin, tolbutamide, glibenclamide, phenformin etc. all can cause disulfiram-like reaction in addition.As the patient during using cefoperazone, drink or drug withdrawal after drink (comprising Chinese liquor, medicated beer, alcopop and confection) in 7 days, oral or intravenous applications contains the medicine of ethanol, perhaps even with ethanol carry out skin degerming or clean cooling, all can produce disulfiram-like reaction, this symptom comes across behind the alcohol exposure 5 to 40 minutes.But although the lighter's spontaneous remission, than severe one even need oxygen uptake and symptomatic treatment.Yet, in the process of preparation Bisolvon concentrated solution, need to use ethanol to be solvent, even but under heated condition, ethanol is also limited to the dissolubility of Bisolvon, therefore in injection, need to introduce a large amount of ethanol, there is larger hazardness in this to patient health so that probably make the patient produce disulfiram-like reaction when Bisolvon injection and antibiotics coupling.
The second, same existence owing to ethanol in the Bisolvon injection, water and ethanol form azeotropic mixture and have reduced sterilising temp in the high temperature sterilize process, and sterilization effect is had a negative impact.
The 3rd, the Bisolvon concentrated solution slightly lets cool, mixes with other carrier concentrated solutions or all may separate out Bisolvon crystallization and crystallization content in the dilute with water process unfixing, causes injection crude drug content unstable behind the decolorization filtering.
Therefore, there is at present the change demand for Bisolvon dissolution process technology, particularly for the demand of the Bisolvon injection that does not contain ethanol.
Summary of the invention
In order to overcome above-mentioned prior art defective, the object of the present invention is to provide a kind of injection of Bisolvon, do not comprise ethanol in this injection.
Another object of the present invention is to provide the preparation method of described Bisolvon injection.
Another purpose of the present invention is to provide the pharmaceutical applications of described Bisolvon injection.
The technical solution used in the present invention is:
On the one hand, the invention provides a kind of Bisolvon injection, the hydrochloric bromhexine of described Bisolvon infusion pump and glucose, and do not comprise ethanol.
Preferably, the concentration of glucose is 50g/L in the described Bisolvon injection; The concentration of Bisolvon is preferably 0.04g/L~0.16g/L in the described Bisolvon injection.
On the other hand, the invention provides the preparation method of described Bisolvon injection, it comprises: then the isotonic aqueous solution of preparation glucose is dissolved in Bisolvon in the described isotonic aqueous solution.
Preferably, bromhexine hydrochloride is dissolved in the described isotonic aqueous solution by supersound process.
Preferably, described preparation method may further comprise the steps:
1) glucose is soluble in water, filter after then adding activated carbon adsorption, filtrate water is diluted to isotonic concentration, thereby obtains the isotonic aqueous solution of glucose; Preferably, described water is water for injection;
2) to through step 1) add Bisolvon in the isotonic aqueous solution that obtains, ultrasonicly make the Bisolvon dissolving, filter after then adding activated carbon adsorption, regulate pH value, filtering with microporous membrane.
According to the specific embodiment of the present invention, described method comprises:
1) the 5000g glucose for injection is dissolved in the 25L water for injection, then adds active carbon 25 to 50g, boil the rear filtering decarbonization of absorption in 30 minutes, then filtrate is diluted to 100L with water for injection, thereby obtains the isotonic aqueous solution of glucose;
2) to through step 1) add 4g~16g Bisolvon in the isotonic aqueous solution that obtains, 30~40 ℃ of lower 25 to 60kHz (preferred 60kHz) made the Bisolvon dissolving in ultrasonic 50 minutes, then add 100g to 400g active carbon (preferably adding the 150g active carbon), filter after stirring absorption in 10 minutes, regulate pH value to 4.0~4.5,0.45 μ m filtering with microporous membrane, packing, sterilization.
Another aspect the invention provides the purposes of described Bisolvon injection in the preparation expectorant.
