CN114699369A - 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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Abstract
The invention belongs to the technical field of bromhexine hydrochloride injection, and provides bromhexine hydrochloride injection and a preparation method and application thereof. The invention provides bromhexine hydrochloride injection, and every 100mL of bromhexine hydrochloride injection comprises the following components: 0.1-1 g of bromhexine hydrochloride; 0.05-0.1 g of methyl p-hydroxybenzoate; 0.01-0.06 g of propyl p-hydroxybenzoate; 0.1-0.35 g of DL-tartaric acid; pH regulator and water for injection. The bromhexine hydrochloride injection provided by the invention takes methyl p-hydroxybenzoate and propyl p-hydroxybenzoate as bactericidal preservatives, and the stability of the bromhexine hydrochloride injection is ensured under the condition of low content.
Description
Technical Field
The invention relates to the technical field of bromhexine hydrochloride injection, in particular to bromhexine hydrochloride injection and a preparation method and application thereof.
Background
Bromhexine hydrochloride is a synthetic derivative of a herbal active ingredient vasicine, is mainly used for medicines used in a respiratory system clinically, can act on bronchial glands, has the effect of reducing the viscosity of sputum, makes the sputum thin and is convenient for coughing. Is mainly suitable for respiratory diseases such as chronic bronchitis, asthma and the like in clinic, and the sputum viscosity is too high, so that the cough is difficult to occur. The composition has the advantages of rapid absorption, high bioavailability, stable property, high safety, and occasional nausea. At present, bromhexine hydrochloride is mainly soluble powder in the dosage form applied to veterinary clinic, the soluble powder is administrated by drinking water, the effect is slow, and the symptoms can not be timely relieved in cases with severe phlegm adhesion. Bromhexine hydrochloride injection is approved to be used for various animals such as pigs, cows, dogs, cats and the like abroad. Therefore, the bromhexine hydrochloride injection with quick response and strong effect has important clinical significance for the auxiliary treatment of the veterinary clinical respiratory diseases in China, and the bromhexine hydrochloride injection has a drug withdrawal period of 0 day in animal-derived edible tissues, is green and has no residue, and cannot cause the problem of veterinary drug residue, so that the bromhexine hydrochloride injection has important practical significance for ensuring the food safety of human beings when being applied to the treatment of the respiratory diseases.
At present, chinese patent with publication number CN102293741A discloses a bromhexine hydrochloride injection, its preparation method and use, specifically: the bromhexine hydrochloride injection comprises bromhexine hydrochloride and glucose, and does not comprise ethanol. Chinese patent with publication number CN103976945A discloses bromhexine hydrochloride glucose injection, which comprises 30-50 mg of bromhexine hydrochloride, 30-50 g of glucose, 1-3 g of ascorbic acid, 3-5 g of arginine and 1000mL of water for injection, and pH is adjusted to 4.0-4.5 by a pH regulator. The invention patent with the patent number CN104306329A discloses an injection containing bromhexine hydrochloride, tartaric acid and stabilizers (mannitol, xylitol and sorbitol). Through the above analysis, the problems and defects of the prior art are as follows: the prescriptions of the patents CN102293741A and CN103976945A both contain glucose, which do not meet the requirement of the national food and drug administration for consistency evaluation. In the patent CN104306329A, although glucose is not contained, mannitol, xylitol and sorbitol are adopted as the stability, so that the stability of the bromhexine hydrochloride injection is ensured; however, the mannitol, the xylitol and the sorbitol have higher cost, so that the overall cost is increased, and the breeding burden of farmers is increased.
Disclosure of Invention
In view of this, the present invention aims to provide a bromhexine hydrochloride injection, a preparation method and applications thereof. The bromhexine hydrochloride injection provided by the invention has good stability and low cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides bromhexine hydrochloride injection, and each 100mL of the bromhexine hydrochloride injection comprises the following components:
0.1-1 g of bromhexine hydrochloride;
0.05-0.1 g of methyl p-hydroxybenzoate;
0.01-0.06 g of propyl p-hydroxybenzoate;
0.1-0.35 g of DL-tartaric acid;
pH regulator and water for injection.
