CN102924302A - Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride - Google Patents
Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride Download PDFInfo
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Abstract
The invention relates to a method for refining injection-grade ambroxol hydrochloride. The method is characterized by comprising the steps of adding oral-taking-grade ambroxol hydrochloride with the proportion smaller than or equal to 20:1 into ethanol water solution with the volume ratio of 5-20%; performing heating to completely dissolve the oral-taking-grade ambroxol hydrochloride; stopping heating and performing cooling to seed out ambroxol hydrochloride; and filtering solvent to obtain crystals and drying the crystals to obtain the injection-grade ambroxol hydrochloride. The invention further relates to ambroxol hydrochloride solution for inhalation prepared by utilizing the prepared injection-grade ambroxol hydrochloride as the raw material. The atomization inhalation solution comprises the ambroxol hydrochloride, a stabilizer, a pH conditioning agent and an osmotic pressure conditioning agent. By means of the scientific preparation adopting the carrier, fewest degradation products of the atomization inhalation preparation can be produced under the high temperature of 121 DEG C for 15 minutes, the atomization inhalation preparation is stable, and the service life of the atomization inhalation preparation is prolonged to 5 years.
Description
Technical field
Process for refining and purifying that the present invention relates to injection stage Ambroxol HCl bulk drug and products thereof reaches to be used.
The present invention relates to a kind of suction Ambroxol HCl solution and its production and use.
Background technology
Ambroxol HCl (Ambroxol Hydrochloride) is respiratory mucus conditioning agent of new generation, has another name called AMB, eliminates the phlegm and improve the characteristics such as the pulmonary function effect is strong to be widely used in clinical.This medicine can act on secretory cell, regulates the secretion of slurries and mucus, and serous secretion is increased, the mucus dissolved dilution, and can strengthen the swing of cilium, and increase the removing ability of mucus haulage system, make sputum be easy to discharge.Ambroxol HCl also is a kind of respiratory system protective material, has anti-oxidant, inflammation-inhibiting medium release, and lax airway smooth muscle promotes the effects such as synthetic and secretion of pulmonary surfactant.Ambroxol HCl can also increase the drug level of microbiotic in air flue, thereby improves antibiotic curative effect.
Ambroxol HCl:
English name: Ambroxol Hydrochloride
Chemical name: trans-4-[(2-amino 3, the 5-dibromo-benzyl) amino] the hexalin hydrochloride
Molecular formula: C
13H
18Br
2N
2OHCl
Structural formula:
HCl
The Ambroxol HCl preparation of selling in the market has oral preparations and injection two large types, wherein, injection liquid divides import and domestic two kinds, the validity period of Imported Ambroxol Hydrochloride injection liquid is 5 years, the injection liquid validity period that the validity period of domestic ambroxol hydrochloride injection only had have in 2 years even only be 1 year.Why like this, be because the related substance growth in the inhalation is too fast, the scope that is above standard (total impurities must not cross 1.0%).In addition, at present commercially available Ambroxol HCl raw material impurity content is generally higher, and as injection formulations, if the content height of impurity is then very likely introduced unknown side effect, therefore how reducing dopant species and content is to be worth problems to discuss.
Result of study shows: ultrasonic atomizatio makes the atomized liquid that is added with Ambroxol HCl produce the following uniform aerosol particles of diameter 5 m by the high frequency oscillation of ultra-sonic generator film, with the whole last tracheae of dark air-breathing arrival and alveolar.Can regulate at any time mist amount size and temperature during operation, avoid causing that the patient is uncomfortable, make medicine reach better curative effect.
The atomizing suction can not only make the sputum dilution, is easy to discharge, and removes bronchospasm, and also wettable respiratory tract reduces stimulation, and normal function and the control respiratory inflammation of keeping the respiratory mucosa ciliated epithelial cell played an important role.The medicine that sucks can reach in tip segmental bronchus, the alveolar, except to the local generation effect of respiratory tract, also can produce the general curative effect by the lung tissue absorption.