When preparation Bisolvon liquid preparation, all adopt a large amount of ethanol to dissolve Bisolvon as solvent at present, this has brought very big defective for the use of liquid preparation.Be compared with existing technology, the present invention proposes a kind of new bromhexine hydrochloride injection And its preparation method, it has the following advantages:
The first, the inventor is through the great many of experiments discovery, and glucose has stronger hydrotropy effect to Bisolvon, Bisolvon directly can be dissolved in the isosmotic solution of glucose; And with supersound process, except directly bromhexine hydrochloride being had the very strong hydrotropy effect, more can make the Bisolvon glucose solution be tending towards complete stability.We have proposed a kind of new preparation process of Bisolvon injection accordingly, the method adopts and configures first the glucose isosmotic solution, dissolve again the step of Bisolvon, carry out again supersound process, successfully avoided the use of existing method ethanol in Bisolvon liquid preparation preparation process, improved the stability of injection, and preparation technology is simple to operate;
The second, adopt method of the present invention successfully to prepare the new injection of Bisolvon, this injection does not contain ethanol, experimental results show that said preparation has good stability, and meets national drug preparation regulation, and therefore stable and reliable product quality is used safely, had no side effect.
Therefore, bromhexine hydrochloride injection And its preparation method provided by the invention has overcome the prior art defective, can use clinically safely and effectively, particularly can be safely and the antibiotics coupling, have great application prospect.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Experimental technique among the following embodiment if no special instructions, is conventional method.Used medicinal raw material, reagent material etc. among the following embodiment if no special instructions, all can be bought and obtain from conventional Chinese medicine, biochemistry, pharmaceutical agent shop.
Embodiment 1 Bisolvon solubility study in water for injection
Precision takes by weighing Bisolvon sample 3g, adds water for injection 1000ml, behind the jolting 20min, have no dissolving, place under the room temperature, respectively at 30min, 60min, 120min, 24h, 48h, 72h under the 1500lx daylight lamp, observe Bisolvon dissolving situation, the result is as follows:
The dissolubility (1) of table 1 Bisolvon in water for injection
Figure BDA0000085985700000041
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
Precision takes by weighing Bisolvon sample 3g, add water for injection 1000ml, 70 ℃ of heating in water bath (adding reflux condenser), 60 turn/min stirs 30min, and most of dissolving has a small amount of precipitate, place under the room temperature, under the 1500lx daylight lamp, observe Bisolvon dissolving situation respectively at 30min, 60min, 120min, 24h, 48h, 72h, the result is as follows:
The dissolubility (2) of table 2 Bisolvon in water for injection
Figure BDA0000085985700000042
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
Precision takes by weighing Bisolvon sample 3g, add water for injection 1000ml, 30~40 ℃ of supersound process (25kHz, 100w), be partly dissolved, precipitate is arranged, place under the room temperature, under the 1500lx daylight lamp, observe Bisolvon dissolving situation respectively at 30min, 60min, 120min, 24h, 48h, 72h, the result is as follows:
The dissolubility (3) of table 3 Bisolvon in water for injection
Figure BDA0000085985700000051
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
Embodiment 2 Bisolvon solubility study in glucose solution
Precision takes by weighing Bisolvon sample 3g, add 5% glucose injection 1000ml, behind the jolting 10min, be partly dissolved, precipitate is arranged, places under the room temperature, respectively at 30min, 60min, 120min, 24h, 48h, 72h under the 1500lx daylight lamp, observe Bisolvon dissolving situation, the result is as follows:
The dissolubility (1) of table 4 Bisolvon in glucose solution
Figure BDA0000085985700000052
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
Precision takes by weighing Bisolvon sample 3g, adds 5% glucose injection 1000ml, 70 ℃ of heating in water bath (adding reflux condenser), 60 turn/min stirs 30min, fully dissolving; Place under the room temperature, under the 1500lx daylight lamp, observe Bisolvon dissolving situation respectively at 30min, 60min, 120min, 24h, 48h, 72h, the result is as follows:
The dissolubility (2) of table 5 Bisolvon in glucose solution
Figure BDA0000085985700000053
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
Previous experiments shows, Bisolvon can be partially dissolved in the glucose injection, illustrates that glucose solution has certain hydrotropy effect to bromhexine hydrochloride, and heated and stirred also can promote its dissolving; But the bromhexine hydrochloride after the dissolving can be separated out from solution again, shows that its stability of solution is poor.
