CN112891300A - Ambroxol hydrochloride injection and preparation method thereof - Google Patents
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Abstract
The invention provides an ambroxol hydrochloride injection and a preparation method thereof, wherein the ambroxol hydrochloride injection comprises 75mg of ambroxol hydrochloride, 16-30mg of pH buffer pair, 0.8-6.2mg of stabilizer and 80-84mg of osmotic pressure regulator, water for injection is added to 10ml, and the pH value of the injection is 4.8-5.2. The preparation method comprises the following steps: regulating temperature and pressure of water for injection, introducing nitrogen, removing residual oxygen by physical means, adding 45-90% of water for injection into pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2; adding the ambroxol hydrochloride with the formula amount, and stirring for dissolving; adding formula amount of stabilizer, osmotic pressure regulator and the rest water for injection, stirring for 10-40min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection during the whole preparation and bottling process, and sterilizing at 121 deg.C for 15 min. The ambroxol hydrochloride injection can effectively promote the elimination of sputum of patients and has small adverse reaction; meanwhile, the storage stability is good, the process is simple and the cost is low.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an ambroxol hydrochloride injection and a preparation method thereof.
Background
Ambroxol Hydrochloride, chemical name: trans-4- [ (2-amino-3, 5-dibromobenzyl) amino ] cyclohexanol hydrochloride of the formula: C13H18Br2N 2O. HCl, molecular weight: 414.57. ambroxol hydrochloride is a new generation of phlegm dissolving agent, is marketed in Germany at the beginning of the 80 th 20 th century, can promote the secretion of lung surfactant, the secretion of airway fluid and ciliary movement, reduce the retention of mucus, can obviously promote sputum excretion and improve respiratory conditions, has definite curative effect and small toxic and side effects, is widely applied to clinic at present, and is marketed in Italy, Switzerland, Argentina, Japan, France, Spain, Singapore, Thailand and other countries in sequence.
The compound is approved to be imported in 1991 in China, is the most powerful of currently clinically known expectorants, and has been used as the first choice drug for the respiratory system to eliminate phlegm. According to the statistics of the IPM data of the medical magic cube, the ambroxol in 7 months to 7 months in 2018 has about 31 hundred million yuan of market scale in the domestic hospital market. The ambroxol hydrochloride injection is suitable for patients who are inconvenient to take orally, reduces the side effect of gastrointestinal tract after administration, and accounts for about 92 percent of market share; is mainly used for the phlegm eliminating treatment of acute and chronic respiratory diseases accompanied with abnormal sputum secretion and phlegm discharging dysfunction in clinic.
When encountering oxidation or alkaline conditions, the ambroxol hydrochloride injection is easy to free ambroxol in the preparation process; the product is easy to degrade when being sterilized at high temperature, exposed to light and placed for a long time, and the conditions of content reduction, related substance increase, even disqualification and the like occur, so that the safety of the product is influenced, and the improvement is also continuously carried out.
The Chinese patent of application No. 201010611335.9 discloses an ambroxol hydrochloride glucose injection and a preparation method thereof, wherein the injection consists of ambroxol hydrochloride, glucose, activated carbon and water for injection; boiling 50% of water for injection, adding glucose for dissolving, adding active carbon for adsorption, and removing carbon; then charging nitrogen, adding ambroxol hydrochloride to dissolve, adding the rest water for injection, cooling to 40-50 deg.C, filtering with 0.22 μm filter membrane, and packaging. The invention has the following defects: the injection water needs to be boiled and nitrogen is introduced for a long time, so that the cost is high; meanwhile, the formula does not contain an antioxidant, and the stability in the storage process is poor.
Chinese patent application No. 201110048193.4 discloses a refining method of injection-grade ambroxol hydrochloride, a product and an injection thereof, wherein ambroxol hydrochloride with the purity of more than 99 percent is taken, 70.2-88 percent ethanol water solution is added into the ambroxol hydrochloride according to the ratio of 1:5.5-9.2, and the mixture is heated, refluxed, dissolved and cooled to be separated out; heating water for injection to 40-50 deg.C, adding refined ambroxol hydrochloride and sodium chloride under stirring, dissolving, adjusting pH to 4.8-5.1, and adding water to full volume; adding 0.1% active carbon, stirring, filtering, fine filtering, and packaging. The invention has the following defects: the ambroxol hydrochloride injection has high requirement on the initial purity of ambroxol hydrochloride, slow dissolving speed, long time consumption and poor stability of the injection under illumination.