Preferably, the mass ratio of the methyl p-hydroxybenzoate to the propyl p-hydroxybenzoate is 2-2.5: 1.
preferably, the pH value of the bromhexine hydrochloride injection is 2.8-3.5.
The invention also provides a preparation method of the bromhexine hydrochloride injection in the technical scheme, which comprises the following steps:
deoxidizing the injection water to obtain deoxidized injection water;
mixing the deoxygenated water for injection, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate to obtain a primary mixed material;
mixing the primary mixed material and DL-tartaric acid, and adding deoxygenated injection water to nearly full volume to obtain a middle mixed material;
and mixing the mixed material with bromhexine hydrochloride, and sequentially adjusting the pH value and quantifying to obtain the bromhexine hydrochloride injection.
Preferably, the oxygen scavenging comprises:
heating the water for injection to boil;
the heating and boiling time is 5-10 min;
the heating boiling is carried out under the condition of flushing nitrogen.
Preferably, the residual oxygen amount of the oxygen-removed water for injection is less than or equal to 0.05 percent.
Preferably, when the deoxygenation water for injection, the methyl p-hydroxybenzoate and the propyl p-hydroxybenzoate are mixed, the temperature of the deoxygenation water for injection is 70-80 ℃.
Preferably, when the primary mixed material and the DL-tartaric acid are mixed, the temperature of the primary mixed material is 40-50 ℃.
Preferably, the agent for adjusting the pH comprises sodium hydroxide.
The invention also provides the application of the bromhexine hydrochloride injection in the technical scheme or the bromhexine hydrochloride injection prepared by the preparation method in the technical scheme in the preparation of veterinary drugs.
The invention provides bromhexine hydrochloride injection, and each 100mL of the bromhexine hydrochloride injection comprises the following components: 0.1-1 g of bromhexine hydrochloride; 0.05-0.1 g of methyl p-hydroxybenzoate; 0.01-0.06 g of propyl p-hydroxybenzoate; 0.1-0.35 g of DL-tartaric acid; pH regulator and water for injection. The bromhexine hydrochloride injection provided by the invention takes methyl p-hydroxybenzoate and propyl p-hydroxybenzoate as bactericidal preservatives, and the stability of the bromhexine hydrochloride injection is ensured under the condition of low content.
The invention also provides a preparation method of the bromhexine hydrochloride injection in the technical scheme, which comprises the following steps: deoxidizing the injection water to obtain deoxidized injection water; mixing the deoxygenated water for injection, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate to obtain a primary mixed material; mixing the primary mixed material and DL-tartaric acid, and adding deoxygenated injection water to nearly full volume to obtain a middle mixed material; and mixing the mixed material with bromhexine hydrochloride, and sequentially adjusting the pH value and quantifying to obtain the bromhexine hydrochloride injection. The preparation method provided by the invention firstly carries out deoxidization on the injection water, thereby ensuring the stability of the finally obtained bromhexine hydrochloride injection. Meanwhile, the preparation method of the invention has the advantages of complete dissolution of the medicine and improvement of the stability of the bromhexine hydrochloride injection. In addition, the preparation method provided by the invention is simple to operate.
Further, the removing oxygen comprises: heating water for injection to boil; the heating and boiling time is 5-10 min; the heating boiling is carried out under the condition of flushing nitrogen. The oxygen removal operation of the invention can ensure that the residual oxygen content in the water for injection is low, and further improve the stability of the obtained bromhexine hydrochloride injection.
Drawings
FIG. 1 shows the results of in vitro hemolysis test of experimental rabbit erythrocytes;
FIG. 2 shows the results of the muscle irritation test of experimental rabbits;
fig. 3 is a graph of mean plasma concentration versus time for injection of bromhexine hydrochloride (test and reference formulations) into pigs.