Embodiment 3 supersound process stability study in the Bisolvon glucose solution
Precision takes by weighing Bisolvon sample 3g, adds 5% glucose injection 1000ml, and 30~40 ℃ of supersound process (25kHz, 100w) 50min dissolves fully.Place under the room temperature, under the 1500lx daylight lamp, observe Bisolvon dissolving situation respectively at 30min, 60min, 120min, 24h, 48h, 72h, the result is as follows:
The stability of Bisolvon glucose solution after table 6 supersound process
Figure BDA0000085985700000061
+ expression can detect the Bisolvon precipitation
-expression does not detect the Bisolvon precipitation
This group is tested and is shown, supersound process can make the Bisolvon glucose solution have no Precipitation more than 72 hours, illustrates that supersound process has stronger Stabilization to the bromhexine hydrochloride glucose solution.
The preparation of embodiment 4 Bisolvon injection of the present invention
Get glucose for injection 5000g and add water for injection 25000ml stirring and dissolving, add the 25g active carbon, boiled 30 minutes, filtering decarbonization gets glucose solution.After letting cool, inject and be diluted with water to 100000ml, stir evenly;
Add Bisolvon 16g, 30~40 ℃ of supersound process (60kHz) 50min makes the dissolving of hydrochloric acid bromocaproic acid, add the 400g active carbon, continue to stir 10 minutes, filter, with sodium hydroxide adjust pH to 4.0~4.5, measure content and related substances, qualified rear mistake 0.45 μ m microporous filter membrane namely gets the Bisolvon glucose injection after the fill.
The preparation of embodiment 5 Bisolvon injection of the present invention
Get glucose for injection 5000g and add water for injection 25000ml stirring and dissolving, add the 50g active carbon, boiled 30 minutes, filtering decarbonization gets glucose solution.After letting cool, inject and be diluted with water to 100000ml, stir evenly;
Add Bisolvon 8g, 30~40 ℃ of supersound process (60kHz) 50min makes the dissolving of hydrochloric acid bromocaproic acid, add the 100g active carbon, continue to stir 10 minutes, filter, with sodium hydroxide adjust pH to 4.0~4.5, measure content and related substances, qualified rear mistake 0.45 μ m microporous filter membrane namely gets the Bisolvon glucose injection after the fill.
The preparation of embodiment 6 Bisolvon injection of the present invention
Get glucose for injection 5000g and add water for injection 25000ml stirring and dissolving, add the 50g active carbon, boiled 30 minutes, filtering decarbonization gets glucose solution.After letting cool, inject and be diluted with water to 100000ml, stir evenly;
Add Bisolvon 4g, 30~40 ℃ of supersound process (60kHz) 50min makes the dissolving of hydrochloric acid bromocaproic acid, add the 150g active carbon, continue to stir 10 minutes, filter, with sodium hydroxide adjust pH to 4.0~4.5, measure content and related substances, qualified rear mistake 0.45 μ m microporous filter membrane namely gets the Bisolvon glucose injection after the fill.
The stability study of embodiment 7 Bisolvon injection of the present invention
According to the requirement of Chinese Pharmacopoeia two appendix XI XC medicine stability test guiding principles in 2010, investigate 40 ℃ of acceleration 6 months and 12 months stability of long-term stable experiment of the Bisolvon glucose injection of embodiment 4 to 6 preparations, the result is as follows:
1, accelerated test
The Bisolvon glucose injection under the listing packing, is placed in the calorstat, and temperature is 40 ± 2 ℃, under relative humidity 75 ± 5% conditions, places six months.Result of the test sees Table 7.