It is the discharge that safely, effectively promotes patient's sputum that the Ambroxol HCl ultrasonic atomizatio sucks, and accelerates the improvement of symptom, sign, improves a kind of effective clinical assist measure of curative ratio, does not have simultaneously obvious adverse reaction, and clinic is promoted.
Find by the investigation to hospital and doctor, the clinical Ambroxol HCl fog inhalation therapy of needing badly, at present domestic not Ambroxol HCl atomizing sucks proprietary formulation listing.Hospital adopts injection usually, be used for the atomization inspiration treatment respiratory system disease, but only be given for intravenous injection in the ambroxol hydrochloride injection specification sheets, this type of usage is to have indication externally applied agent, research data to lack and all multi-risk Systems such as usage and dosage is indefinite, therefore, the atomizing of Ambroxol HCl sucks and can satisfy the clinical application tight demand with the exploitation of pharmaceutical solutions.
Summary of the invention
First purpose of the present invention is to overcome the deficiencies in the prior art, and a kind of process for purification of injection stage Ambroxol HCl is provided, and improves the purity of existing Ambroxol HCl raw material, and while method is simple and feasible.
Second purpose of the present invention provides a kind of suction Ambroxol HCl solution, improves its stability with extension of validity to 5 year; Improve simultaneously the quality of medicine and the security in the clinical use thereof.
First purpose of the present invention is achieved in that
According to " physico-chemical property that the Ambroxol HCl quality standard is put down in writing among Chinese pharmacopoeia version in 2010 and the EP7.0: Ambroxol HCl dissolves in methyl alcohol, and is slightly molten in water, slightly soluble in ethanol.The inventor is surprised to find that Ambroxol HCl is heating back under the condition of heating up in a steamer in the aqueous ethanolic solution of 5%～20% weightmeasurement ratio more soluble, and at easy crystallization of when cooling.
The process for purification concrete steps of injection stage Ambroxol HCl are as follows:
(1) with oral grade hydrochloric acid Transbroncho with the aqueous ethanolic solution of 5%～20% volume ratio heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this aqueous ethanolic solution fully, described solvent compares less than or equal to 20:1 with the volume mass of Ambroxol HCl, and Heating temperature is 60～100 ℃; The unit of described solvent is ml, and the unit of Ambroxol HCl is g;
(2) add gac, the add-on of gac is the 0%-5% of Ambroxol HCl quality;
(3) charcoal, then heat filtering are taken off in heating;
(4) above-mentioned filtrate is left standstill be placed in-4～30 ℃ of environment to room temperature and carried out crystallization, then filter, collect filter cake;
(5) above-mentioned filter cake oven dry is namely got product;
Described Ambroxol HCl is Transbroncho, tartrate Transbroncho, Hydrogen bromide Transbroncho and other pharmacologically acceptable salt.
Described solvent is the aqueous ethanolic solution of 5%～20% volume ratio
Described crystallization is stirring and crystallizing or naturally leaves standstill crystallization; Or adding crystal seed; Recrystallization temperature is-4 ℃～30 ℃.
Described solvent is 3:1-20 with the volume mass ratio of Ambroxol HCl: 1.
Described solvent is 5:1-12 with the volume mass ratio of Ambroxol HCl: 1.
The invention has the beneficial effects as follows the purity that has greatly improved Ambroxol HCl, reduced owing to there is the untoward reaction that causes in impurity, Ambroxol HCl after refining namely can be applicable to injection, also can be applicable to oral liquid or sucks with other drug formulations such as solution.
Second purpose of the present invention is achieved in that
The invention provides a kind of suction with Ambroxol HCl solution liquid, take the injection stage Ambroxol HCl as activeconstituents, with the stable form pharmaceutical composition of pharmaceutically acceptable carrier composition.Particularly, be exactly by active ingredient hydrochloric acid Transbroncho, stablizer, pH adjusting agent, osmotic pressure regulator forms.Under aqueous solution state, its pH value is 4.0-7.0 to preparation of the present invention (suck and use Ambroxol HCl solution).