Detailed Description
The invention provides bromhexine hydrochloride injection, and each 100mL of the bromhexine hydrochloride injection comprises the following components:
0.1-1 g of bromhexine hydrochloride;
0.05-0.1 g of methyl p-hydroxybenzoate;
0.01-0.06 g of propyl p-hydroxybenzoate;
0.1-0.35 g of DL-tartaric acid;
pH regulator and water for injection.
The bromhexine hydrochloride injection provided by the invention contains 0.1-1 g, preferably 0.2-0.8 g, and more preferably 0.4-0.6 g of bromhexine hydrochloride per 100 mL.
The bromhexine hydrochloride injection provided by the invention contains 0.05-0.1 g of methyl p-hydroxybenzoate per 100mL, preferably 0.06-0.09 g, and more preferably 0.07-0.08 g.
The bromhexine hydrochloride injection provided by the invention contains 0.01-0.06 g of propyl p-hydroxybenzoate per 100mL, preferably 0.02-0.05 g, and further preferably 0.03-0.04 g.
The mass ratio of methyl p-hydroxybenzoate to propyl p-hydroxybenzoate in each 100mL of bromhexine hydrochloride injection provided by the invention is preferably 2-2.5: 1.
the bromhexine hydrochloride injection provided by the invention contains 0.1-0.35 g of DL-tartaric acid per 100mL, and preferably 0.2-0.3 g.
Every 100mL of bromhexine hydrochloride injection provided by the invention contains a pH regulator; the pH adjusting agent is preferably an inorganic base, which preferably comprises sodium hydroxide. The dosage of the pH regulator is not particularly limited, as long as the pH value of the bromhexine hydrochloride injection meets the requirement.
The bromhexine hydrochloride injection provided by the invention contains the rest of water for injection in each 100 mL.
In the invention, the pH value of the bromhexine hydrochloride injection is preferably 2.8-3.5.
The invention also provides a preparation method of the bromhexine hydrochloride injection in the technical scheme, which comprises the following steps:
deoxidizing the injection water to obtain deoxidized injection water;
mixing the deoxygenated water for injection, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate to obtain a primary mixed material;
mixing the primary mixed material and DL-tartaric acid, and adding oxygen-removing injection water to nearly full volume to obtain a secondary mixed material;
and mixing the mixed material with bromhexine hydrochloride, and sequentially adjusting the pH value and quantifying to obtain the bromhexine hydrochloride injection.
In the present invention, the starting materials used in the present invention are preferably commercially available products unless otherwise specified.
The invention can remove oxygen from the injection water to obtain the oxygen-removed injection water. In the present invention, the oxygen removal preferably comprises boiling water for injection by heating. In the invention, the heating and boiling time is preferably 5-10 min; the heating and boiling are preferably carried out under nitrogen flushing. In the present invention, the residual oxygen amount of the oxygen-removed water for injection is preferably 0.05% or less. In the invention, the heating boiling is carried out under the condition of nitrogen filling, so that oxygen redissolution can be prevented, the oxygen residual quantity in water for injection is reduced, and the stability of the final bromhexine hydrochloride injection is improved.
After the deoxygenated water for injection is obtained, the deoxygenated water for injection, the methyl p-hydroxybenzoate and the propyl p-hydroxybenzoate are mixed to obtain a primary mixed material. In the invention, when the deoxygenation water for injection, the methyl p-hydroxybenzoate and the propyl p-hydroxybenzoate are mixed, the temperature of the deoxygenation water for injection is preferably 70-80 ℃. In the present invention, the mixing is preferably performed under stirring, and the rotation speed and time of the stirring are not particularly limited as long as the substances can be completely dissolved and mixed.