The chinese patent application No. 201710574847.4 discloses an ambroxol hydrochloride injection and a preparation method thereof, wherein each ambroxol hydrochloride injection contains: 15mg of ambroxol hydrochloride, 2-4mg of ascorbic acid, 7-10mg of disodium hydrogen phosphate, 15-30mg of sodium chloride, 1.5-3mg of glutathione, 0.5-0.8mg of sodium metabisulfite and 2ml of water for injection. The invention has the following defects: the formula is complex, the using amount of auxiliary materials is large, and the auxiliary materials contain sodium metabisulfite, so that adverse reactions are easily caused; meanwhile, oxides generated by residual oxygen in the water for injection are removed through sodium metabisulfite and glutathione, so that the safety of the final product is difficult to guarantee.
Chinese patent application No. 202011191218.1 discloses a stable ambroxol hydrochloride injection, comprising: 7.5g/L ambroxol hydrochloride, 1.8-2.2 g/L disodium hydrogen phosphate, 0.6-1.8 g/L citric acid, 0.1-0.3 g/L amino acid antioxidant and 0.05-0.1 g/L edetate; adding disodium hydrogen phosphate, citric acid, amino acid antioxidant and edetate into water, dissolving completely, adding ambroxol hydrochloride, dissolving completely, regulating osmotic pressure to isotonic, metering volume, filtering, filling nitrogen, bottling, and sterilizing. The invention has the following defects: the quality requirement on the ambroxol hydrochloride raw material is extremely high, and the used edetate is easy to cause adverse reaction; meanwhile, the amino acid antioxidant reacts with residual oxygen, so that the quality of the product is difficult to control.
Therefore, the preparation of the ambroxol hydrochloride injection with low content of related substances, high stability, high safety and simple formula is a technical problem to be solved by the technical personnel in the field.
Disclosure of Invention
In view of the above, the present invention aims to provide an ambroxol hydrochloride injection and a preparation method thereof, so as to overcome the defects of the prior art, and provide an ambroxol hydrochloride injection with high stability, especially stability under illumination conditions, less impurities and low cost.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
an ambroxol hydrochloride injection comprises 75mg of ambroxol hydrochloride, 16-30mg of pH buffer, 0.8-6.2mg of stabilizer, 80-84mg of osmotic pressure regulator, 10ml of water for injection, and the pH value of the injection is 4.8-5.2.
Preferably, the pH buffer pair is an acid-base buffer pair consisting of salts of weak acid and strong base weak acid root, accounts for 0.16-0.3% of the total amount of the solution, and can be any one or more of citric acid-disodium hydrogen phosphate, citric acid-sodium citrate and phosphoric acid-disodium hydrogen phosphate. Preferably, the weak acid content is 4-12mg/10ml, and the salt content of the weak acid radical of the strong base is 12-18mg/10 ml. Preferably, the pH buffer pair is citric acid-disodium hydrogen phosphate.
Preferably, the stabilizer comprises any one of L-proline, cysteine, methionine and tryptophan.
Preferably, the stabilizer comprises L-proline and glutathione, wherein the content of the L-proline is 0.8-1.2mg/10ml, and the content of the glutathione is 1.5-5.0mg/10 ml.
More preferably, the stabilizer consists of L-proline, glutathione and chitosan selenite, wherein the ratio of L-proline: glutathione: chitosan selenite ═ 8-12: 20: 15. preferably, the chitosan selenite is prepared by the following method: s31, weighing 0.5g of chitosan, adding 100ml of 1.2% (W/V) nitric acid, stirring at 300rpm for 10min, and standing for 10 h; performing nitrogen protection in the reaction; s32, adding 1.1g of barium chloride and 0.3g of selenious acid under ultrasound, heating to 70 ℃, reacting for 20min, and cooling to room temperature; preferably, the ultrasonic conditions are: the power is 5.5kW, and the frequency is 25 kHz; s33, carrying out vacuum filtration, stirring and dripping 20ml of 1.5mol/L sulfuric acid into the filtrate, standing for 5min, and centrifuging at 30 ℃ and 4000rpm for 10 min; s34, taking the supernatant, adjusting the pH value to 6-7, performing ultrafiltration, replacing 15-30 times volume of the supernatant with purified water until 2% (M/M) ascorbic acid solution is detected to have no red color, concentrating under reduced pressure (50 ℃, 0.06Mpa) to 1/10 of the original volume, adding 0.8 times (v/v) ethanol for precipitation, standing for 3h, centrifuging, and freeze-drying the precipitate to obtain the compound. Preferably, the freeze-drying condition is-50 ℃ and 0.01 MPa.