Suction of the present invention with the stablizer of Ambroxol HCl solution be selected from Citric Acid, lactic acid, cysteine hydrochloride is a kind of or wherein several combination.
Suction of the present invention is to be selected from sodium hydroxide with the pH adjusting agent of Ambroxol HCl solution, yellow soda ash, a kind of or wherein several combination of calcium hydroxide.
Suction of the present invention is to be selected from a kind of of sodium-chlor, calcium chloride, Repone K or wherein several combination with the osmotic pressure regulator of Ambroxol HCl solution.
Suction of the present invention is 0.5 – 20mg/ml with Ambroxol HCl solution Chinese traditional medicine concentration
Among the preparation method of suction of the present invention with Ambroxol HCl solution, dissolve first Ambroxol HCl, press conditioning agent and stablizer at solution pervasion, be conducive to the dissolving of Ambroxol HCl, overcome the slightly water-soluble defective of Ambroxol HCl.
Among the preparation method of suction of the present invention with Ambroxol HCl solution, add the liquid preparation withstand high temperatures sterilization that stablizer can make Ambroxol HCl, the preparation nature after the sterilization is stable, does not produce other degraded products.
Among the preparation method of suction of the present invention with Ambroxol HCl solution, the pH after the dissolving is adjusted in 4.0-7.0, can makes Ambroxol HCl more stable, do not degrade, do not produce other degradation products.
Among the preparation method of suction of the present invention with Ambroxol HCl solution, add Medicinal Charcoal amount 0.01%-0.2%(W/V) time, less to the absorption of main ingredient, and can effectively remove thermal source again.
Among the preparation method of suction of the present invention with Ambroxol HCl solution, the processing condition of sterilization steps are 115 ℃-121 ℃, pressure sterilizing 8-50 minute, and make the sterility assurance level of product reach the F0 value for 10-30, make product reach aseptic assurance requirement.
It is as follows that suction of the present invention prepares concrete steps with Ambroxol HCl solution:
Prescription forms: Ambroxol HCl 2.0% – 0.01%, stablizer 0.01% – 3.0%, pH adjusting agent 0.01% – 13%, osmotic pressure regulator 0.1% – 3.0%, water for injection 80% – 98%;
Method steps: add the water for injection of recipe quantity 50%～80% in liquid dispensing container, temperature adds the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again osmotic pressure regulator and the stablizer of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 4.0-7.0 with the pH adjusting agent of 0.2M – 1M; Add Medicinal Charcoal 0.1%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 1ml or 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Suction of the present invention is 5 years with Ambroxol HCl solution validity period
Compared with prior art, the present invention becomes the Ambroxol HCl feed purification of oral level the Ambroxol HCl raw material of injection stage, and purity reaches more than 99.97%; And the present invention is refining, purifying technique safety, and the Ambroxol HCl proterties does not present variation.The present invention is easy and simple to handle, cost is lower, do not need specific installation, the Ambroxol HCl raw material that is highly suitable in the large-scale industrial production injection stage produced through the inventive method has significantly increased the stability that sucks with Ambroxol HCl solution-with extension of validity to 5 year; Improve simultaneously the quality of medicine, guaranteed the security of medication.
Embodiment:
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 5% volume ratio of 700ml, bath temperature 90-100 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, heating and filtering (use suction filtration) is then collected filtrate and is also left standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization and (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, the gained filter cake namely gets product with oven drying.