After the primary mixed material is obtained, the primary mixed material and DL-tartaric acid are mixed, and oxygen-removing injection water is added to the mixture to the full extent to obtain a middle mixed material. In the invention, when the primary mixed material and DL-tartaric acid are mixed, the temperature of the primary mixed material is preferably 40-50 ℃. In the present invention, the mixing is preferably performed under stirring, and the rotation speed and time of the stirring are not particularly limited as long as the substances can be completely dissolved and mixed.
After the intermediate mixture is obtained, the intermediate mixture and bromhexine hydrochloride are mixed, and the pH value is sequentially adjusted and quantified to obtain the bromhexine hydrochloride injection. In the present invention, the agent for adjusting pH is preferably a pH adjuster.
After the quantification, the method preferably further comprises stirring, filtering and detecting in sequence. The rotation speed and the time of the stirring are not particularly limited, and the stirring can be performed only if all substances can be dissolved and mixed. In the present invention, the filtration preferably includes sequentially performing the first filtration and the second filtration. In the present invention, the pore size of the first filtration membrane is preferably 0.45 μm; the pore size of the second filtration membrane is preferably 0.22 μm.
After the bromhexine hydrochloride injection is obtained, the invention preferably also comprises the steps of sequentially detecting, subpackaging, sealing, packaging and sterilizing.
In the present invention, the items to be detected preferably include a trait, a visible foreign substance, and a content of a related substance. In the present invention, the temperature of the sterilization is preferably 121 ℃ and the time is preferably 15 min.
After the sterilization, the invention preferably also comprises the steps of slowly flushing the water by warm water to reduce the temperature,
the invention also provides the bromhexine hydrochloride injection in the technical scheme or the application of the bromhexine hydrochloride injection obtained by the preparation method in the technical scheme in preparing veterinary drugs.
The application mode of the bromhexine hydrochloride injection is not particularly limited, and the operation known by the skilled person in the art is adopted.
The bromhexine hydrochloride injection provided by the invention, the preparation method and the application thereof are explained in detail by combining the examples below, but the preparation method and the application thereof are not to be construed as limiting the protection scope of the invention.
Example 1
10L of bromhexine hydrochloride injection contains: 30g of bromhexine hydrochloride, 7g of methyl p-hydroxybenzoate, 3g of propyl p-hydroxybenzoate, 10g of DL-tartaric acid and the balance of water for injection.
The preparation method of the bromhexine hydrochloride injection for livestock comprises the following steps:
step one, 8L of water for injection is taken, heated, boiled and boiled for 5min, oxygen in the water for injection is removed, and the residual oxygen is controlled to be less than 0.2%. In the process of deoxidization, nitrogen flushing protection is continuously carried out above the liquid preparation tank so as to prevent oxygen from redissolving.
Step two, when the temperature of the deoxygenated injection water is reduced to 80-90 ℃, adding methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, and stirring until the methyl p-hydroxybenzoate and the propyl p-hydroxybenzoate are completely dissolved to obtain a primary mixed material;
step three, when the temperature of the primary mixed material is reduced to 40-50 ℃, adding DL-tartaric acid, adding deoxygenated injection water to nearly full amount, and stirring until the materials are completely dissolved to obtain a secondary mixed material;
adding bromhexine hydrochloride into the mixed material, and stirring until the bromhexine hydrochloride is completely dissolved; adjusting pH to 3.2 with sodium hydroxide, quantifying with deoxygenated water for injection, and stirring for 20 min.
And step five, filtering the mixture by filter elements with the diameters of 0.45 mu m and 0.22 mu m in sequence, and filtering the mixture until the mixture is clear. Informing a site QA to take a semi-finished product for inspection, and checking characters, visible foreign matters, contents and related substances;
and step six, sub-packaging, sealing and packaging the semi-finished products after the semi-finished products are inspected to be qualified, sterilizing at 121 ℃ for 15min, and slowly flushing warm water to cool after sterilization is finished. And (5) warehousing after the finished product is qualified through inspection.