Preferably, the osmotic pressure regulator is sodium chloride or glucose.
A preparation method of ambroxol hydrochloride injection comprises the following steps:
(1) adding 45-90% of water for injection into pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2; preferably, the injection water is used for removing residual oxygen by adopting a physical means through simultaneously regulating and controlling temperature and pressure and introducing nitrogen.
(2) Then adding the ambroxol hydrochloride with the formula amount, and stirring for dissolving; adding formula amount of stabilizer, osmotic pressure regulator and the rest water for injection, and stirring for 10-40 min;
(3) filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 15 min.
Preferably, the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; for example, a vacuum is applied to 0.035 MPa; s12, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, pressurizing, stirring for 30min, and standing to normal temperature and normal pressure for later use. Preferably, the step S11 is vacuumized to 0.035MPa, and the step S12 is aerated with nitrogen to 0.15 MPa.
More preferably, the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; s12, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, and pressurizing and stirring for 30 min; s13, slowly heating to 50-65 deg.C at a speed of 15 deg.C/h, and slowly reducing pressure to 0.015-0.045MPa at a speed of 0.04MPa/h, such as 0.0025MPa, and stirring for 30-60 min; s14, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, simultaneously slowly introducing nitrogen into the stirring kettle at the speed of 0.04Mpa/h, pressurizing to 0.15-0.35Mpa, pressurizing and stirring for 30-70min, and standing to normal temperature and normal pressure for standby.
Preferably, the ambroxol hydrochloride is refined by the following method: s21, mixing ambroxol hydrochloride according to the weight ratio of 1: 10-12 (m/v, g/ml) is added into 75% (v/v) ethanol water solution; s22, heating to 55-60 ℃, and refluxing to fully dissolve; s23, cooling to 20 ℃ within 15-30min, stirring and preserving heat for 1 h; s24, cooling to-5-8 ℃ within 20-40min, standing for 5h, filtering and drying to obtain the product. More preferably, the ambroxol hydrochloride is refined by adopting the following method: s21, mixing ambroxol hydrochloride according to the weight ratio of 1: 10-12 (m/v, g/ml) is added into 75% (v/v) ethanol water solution; s22, heating to 55-60 ℃, adding 1/2-2/3 formula amount of L-proline while stirring, and refluxing to fully dissolve; s23, cooling to 20 ℃ within 20min, stirring and preserving heat for 1 h; s24, cooling to-5-8 ℃ within 20-40min, standing for 5h, filtering and drying to obtain the product.
Compared with the prior art, the ambroxol hydrochloride injection and the preparation method thereof have the following advantages:
(1) the ambroxol hydrochloride injection disclosed by the invention has the advantages that residual oxygen in the solution is removed by a physical method, the use of a chemical antioxidant is avoided, the components are simple, the quality is stable, the generation of impurities in the storage process is reduced, and the adverse reaction rate is low during use; meanwhile, the method avoids the use of less nitrogen, proper heating temperature and low cost; (2) in the preparation process, the pH value is controlled within the range of 4.8-5.2, and the addition sequence of the auxiliary materials L-proline is changed, so that the purity of the ambroxol hydrochloride serving as a raw material is improved; the content of impurities is kept stable and low in the storage period, and the stability and safety of the product are high; (3) during production, the pH buffer pair is dissolved in water for injection, the pH of the solution is adjusted to be acidic, and degradation caused by the reaction of acidic ambroxol hydrochloride and alkaline disodium hydrogen phosphate in the preparation process is avoided.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
Although the ambroxol hydrochloride injection has obvious clinical curative effect, the safety and quality problems are frequently reported. The existing ambroxol hydrochloride injection still has certain potential safety hazard and has more adverse reaction cases. The safety of the preparation is influenced by the technical process and the stability of the preparation; specifically, the technological process determines the amount of impurities in the preparation and the production cost, and the quality of the stability determines whether new impurities are generated. In the prior art, the main medicine degradation caused by pH fluctuation can be avoided by controlling the feeding sequence; in addition, nitrogen is introduced in the whole process to form separation between the atmosphere (oxygen molecules) and the preparation solution and/or auxiliary materials such as glutathione, sodium metabisulfite and the like are added to consume residual oxygen in the preparation by a chemical method, so that degradation can be effectively avoided, and the stability is improved; however, the above method also has certain disadvantages.