Embodiment 2: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 5% volume ratio of 1200ml, bath temperature 60-80 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, add gac, the add-on of gac is 5% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
Embodiment 3: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 10% volume ratio of 500ml, bath temperature 80-95 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, add gac, the add-on of gac is 3% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
Embodiment 4: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 10% volume ratio of 1100ml, bath temperature 60-80 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, add gac, the add-on of gac is 5% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
Embodiment 5: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 20% volume ratio of 400ml, bath temperature 80-100 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, add gac, the add-on of gac is 5% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
Embodiment 6: the preparation of injection stage Ambroxol HCl
The Ambroxol HCl that takes by weighing 100g places there-necked flask, adds the aqueous ethanolic solution of 20% volume ratio of 1000ml, bath temperature 60-80 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this solvent fully; Stopped heating, add gac, the add-on of gac is 5% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
Embodiment 7: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 17.2g |
| Citric Acid | 1.0g |
| 0.2M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 1000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the Citric Acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.0-5.5 with the 0.2M sodium hydroxide solution; Add Medicinal Charcoal 0.01%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 8: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 14g |
| Lactic acid | 1.1g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 1000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the lactic acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 4.5-5.0 with the 0.5M sodium hydroxide solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 9: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 17g |
| Cysteine hydrochloride | 0.9g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 1000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the cysteine hydrochloride of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.5-6.0 with the 0.5M sodium hydroxide solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 10: suck the preparation with Hydrogen bromide Transbroncho solution
| Prescription Hydrogen bromide Transbroncho | 15.0g |
| Sodium-chlor | 17g |
| Citric Acid | 0.9g |
| 0.5M sodium carbonate solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add recipe quantity Hydrogen bromide Transbroncho, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the Citric Acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.5-6.0 with the 0.5M sodium carbonate solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 11: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 18.0g |
| Citric Acid | 0.9g |
| 0.2M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the Citric Acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.0-5.5 with the 0.2M sodium hydroxide solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 1ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 12: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 16.8g |
| Lactic acid | 1.0g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the lactic acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 4.5-5.0 with the 0.5M sodium hydroxide solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 1ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 13: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 17g |
| Cysteine hydrochloride | 1.1g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
The water for injection that adds recipe quantity 50%～80% in liquid dispensing container, temperature add the recipe quantity Ambroxol HCl, after the stirring and dissolving at 55～85 ℃; Add again again sodium-chlor and the cysteine hydrochloride of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.5-6.0 with the 0.5M sodium hydroxide solution; Add Medicinal Charcoal 0.05%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 1ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 14: suck the preparation with Ambroxol HCl solution
| The prescription Ambroxol HCl | 15.0g |
| Sodium-chlor | 17.8g |
| Lactic acid | 1.1g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
Get recipe quantity water for injection 80%, temperature adds the Ambroxol HCl of recipe quantity, after the stirring and dissolving at 55-85 ℃; Add again again sodium-chlor and the lactic acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.0-5.5 with the sodium hydroxide solution of 0.5M; Add Medicinal Charcoal 0.1%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; With every 1ml embedding; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
Embodiment 15: suck the preparation with tartrate Transbroncho solution
| Prescription tartrate Transbroncho | 15.0g |
| Sodium-chlor | 18g |
| Lactic acid | 1.2g |
| 0.5M sodium hydroxide solution | In right amount |
| Water for injection | 2000ml |
| ? | Make 2000 |
Get recipe quantity water for injection 80%, temperature adds the Ambroxol HCl of recipe quantity, after the stirring and dissolving at 55-85 ℃; Add again again sodium-chlor and the lactic acid of recipe quantity in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 5.0-5.5 with the 0.5M sodium carbonate solution; Add Medicinal Charcoal 0.1%(W/V), stirred 20 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; With every 1ml embedding; Sterilization; The lamp inspection; Warehouse-in; Namely get and suck with tartrate Transbroncho solution.