Example 2
The differences from example 1 are: the amount of propyl p-hydroxybenzoate was 3.5g, and the rest was the same as in example 1.
Comparative example 1
The differences from example 1 are: in step 1, nitrogen flushing protection is not carried out above the liquid preparation tank, and the rest is the same as that of the embodiment 1.
Comparative example 2
The differences from example 1 are: the methylparaben was omitted and the process was repeated as in example 1.
The high temperature (60 ℃) test was performed on the bromhexine hydrochloride injection obtained in examples 1 to 2 and comparative examples 1 to 2 according to the established quality standard draft of bromhexine hydrochloride injection, and the results are shown in table 1.
TABLE 1 Performance test results of bromhexine hydrochloride injection obtained in examples 1-2 and comparative examples 1-2
As can be seen from table 1: the bromhexine hydrochloride injection obtained in the embodiment 1 and the embodiment 2 has no obvious difference; compared with the examples 1 and 2, when the bromhexine hydrochloride injection is not filled with nitrogen for protection, the color of the bromhexine hydrochloride is slightly yellowish under the condition of high temperature, related substances are increased, and the content of the bromhexine hydrochloride is slightly reduced. Comparative example 2 compared with examples 1 and 2, the color of bromhexine hydrochloride in the obtained bromhexine hydrochloride injection is deepened under the high temperature condition, which shows that the effect of antisepsis effect is reduced under the high temperature environment after the p-hydroxybenzoic acid methyl ester which is a bactericidal preservative is lacked. The bromhexine hydrochloride injection prepared in the examples 1 and 2 has no obvious change, and all indexes are superior to those of the comparative example 1.
First, influencing factor
Bromhexine hydrochloride injection obtained in example 1 was placed upright and laid flat, and subjected to a strong light irradiation test (with an illumination of 45001x +/-5001 x), a high temperature test (at 60 ℃) and a high humidity test (with a relative humidity of 90%) according to the technical guidance of veterinary drug stability test in the 'Chinese animal pharmacopoeia' 2020 edition, and the results are shown in tables 2 to 3.
TABLE 2 influence factor test results of bromhexine hydrochloride injection (batch number: XBH210702) (front set)
TABLE 3 bromhexine hydrochloride injection influencing factor test results (batch number: XBH210702) (lay flat)
As can be seen from tables 2 and 3: after 10 days, the properties, pH, methyl hydroxybenzoate content, propyl hydroxybenzoate content, bromhexine hydrochloride content and related substances of the bromhexine hydrochloride injection prepared by the invention have no obvious change.
Second, accelerated test
Bromhexine hydrochloride injection obtained in example 1 is sampled at regular time in 0, 1, 2, 3 and 6 months according to the technical guide principle of veterinary drug stability test in the Chinese veterinary pharmacopoeia 2020 edition under the test conditions of 40 +/-2 ℃ and 75 +/-5% RH, and various indexes are determined according to stability investigation items, and the results are shown in tables 4-5.
TABLE 4 acceleration test results of bromhexine hydrochloride injection (open)
TABLE 5 accelerated test results of bromhexine hydrochloride injection (Flat-laying)
As can be seen from tables 4 and 5: the bromhexine hydrochloride injection obtained by the invention is relatively stable under an accelerated condition, which shows that the preparation method of the invention can meet the large-scale production of a GMP workshop, and the prepared sample has relatively good stability.
Three, long term test
Bromhexine hydrochloride injection obtained in example 1 is sampled at regular time in 0, 3 and 6 months according to the technical guide principle of veterinary drug stability test in the Chinese veterinary pharmacopoeia 2020 edition at 25 +/-2 ℃ and RH 60% +/-10% test conditions, and various indexes are determined according to stability examination items, and the results are shown in tables 6-7.