Meanwhile, the applicant found in the research that: the ambroxol hydrochloride injection has poor stability under the illumination condition, especially under the condition of synergistic action of illumination and temperature. The present invention will be described in detail with reference to examples, in which the purity of ambroxol hydrochloride as a raw material is 99.1%.
Example 1
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 14mg of sodium citrate, 4mg of citric acid, 0.8mg of methionine and 10ml of water for injection.
The preparation method comprises the following steps: (1) taking 75% of injection water according to formula amount, adding sodium citrate and citric acid according to formula amount, stirring at 150rpm for 15min to completely dissolve, and controlling pH to be 4.8; (2) then adding ambroxol hydrochloride with the formula amount, and stirring at 200rpm for 25 min; (3) adding methionine and the rest water for injection, stirring for 30min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 15 min.
Example 2
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 12mg of phosphoric acid, 90mg of sodium chloride, 1.2mg of cysteine and 10ml of water for injection.
The preparation method comprises the following steps: (1) taking 85% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and phosphoric acid, stirring at 200rpm for 10min to completely dissolve, and controlling pH to 4.9; (2) then adding ambroxol hydrochloride with the formula amount, and stirring for 30min at 150 rpm; (3) adding cysteine, sodium chloride and the rest water for injection, stirring for 35min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 15 min.
Example 3
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline and 10ml of water for injection.
The preparation method comprises the following steps: (1) taking 65% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 180rpm for 12min to completely dissolve, and controlling pH to 4.9; (2) then adding ambroxol hydrochloride with the formula amount, and stirring at 160rpm for 25 min; (3) adding L-proline, glucose and the rest water for injection, stirring for 25min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 15 min.
Example 4
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline and 10ml of water for injection.
The same procedure as in example 3 was repeated except that the injection water for the ambroxol hydrochloride injection was pretreated. Specifically, the pretreatment specifically comprises: pre-filling nitrogen into the stirring kettle, adding water for injection, heating to 65 deg.C, vacuumizing to 0.035Mpa, and stirring under reduced pressure for 30 min; slowly cooling to 4 deg.C at a speed of 10 deg.C/h, introducing nitrogen gas to 0.15Mpa, pressurizing, stirring for 30min, and standing at normal temperature and normal pressure.
Example 5
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline and 10ml of water for injection.
The same procedure as in example 3 was repeated except that the injection water for the ambroxol hydrochloride injection was pretreated. Specifically, the pretreatment specifically comprises: pre-filling nitrogen into the stirring kettle, adding water for injection, heating to 55 deg.C, vacuumizing to 0.035Mpa, and stirring under reduced pressure for 45 min; slowly reducing the temperature to 8 ℃ at the speed of 10 ℃/h, introducing nitrogen into the stirring kettle to 0.15Mpa, and stirring for 30min under pressure; slowly heating to 65 deg.C at 15 deg.C/h, slowly reducing pressure to 0.025MPa at 0.04MPa/h, stirring for 40min, slowly reducing temperature to 4 deg.C at 10 deg.C/h, slowly introducing nitrogen gas into the stirring kettle at 0.04MPa/h to pressurize to 0.15MPa, stirring under pressure for 30min, and standing at room temperature and normal pressure.
Example 6
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline, 3.5mg of glutathione and 10ml of water for injection.
The preparation method comprises the following steps: (1) the method of example 5 was used to pretreat water for injection; (2) taking 70% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 170rpm for 15min to completely dissolve, and controlling pH to 4.9; (2) then adding ambroxol hydrochloride with the formula amount, and stirring for 25min at 180 rpm; (3) adding L-proline, glutathione, glucose and the rest water for injection, stirring for 35min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection during the whole preparation and bottling process, and sterilizing at 121 deg.C for 15 min.