Embodiment 16: the refining rear stability of Ambroxol HCl is investigated
Get the injection stage Ambroxol HCl of embodiment 1 gained, be positioned over relative humidity 75%, in 40 ℃ of biochemical cultivation cases of temperature, respectively at 1,2,3,6 sampling at the end of month, investigate outward appearance, pH, related substance, content.The results are shown in Table 1
The refining rear stability of table 1 Ambroxol HCl is investigated
| Time | Outward appearance | pH | Impurity B % | Impurity E % | Maximum single impurity % | Total impurities % | Content % |
| 0 month | White crystalline powder | 5.12 | 0.01 | Do not detect | 0.01 | 0.02 | 99.9 |
| January | White crystalline powder | 5.17 | 0.01 | Do not detect | 0.02 | 0.02 | 100.3 |
| February | White crystalline powder | 5.10 | Do not detect | Do not detect | 0.01 | 0.03 | 99.7 |
| March | White crystalline powder | 5.13 | 0.01 | Do not detect | 0.02 | 0.03 | 100.5 |
| June | White crystalline powder | 5.16 | 0.02 | Do not detect | 0.02 | 0.03 | 99.8 |
Through investigating, to accelerate to place 6 months, this product quality is without considerable change.
Embodiment 17: suck with the qualitative investigation of Ambroxol HCl solution
Get the suction Ambroxol HCl solution of embodiment 7 gained, be positioned over relative humidity 75%, in 40 ℃ of biochemical cultivation cases of temperature, respectively at 1,2,3,6 sampling at the end of month, investigate outward appearance, pH, related substance, content the results are shown in Table 2.
Table 2 sucks with the Ambroxol HCl stability of solution and investigates
| Time | Outward appearance | pH | Impurity B % | Impurity E % | Maximum single impurity % | Total impurities % | Content % |
| 0 month | Colourless clear liquid | 4.97 | 0.02 | Do not detect | 0.02 | 0.03 | 100.1 |
| January | Colourless clear liquid | 5.02 | 0.02 | Do not detect | 0.02 | 0.02 | 99.6 |
| February | Colourless clear liquid | 4.84 | Do not detect | Do not detect | 0.01 | 0.03 | 99.5 |
| March | Colourless clear liquid | 4.92 | Do not detect | Do not detect | 0.02 | 0.03 | 101.5 |
| June | Colourless clear liquid | 5.07 | 0.02 | 0.01 | 0.02 | 0.03 | 100.5 |
| September | Colourless clear liquid | 4.94 | Do not detect | Do not detect | 0.01 | 0.03 | 99.3 |
| December | Colourless clear liquid | 5.01 | Do not detect | Do not detect | 0.02 | 0.02 | 100.8 |
Through investigating, to accelerate to place 6 months, this product quality is without considerable change.
Embodiment 18: atomizing of the present invention sucks with the atomizing effect of solution and injection and parameter compares
The atomizing effect that Transbroncho single dose atomizing provided by the invention is sucked with solution and injection liquor compares, and sucks whether possess technical superiority with solution with the atomizing of reflection single dose.
Prior art and document confirm: the pH value of inhalation, osmotic pressure, dynamic viscosity, surface tension and after the atomizer atomizing entrance diameter of particle (DD) all can affect the curative effect of atomization inspiration treatment.The diameter of particle that human body can suck should can suck particle diameter (RD) less than 5 microns (um), and the pH value of inhalation, osmotic pressure, dynamic viscosity, surface tension all may affect the particle diameter of atomized particles.Particle diameter can characterize external atomizing effect less than 5 microns particulate ratio, is defined as: RF(Respirable Fraction)=RD/DD*100%, the RF value is larger, and the curative effect of atomization inspiration treatment may be better.