TABLE 6 Long-term test results (positive release) for bromhexine hydrochloride injection
TABLE 7 Long-term test results (Flat placement) for bromhexine hydrochloride injection
As can be seen from tables 6 and 7: the bromhexine hydrochloride injection obtained by the invention is stable under long-term conditions, which shows that the preparation process can meet the large-scale production of GMP workshops, and the prepared sample has good stability.
Fourth, evaluation test of special safety
The bromhexine hydrochloride injection obtained in example 1 was subjected to in vitro hemolysis test of rabbit blood, rabbit muscle irritation test and guinea pig active systemic anaphylaxis test of the prepared bromhexine hydrochloride injection by committing the new drug evaluation center of the pharmaceutical sciences academy of medicine of Shandong province according to the regulations of veterinary drug non-clinical research quality management (GLP) of the Ministry of agricultural rural China.
In the in vitro hemolysis test, substances were added according to the sample adding sequence in table 8, and different amounts of bromhexine hydrochloride injection, 0.9% sodium chloride injection and sterile water for injection were added to the obtained 2% erythrocyte suspension, and the obtained results are shown in fig. 1, fig. 1 is the in vitro hemolysis test result of experimental rabbit erythrocytes, and it can be seen from fig. 1 that: the No. 7 positive control tube has clear and bright red liquid, almost no erythrocyte residue at the tube bottom, and is full-hemolytic blood; no. 6 negative control tube, supernatant was colorless and clear, and erythrocytes gradually settled to the bottom of the tube. The color is bright red, and erythrocytes deposited at the tube bottom can be completely dispersed after being gently shaken, so that hemolysis is avoided; the supernatant of the bromhexine hydrochloride injection tube with the concentrations of No. 1 to No. 5 of rabbit blood erythrocytes is colorless and clear, the erythrocytes gradually sink to the bottom of the tube, and the erythrocytes can be completely dispersed after being lightly shaken, which shows that the rabbit blood erythrocytes have no hemolysis and no erythrocyte agglutination reaction. The bromhexine hydrochloride injection of the invention has no hemolysis.
TABLE 8 sample loading sequence of each tube of the test sample
FIG. 2 shows the results of the muscle stimulation test of the experimental rabbits, as can be seen from FIG. 2: the bromhexine hydrochloride injection has no pathological change on rabbit muscle tissue sections. The bromhexine hydrochloride injection of the invention has no irritation to muscles.
Table 9 shows the results of the systemic anaphylaxis test of the bromhexine hydrochloride injection in guinea pigs.
TABLE 9 results of active systemic anaphylaxis test of guinea pig with bromhexine hydrochloride injection
As can be seen from table 9: allergic reaction of each test article no obvious abnormality and no allergic signs were observed in the negative control guinea pigs within 3h after the challenge injection. The positive control guinea pigs all developed symptoms of allergic reactions within 30min after challenge administration, manifested by nasal itching, coughing, sneezing, piloerection, urination, and eventual cramping. The following conditions were observed after priming of each test group: no obvious abnormality and allergic signs appear in the high and low dose groups and the parallel control group of the test object within 3 hours after the injection is stimulated. The bromhexine hydrochloride injection of the invention has no allergy to guinea pigs. The bromhexine hydrochloride injection has higher safety.
Fifth, biological isosexual test of target animal pig
The bromhexine hydrochloride injection obtained in example 1 was subjected to bioequivalence test in pigs by committing the supervision of veterinary drug feeds in Henan province according to the "quality control protocol for veterinary drug clinical research (GCP) regulation of the Ministry of agricultural rural areas in China. Mean plasma concentrations of bromhexine hydrochloride (reference and test formulations) injected versus time were plotted using graphpad prism 6.0 software, see figure 3.
Adopting WinNonlin 8.1 software bioequivalence analysis module to carry out AUC after natural logarithm conversion0→t、AUC0→∞、CmaxThe data were analyzed for bioequivalence, and the results are shown in tables 10 and 11.