Example 7
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline, 7.5mg of glutathione and 10ml of water for injection.
The preparation method of this example is the same as example 6, and is not described herein again.
Example 8
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline, 3.5mg of glutathione and 10ml of water for injection.
The preparation method comprises the following steps: (1) the method of example 5 was used to pretreat water for injection; (2) refining ambroxol hydrochloride, namely S21, and mixing ambroxol hydrochloride (purity 99.1%) according to the weight ratio of 1: 10(m/v, g/ml) of ethanol aqueous solution of 75% (v/v); s22, heating to 60 ℃, and refluxing to fully dissolve; s23, cooling to 20 ℃ within 20min, stirring and preserving heat for 1 h; cooling to-6 deg.C within 30min, standing for 5 hr, filtering, and drying; (3) taking 70% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 170rpm for 15min to completely dissolve, and controlling pH to 4.9; (4) adding the ambroxol hydrochloride crystal prepared in the step (2), and stirring at 180rpm for 25 min; (5) adding L-proline, glutathione, glucose and the rest water for injection, stirring for 35min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection during the whole preparation and bottling process, and sterilizing at 121 deg.C for 15 min.
Example 9
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline, 3.5mg of glutathione and 10ml of water for injection.
The preparation method comprises the following steps: (1) the method of example 5 was used to pretreat water for injection; (2) refining ambroxol hydrochloride, namely S21, and mixing ambroxol hydrochloride (purity 98.0%) according to the proportion of 1: 11(m/v, g/ml) was added 75% (v/v) ethanol aqueous solution; s22, heating to 60 ℃, adding 2/3 formula amount of L-proline while stirring, and refluxing to fully dissolve; s23, cooling to 20 ℃ within 20min, stirring and preserving heat for 1 h; cooling to-5 deg.C within 30min, standing for 5 hr, filtering, and drying; (3) taking 70% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 170rpm for 15min to completely dissolve, and controlling pH to 4.9; (4) then adding the ambroxol hydrochloride eutectic compound prepared in the step (2), and stirring at 180rpm for 25 min; (5) adding glutathione, glucose, rest water for injection and rest 1/3L-proline, stirring for 35min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection during the whole preparation and bottling process, and sterilizing at 121 deg.C for 15 min.
Example 10
An ambroxol hydrochloride injection contains 75mg of ambroxol hydrochloride, 18mg of disodium hydrogen phosphate, 8mg of citric acid, 100mg of glucose, 1.0mg of L-proline, 1.5mg of chitosan selenite and 2.0mg of glutathione, and the volume of water for injection is increased to 10 ml.
Wherein the chitosan selenite is prepared by the following method: (1) weighing 0.5g chitosan (purity 92.5%), adding 1.2% (W/V) nitric acid to dissolve 100ml, stirring at 300rpm for 10min, and standing for 10 h; performing nitrogen protection in the reaction; (2) adding 1.1g of barium chloride and 0.3g of selenious acid under ultrasound, heating to 70 ℃, reacting for 20min, and cooling to room temperature; wherein the ultrasonic conditions are as follows: the power is 5.5kW, and the frequency is 25 kHz. (3) Vacuum filtering, stirring the filtrate, adding 1.5mol/L sulfuric acid 20ml dropwise, standing for 5min, centrifuging at 30 deg.C and 4000rpm for 10 min; (4) adjusting the pH of the supernatant to 6-7, performing ultrafiltration, replacing 18 times volume of the supernatant with purified water to 2% (M/M) ascorbic acid solution, detecting no red color, concentrating under reduced pressure (50 ℃, 0.06Mpa) to 1/10 of the original volume, adding 0.8 times (v/v) ethanol for precipitation, standing for 3h, centrifuging, and freeze-drying the precipitate at-50 ℃ and 0.01MPa to obtain the compound;
the chitosan selenite and the glutathione are added in the step (5), and other preparation methods are the same as those of the example 9 and are not repeated herein.
Comparative example 1
The ambroxol hydrochloride injection is prepared by adopting the formula and the preparation method of the embodiment 1 in the Chinese patent with the application number of 201710574847.4.
Comparative example 2
The ambroxol hydrochloride injection is prepared by adopting the formula and the preparation method of the embodiment 1 in the Chinese patent with the application number of 201010611335.9.