Table 7 Bisolvon glucose injection accelerated test result of the test
Figure BDA0000085985700000071
Figure BDA0000085985700000091
2, room temperature keeps sample and investigates test
The Bisolvon glucose injection under the listing packing, in 25 ℃ ± 2 ℃ of temperature, is placed under relative humidity 60% ± 10% condition for a long time.Timing sampling detects, and result of the test sees Table 8.
Table 8 Bisolvon glucose injection long-term test results
Figure BDA0000085985700000092
Figure BDA0000085985700000101
Figure BDA0000085985700000111
Simulation listing packing three batch samples of the present invention preparation were tested 6 months under 40 ℃, RH75% condition, keep sample in room temperature and to have investigated 12 months, experimental result shows, this three batch sample has good stability, the indexs such as its appearance luster, acidity, Clarity and colour of solution, visible foreign matters, related substance, content are without significant change, and are all up to specification.

Claims (8)

1. Bisolvon injection, it is characterized in that, the hydrochloric bromhexine of described Bisolvon infusion pump and glucose, and do not comprise ethanol, the concentration of glucose is 50g/L in the wherein said Bisolvon injection, the concentration of Bisolvon is 0.04g/L ~ 0.16g/L, and the preparation method of described Bisolvon injection comprises: then the isotonic aqueous solution of preparation glucose is dissolved in Bisolvon in the described isotonic aqueous solution by supersound process.
2. the preparation method of Bisolvon injection according to claim 1 is characterized in that, described preparation method comprises: then the isotonic aqueous solution of preparation glucose is dissolved in Bisolvon in the described isotonic aqueous solution by supersound process.
3. preparation method according to claim 2 is characterized in that, described preparation method may further comprise the steps:
1) glucose is soluble in water, filter after then adding activated carbon adsorption, filtrate water is diluted to isotonic concentration, thereby obtains the isotonic aqueous solution of glucose;
2) in the isotonic aqueous solution that obtains through step 1), add Bisolvon, ultrasonicly make hydrochloric acid bromocaproic acid dissolving, filter after then adding activated carbon adsorption, regulate pH value, filtering with microporous membrane.
4. preparation method according to claim 3 is characterized in that, the water in the described step 1) is water for injection.
5. each described preparation method in 4 according to claim 2 is characterized in that, described method comprises:
1) the 5000g glucose for injection is dissolved in the 25L water for injection, adds active carbon 25 to 50g, boil the rear filtering decarbonization of absorption in 30 minutes, then filtrate is diluted to 100L with water for injection, thereby obtains the isotonic aqueous solution of glucose;
2) in the isotonic aqueous solution that obtains through step 1), add 4g ~ 16g Bisolvon, made the dissolving of hydrochloric acid bromocaproic acid in ultrasonic 50 minutes for 30 ~ 40 ℃ lower 25 to 60kHz, then add 100g to 400g active carbon, filter after stirring absorption in 10 minutes, regulate pH value to 4.0 ~ 4.5,0.45 μ m filtering with microporous membrane, packing, sterilization.
6. preparation method according to claim 5 is characterized in that, described step 2) in made hydrochloric acid bromocaproic acid dissolving in ultrasonic 50 minutes at 30 ~ 40 ℃ of lower 60kHz.
7. preparation method according to claim 5 is characterized in that, described step 2) the middle 150g active carbon that adds.
8. Bisolvon injection according to claim 1 is in the purposes of preparation in the expectorant.
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CN103976945B8 (en) * 2014-06-04 2016-12-21 回音必集团(江西)东亚制药有限公司 A kind of Bisolvon glucose injection
CN104434786B (en) * 2014-12-09 2017-04-12 河北仁合益康药业有限公司 Stable bromhexine hydrochloride sodium chloride injection composition
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
CN111714477B (en) * 2020-07-23 2021-06-15 山东迅达康兽药有限公司 Phlegm eliminating composition and preparation method of oral liquid thereof

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CN1184963C (en) * 2002-09-10 2005-01-19 张嵩 Bromhexine hydrochloride injection and its preparation method
CN1259041C (en) * 2004-02-05 2006-06-14 马小歧 Bromhexine Hydrochloride aseptic freeze-drying formulation for injection and its preparation method
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