TABLE 10 analysis of variance
TABLE 11 bioequivalence analysis parameters of bromhexine hydrochloride injection test and reference formulations
As can be seen from fig. 3, table 10 and table 11: ln (C) of test and reference formulationsmax)、Ln(AUC0－t) And Ln (AUC)0－∞) All have no significant difference (P is more than 0.05), and the tested preparation Ln (C)max) The 90% confidence interval is 97.70% -107.38%, between the specified 70% -143%; ln (AUC)0－t) The 90% confidence region is 98.29% -105.41%, Ln (AUC)0-∞) The 90% confidence interval is 98.43% -105.11%, and is between 80% -125% of the specification; meets the requirements of 'guidance principle of bioequivalence test of chemical drugs for animals'.
The result of a bioequivalence test shows that the bromhexine hydrochloride injection prepared by the invention has bioequivalence compared with foreign reference preparations, and reaches the domestic advanced level.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The bromhexine hydrochloride injection is characterized in that every 100mL of the bromhexine hydrochloride injection comprises the following components:
0.1-1 g of bromhexine hydrochloride;
0.05-0.1 g of methyl p-hydroxybenzoate;
0.01-0.06 g of propyl p-hydroxybenzoate;
0.1-0.35 g of DL-tartaric acid;
pH regulator and water for injection.
2. The bromhexine hydrochloride injection according to claim 1, wherein the mass ratio of the methyl p-hydroxybenzoate to the propyl p-hydroxybenzoate is 2-2.5: 1.
3. the bromhexine hydrochloride injection according to claim 1 or 2, wherein the pH value of the bromhexine hydrochloride injection is 2.8-3.5.
4. A method for preparing bromhexine hydrochloride injection according to any one of claims 1 to 3, comprising the steps of:
deoxidizing the injection water to obtain deoxidized injection water;
mixing the deoxygenated water for injection, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate to obtain a primary mixed material;
mixing the primary mixed material and DL-tartaric acid, and adding deoxygenated injection water to nearly full volume to obtain a middle mixed material;
and mixing the mixed material with bromhexine hydrochloride, and sequentially adjusting the pH value and quantifying to obtain the bromhexine hydrochloride injection.
5. The production method according to claim 4, wherein the oxygen removal includes:
heating the water for injection to boil;
the heating and boiling time is 5-10 min;
the heating boiling is carried out under the condition of flushing nitrogen.
6. The method according to claim 4 or 5, wherein the oxygen-removed water for injection has a residual oxygen content of 0.05% or less.
7. The preparation method according to claim 4, wherein the temperature of the oxygen-removing water for injection is 70 to 80 ℃ when the oxygen-removing water for injection, the methyl paraben and the propyl paraben are mixed.
8. A preparation method according to claim 4, wherein the temperature of the initial mixture is 40-50 ℃ when the initial mixture and the DL-tartaric acid are mixed.
9. The method of claim 4, wherein the pH adjusting agent comprises sodium hydroxide.
10. Use of bromhexine hydrochloride injection according to any one of claims 1 to 3 or obtained by the preparation method according to any one of claims 4 to 9 for the preparation of veterinary medicaments.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1303992C (en) * | 1987-07-06 | 1992-06-23 | Teva Pharmaceutical Industries Ltd. | Stable injectable solutions of vinca dimer salts |
| CN1411806A (en) * | 2002-09-10 | 2003-04-23 | 南昌亿博医药科技有限公司 | Bromhexine hydrochloride injection and its preparation method |
| 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 |
| 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 |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1303992C (en) * | 1987-07-06 | 1992-06-23 | Teva Pharmaceutical Industries Ltd. | Stable injectable solutions of vinca dimer salts |
| CN1411806A (en) * | 2002-09-10 | 2003-04-23 | 南昌亿博医药科技有限公司 | Bromhexine hydrochloride injection and its preparation method |
| 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 |
| 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 |
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