Comparative example 3
The ambroxol hydrochloride injection is prepared by the method described in paragraph 0039-0044 of the Chinese patent with the application number 201110048193.4.
Experimental example 1 illumination stability experiment
Ambroxol hydrochloride injection prepared in examples 1-10 and comparative examples 1-3 is taken, placed in a clean container, placed under the conditions of the illumination of 4500lx and the temperature of 30 +/-0.5 ℃ for 30 days, sampled on the 15 th day and the 30 th day, tested according to the stability focus item, and the results are compared with 0 day and shown in tables 1 and 2.
TABLE 1 Effect of light conditions on the stability of the injections prepared in examples 1-7
TABLE 2 Effect of light conditions on the stability of the injections prepared in examples 8 to 10 and comparative examples 1 to 3
The applicant finds in research that the stability of the ambroxol hydrochloride injection is poor, particularly the stability under the strong light condition, and impurities are generated to easily cause poor safety of the medicine and even cause medical accidents. Two impurity sources are analyzed, one of the two impurity sources is the raw material, namely the residual impurity of the ambroxol hydrochloride after being refined, and the impurities are usually removed by refining for many times or multiple steps; therefore, the injection ambroxol hydrochloride injection has extremely high requirements on raw materials, and the additional refining operation increases the production cost; secondly, the ambroxol hydrochloride injection is newly generated under the conditions of light, heat and the like in the storage process, wherein the ambroxol hydrochloride in the solution is also unstable to oxygen; the stability is generally improved by utilizing a nitrogen barrier solution to contact with oxygen and/or adding antioxidants such as sodium metabisulfite, ascorbic acid, nicotinamide and the like in the production process to consume residual oxygen in the solution; however, other added components easily cause adverse reactions of patients, and the stability of the medicine is difficult to control.
In order to further improve the stability of the ambroxol hydrochloride injection, particularly the stability under strong light and avoid the generation of related impurities, the applicant firstly optimizes the formula of the ambroxol hydrochloride injection, and a large number of experiments show that: compared with other amino acids, the L-proline can improve the stability of the ambroxol hydrochloride injection, meanwhile, the components are simple, the product quality (pH and appearance) is easy to control, and finally, the stability under the illumination condition is equivalent to that of the comparative example 1 on the premise of not adding other antioxidants; the applicant further studied and found that the residual oxygen content in the solution can be effectively removed by pretreating the water for injection by controlling the temperature and pressure, and the stability of the solution can be improved by a physical method on the premise of avoiding using a chemical antioxidant (see example 4). Meanwhile, as the number of pretreatments of the water for injection increases, the residual oxygen content in the solution further decreases and the stability of the sample improves (example 5). On the basis, the applicant further studies the formula of the ambroxol hydrochloride injection, and finds that a small amount of glutathione can further improve the stability of the ambroxol hydrochloride injection (examples 6 and 7), and the combination and matching effect of the glutathione and chitosan selenite is the best (example 10), and the possible reason is that the glutathione is polypeptide and can play a role in protecting the ambroxol hydrochloride; the chitosan selenite has strong oxidation resistance, further consumes trace residual oxygen in water, and avoids the oxidative degradation of ambroxol hydrochloride.
In addition, the applicant researches the refining process of ambroxol hydrochloride and unexpectedly finds that: further impurities can be removed by refining operations; part of L-proline is added in the crystals, and the L-proline and the ambroxol hydrochloride form a crystal material which is regularly arranged in the same crystal lattice through a certain acting force possibly in the crystallization process, and a eutectic phenomenon exists between the L-proline and the ambroxol hydrochloride, so that the refining effect is better, and the purity of the ambroxol hydrochloride is improved; the addition sequence of the auxiliary material L proline is only changed in the production, and the operation is simple. As can be seen from tables 1 and 2, the residual oxygen content in the ambroxol hydrochloride injection is reduced by a physical method, the generation of new impurities is reduced, and the stability of the injection is improved; meanwhile, the feeding sequence of the auxiliary materials is changed, so that the content of impurities in the raw materials is reduced, and the storage stability and the medication safety of the medicine are improved together.