Adopt the embodiment of the invention 5 described Ambroxol HCl single dose atomized inhalation samples and Discussion on Chinese Listed ambroxol hydrochloride injection (Ambroxol Hydrochloride injection 15mg/2ml), the instruments such as the inhalation machine (children with) that atomizes with PARI JuniorBOYN are tested.
| ? | pH | Osmotic pressure (mosmol/kg) | Dynamic viscosity (mPa/s) | Surface tension (Mn/m) |
| The single dose atomized inhalation | 4.98 | 298 | 1.05 | 71.27 |
| Injection liquid | 5.07 | 287 | 1.02 | 65.3 |
Measure diameter of particle data such as following table after adopting atomizer with above-mentioned test sample atomizing:
| Parameter | The single dose atomized inhalation | Injection liquid |
| The dosage specification | 15mg/2ml | 15mg/2ml |
| Nebulisation time (min) | 5.0 | 7.5 |
| Particle diameter median (um) | 3.7 | 4.7 |
| Can suck particulate than (RF%) | 79.0 | 62.3 |
Claims (10)
1. the process for purification concrete steps of injection stage Ambroxol HCl are as follows:
With the aqueous ethanolic solution of oral grade hydrochloric acid Transbroncho with 5%～20% volume ratio; Described aqueous ethanolic solution compares less than or equal to 20:1 with the volume mass of Ambroxol HCl; Bath temperature 60-100 ℃,, heat back heat up in a steamer 30 minutes after, Ambroxol HCl is dissolved in this this aqueous ethanolic solution fully; Stopped heating, add gac, the add-on of gac is 0%～5% of Ambroxol HCl quality, then heating and filtering (use suction filtration), collect filtrate and also leave standstill to room temperature, filtrate is placed-4～30 ℃ of environment carry out crystallization (can add crystal seed, stirring and crystallizing or leave standstill crystallization), suction filtration is also collected filter cake, and the gained filter cake namely gets product with oven drying.
2. one kind sucks the preparation method who uses Ambroxol HCl solution, it is characterized in that containing Ambroxol HCl, osmotic pressure regulator, stablizer, the pH adjusting agent of pharmaceutical dosage; Its drug level is 0.5 – 20mg/ml.
3. according to the process for purification of right 1 described injection stage Ambroxol HCl, it is characterized in that described Ambroxol HCl is Transbroncho, tartrate Transbroncho, Hydrogen bromide Transbroncho and other pharmacologically acceptable salt; Described solvent is the aqueous ethanolic solution of 5%～20% volume ratio; Described crystallization is stirring and crystallizing or naturally leaves standstill crystallization; Or adding crystal seed; Recrystallization temperature is-4 ℃～30 ℃; Described solvent is 3:1-20 with the volume mass ratio of Ambroxol HCl: 1; Preferred solvent is 5:1-12 with the volume mass ratio of Ambroxol HCl: 1.
4. according to the preparation method of the described suctions of right 2 with the Ambroxol HCl solution, it is characterized in that being that related stablizer is Citric Acid, lactic acid, cysteine hydrochloride is a kind of or wherein several combination; Related pH adjusting agent is sodium hydroxide, yellow soda ash, a kind of or wherein several combination of calcium hydroxide; Related osmotic pressure regulator is a kind of of sodium-chlor, calcium chloride, Repone K or wherein several combination.
5. according to the preparation method of right 2 described suctions with Ambroxol HCl solution, it is characterized in that dissolving first Ambroxol HCl, press conditioning agent and stablizer at solution pervasion, be conducive to the dissolving of Ambroxol HCl, overcome the slightly water-soluble defective of Ambroxol HCl.
6. use the preparation method of Ambroxol HCl solution according to right 2,5 described suctions, it is characterized in that adding the liquid preparation withstand high temperatures sterilization that stablizer can make Ambroxol HCl, the preparation nature after the sterilization is stable, does not produce other degraded products.
7. use the preparation method of Ambroxol HCl solution according to right 2,5 described suctions, the processing condition that it is characterized in that sterilization steps are 115 ℃-121 ℃, pressure sterilizing 8-50 minute, make the sterility assurance level of product reach the F0 value and be 10-30, make product reach aseptic assurance requirement.