Experimental example 2 product stability test
The ambroxol hydrochloride injection of the examples 3,5, 6, 9 and 10 and the comparative examples 1-2 are subjected to an accelerated test, the accelerated test conditions are 40 ℃, 75% RH, the ambroxol hydrochloride injection is placed for 6 months, samples are taken at 0 th, 2 th, 4 th and 6 th months respectively, the properties, pH, related substances and contents of the ambroxol hydrochloride injection are detected, the detection methods of the related substances and contents refer to the contents of the ambroxol hydrochloride injection in the second department of Chinese pharmacopoeia 2015 edition, and the test results are shown in Table 3.
TABLE 3 accelerated test results of ambroxol hydrochloride injection
As can be seen from Table 3, the ambroxol hydrochloride injection prepared by the method has good stability.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention, and any person skilled in the art can make equivalents or changes in the technical solutions and concepts of the present invention within the technical scope of the present invention.
Claims (9)
1. An ambroxol hydrochloride injection is characterized by comprising 75mg of ambroxol hydrochloride, 16-30mg of pH buffer, 0.8-6.2mg of stabilizer, 80-84mg of osmotic pressure regulator, 10ml of water for injection and 4.8-5.2 of injection pH value.
2. The ambroxol hydrochloride injection according to claim 1, wherein the pH buffer pair is an acid-base buffer pair consisting of a salt of a weak acid and a weak base, wherein the weak acid content is 4-12mg/10ml and the weak base salt content is 12-18mg/10 ml.
3. The ambroxol hydrochloride injection according to claim 1, wherein the stabilizer comprises any one of L-proline, cysteine, methionine and tryptophan.
4. The ambroxol hydrochloride injection as claimed in claim 3, wherein the stabilizer comprises L-proline and glutathione, the content of the L-proline is 0.8-1.2mg/10ml, and the content of the glutathione is 1.5-5.0mg/10 ml.
5. The preparation method of the ambroxol hydrochloride injection is characterized by comprising the following steps:
(1) adding 45-90% of water for injection into pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2; (2) then adding the ambroxol hydrochloride with the formula amount, and stirring for dissolving; adding formula amount of stabilizer, osmotic pressure regulator and the rest water for injection, and stirring for 10-40 min; (3) filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 15 min.
6. The method for preparing ambroxol hydrochloride injection according to claim 5, characterized in that the injection water in step (1) is subjected to physical means to remove residual oxygen by simultaneously controlling temperature and pressure and introducing nitrogen.
7. The method for preparing ambroxol hydrochloride injection according to claim 6, characterized in that the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; (ii) a S12, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, pressurizing, stirring for 30min, and standing to normal temperature and normal pressure for later use.
8. The method of claim 7, wherein the vacuum in step S11 is reduced to 0.035MPa, and the nitrogen gas is introduced into step S12 to 0.15 MPa.
9. The method for preparing ambroxol hydrochloride injection according to claim 5, characterized in that the ambroxol hydrochloride in the step (2) is refined by the following method: s21, mixing ambroxol hydrochloride according to the weight ratio of 1: 10-12 (m/v, g/ml) is added into 75% (v/v) ethanol water solution; s22, heating to 55-60 ℃, and refluxing to fully dissolve; s23, cooling to 20 ℃ within 15-30min, stirring and preserving heat for 1 h; s24, cooling to-5-8 ℃ within 20-40min, standing for 5h, filtering and drying to obtain the product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113425678A (en) * | 2021-08-04 | 2021-09-24 | 珠海润都制药股份有限公司 | Higenamine hydrochloride injection 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 |
| CN114767628A (en) * | 2022-05-17 | 2022-07-22 | 海南灵康制药有限公司 | Stable ambroxol hydrochloride injection and preparation method thereof |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000007561A (en) * | 1998-06-18 | 2000-01-11 | Nissho Corp | Ambroxol hydrochloride aqueous solution preparation |
| CN101104643A (en) * | 2006-07-14 | 2008-01-16 | 陈艺新 | Polysaccharide sulfate selenide compound and its preparation method and application |
| CN101104644A (en) * | 2006-07-14 | 2008-01-16 | 陈艺新 | Preparation for polysaccharide selenite and application thereof |
| CN101836952A (en) * | 2010-06-09 | 2010-09-22 | 云南龙海天然植物药业有限公司 | Ambroxol injection and preparation method thereof |
| CN102153482A (en) * | 2011-02-28 | 2011-08-17 | 天津市铭泰医药科技有限公司 | Method for refining injection-level ambroxol hydrochloride, product and injection thereof |
| CN102302489A (en) * | 2011-07-14 | 2012-01-04 | 青岛华仁药业股份有限公司 | Preparation method of compound amino acid injection |
| CN102552119A (en) * | 2010-12-28 | 2012-07-11 | 四川科伦药物研究有限公司 | Ambroxol hydrochloride glucose injection and preparation method thereof |
| CN103897069A (en) * | 2014-03-13 | 2014-07-02 | 杭州世博生物技术开发研究所有限公司 | Method capable of improving selenium content for preparing polysaccharide selenite |
| CN107519127A (en) * | 2017-08-08 | 2017-12-29 | 遂成药业股份有限公司 | A kind of ambroxol hydrochloride injection and preparation method thereof |
| CN109369735A (en) * | 2018-11-30 | 2019-02-22 | 湖南泽迈生物科技有限公司 | A kind of preparation method and application of six-carbon monosaccharide selenous acid ester type compound |
| CN110151688A (en) * | 2019-05-17 | 2019-08-23 | 石家庄学院 | A kind of ambroxol hydrochloride injection composition and preparation method thereof |
| CN111544421A (en) * | 2020-05-25 | 2020-08-18 | 朗天药业(湖北)有限公司 | Ambroxol hydrochloride solution for inhalation and preparation method thereof |
-
2021
- 2021-01-28 CN CN202110118556.0A patent/CN112891300B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000007561A (en) * | 1998-06-18 | 2000-01-11 | Nissho Corp | Ambroxol hydrochloride aqueous solution preparation |
| CN101104643A (en) * | 2006-07-14 | 2008-01-16 | 陈艺新 | Polysaccharide sulfate selenide compound and its preparation method and application |
| CN101104644A (en) * | 2006-07-14 | 2008-01-16 | 陈艺新 | Preparation for polysaccharide selenite and application thereof |
| CN101836952A (en) * | 2010-06-09 | 2010-09-22 | 云南龙海天然植物药业有限公司 | Ambroxol injection and preparation method thereof |
| CN102552119A (en) * | 2010-12-28 | 2012-07-11 | 四川科伦药物研究有限公司 | Ambroxol hydrochloride glucose injection and preparation method thereof |
| CN102153482A (en) * | 2011-02-28 | 2011-08-17 | 天津市铭泰医药科技有限公司 | Method for refining injection-level ambroxol hydrochloride, product and injection thereof |
| CN102302489A (en) * | 2011-07-14 | 2012-01-04 | 青岛华仁药业股份有限公司 | Preparation method of compound amino acid injection |
| CN103897069A (en) * | 2014-03-13 | 2014-07-02 | 杭州世博生物技术开发研究所有限公司 | Method capable of improving selenium content for preparing polysaccharide selenite |
| CN107519127A (en) * | 2017-08-08 | 2017-12-29 | 遂成药业股份有限公司 | A kind of ambroxol hydrochloride injection and preparation method thereof |
| CN109369735A (en) * | 2018-11-30 | 2019-02-22 | 湖南泽迈生物科技有限公司 | A kind of preparation method and application of six-carbon monosaccharide selenous acid ester type compound |
| CN110151688A (en) * | 2019-05-17 | 2019-08-23 | 石家庄学院 | A kind of ambroxol hydrochloride injection composition and preparation method thereof |
| CN111544421A (en) * | 2020-05-25 | 2020-08-18 | 朗天药业(湖北)有限公司 | Ambroxol hydrochloride solution for inhalation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 顾健: "盐酸氨溴索注射液的制备工艺路线研究", 《临床药学》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113425678A (en) * | 2021-08-04 | 2021-09-24 | 珠海润都制药股份有限公司 | Higenamine hydrochloride injection and preparation method thereof |
| CN113425678B (en) * | 2021-08-04 | 2023-02-10 | 珠海润都制药股份有限公司 | Higenamine hydrochloride injection 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 |
| CN114767628A (en) * | 2022-05-17 | 2022-07-22 | 海南灵康制药有限公司 | Stable ambroxol hydrochloride injection and preparation method thereof |
| CN114767628B (en) * | 2022-05-17 | 2024-01-12 | 海南灵康制药有限公司 | Stable ambroxol hydrochloride injection and preparation method thereof |
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