8. according to the preparation method of right 2 described suctions with Ambroxol HCl solution, it is characterized in that prescription consists of Ambroxol HCl 2.0% – 0.01%, stablizer 0.01% – 3.0%, pH adjusting agent 0.01% – 13%, osmotic pressure regulator 0.1% – 3.0%, water for injection 80% – 98%.
9. use the preparation method of Ambroxol HCl solution according to right 2,5,7 described suctions, it is characterized in that preparing concrete steps in liquid dispensing container, adding the water for injection of recipe quantity 10%～100%, temperature adds the Ambroxol HCl of recipe quantity 90%～115%, after the stirring and dissolving at 55～85 ℃; Add again again osmotic pressure regulator and the stablizer of recipe quantity 90%～115% in the solution, be stirred to dissolve complete; Record initial pH value, according to initial pH value, regulate pH value scope at 4.0-7.0 with the pH adjusting agent of 0.2M – 1M; Add Medicinal Charcoal 0.01%～1%(W/V), stirred 10～60 minutes, remove by filter Medicinal Charcoal, the supplementary injection water mixes to full dose; Measure intermediate content and pH value; The essence filter; In ampoule, fill nitrogen with every 1ml or 2ml can, sealing; Sterilization; The lamp inspection; Warehouse-in; Namely get to suck and use Ambroxol HCl solution.
10. suck the purposes with Ambroxol HCl solution atomization drug-delivery preparation, be mainly used in for the acute and dyssecretosis chronic bronchial pulmonary infection.
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| CN104027326A (en) * | 2013-03-04 | 2014-09-10 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride atomization inhalant, and preparation method and application thereof |
| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104829467A (en) * | 2015-04-14 | 2015-08-12 | 天津梅花生物医药科技有限公司 | Ambroxol hydrochloride dihydrate compound |
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| CN104971057A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Ambroxol hydrochloride composition capsule medicine for treating respiratory system diseases |
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| CN106631837A (en) * | 2016-12-22 | 2017-05-10 | 合肥久诺医药科技有限公司 | Method of refining ambroxol hydrochloride for injection |
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| RU2657764C1 (en) * | 2017-02-20 | 2018-06-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Самарский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Pharmaceutical form of ambroxol hydrochloride and method of its delivery to respiratory tract |
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| CN104027326A (en) * | 2013-03-04 | 2014-09-10 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride atomization inhalant, and preparation method and application thereof |
| CN104829467A (en) * | 2015-04-14 | 2015-08-12 | 天津梅花生物医药科技有限公司 | Ambroxol hydrochloride dihydrate compound |
| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
| CN104971057A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Ambroxol hydrochloride composition capsule medicine for treating respiratory system diseases |
| CN105055321A (en) * | 2015-09-01 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal ambroxol hydrochloride composition dry suspension for treating coughs |
| CN106176693A (en) * | 2016-08-31 | 2016-12-07 | 杭州百诚医药科技股份有限公司 | One is used for treating angina pectoris Neulized inhalation preparation |
| CN106631837A (en) * | 2016-12-22 | 2017-05-10 | 合肥久诺医药科技有限公司 | Method of refining ambroxol hydrochloride for injection |
| CN106631837B (en) * | 2016-12-22 | 2019-04-16 | 合肥久诺医药科技有限公司 | A kind of refining methd of Ambroxol Hydrochloride for Injection |
| RU2657764C1 (en) * | 2017-02-20 | 2018-06-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Самарский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Pharmaceutical form of ambroxol hydrochloride and method of its delivery to respiratory tract |
| CN107362134A (en) * | 2017-07-23 | 2017-11-21 | 南京正宽医药科技有限公司 | A kind of ambroxol hydrochloride oral solution and preparation method thereof |
| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| 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 |
| CN111544421B (en) * | 2020-05-25 | 2021-05-18 | 朗天药业(湖北)有限公司 | Ambroxol hydrochloride solution for inhalation and preparation method thereof |
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