CN100506217C - Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof - Google Patents
Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof Download PDFInfo
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- CN100506217C CN100506217C CNB2008100091838A CN200810009183A CN100506217C CN 100506217 C CN100506217 C CN 100506217C CN B2008100091838 A CNB2008100091838 A CN B2008100091838A CN 200810009183 A CN200810009183 A CN 200810009183A CN 100506217 C CN100506217 C CN 100506217C
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Abstract
The invention relates to an ambroxol hydrochloride freeze-dried powder injection and a preparation method thereof. The freeze-dried powder injection comprises ambroxol hydrochloride and mannitol. The ambroxol hydrochloride freeze-dried powder injection prepared by a freeze-drying technology has good stability and high dissolution velocity while all other indexes accord with regulation.
Description
Technical field
The present invention relates to a kind of ambroxol hydrochloride freeze-dried powder injection, also relate to the preparation method of ambroxol hydrochloride freeze-dried powder injection, belong to technical field of medicine.
Background technology
Ambroxol hydrochloride has another name called Ambroxol Hydrochloride, be lubricated expectorant of a kind of respiratory tract and mucolytic, have the characteristic that mucus is got rid of facilitation and dissolving secretions, it can promote the eliminating of thick secretions in the respiratory tract and reduce mucous delay, thereby significantly promote expectoration, improve breath state.Can promote the secretion of pulmonary surfactant, the secretion and the ciliary movement of air flue liquid.
Ambroxol hydrochloride (Ambroxol Hydrochloride), chemical name are trans-4-[(2-amino-3, the 5-dibromo-benzyl) amino] the Hexalin hydrochlorate, chemical structural formula:
Ambroxol hydrochloride is widely used in thick sputum, the dys-expectoration that various acute and chronic respiratory tract diseases cause clinically, at present, the preparation type of domestic ambroxol hydrochloride has ambroxol hydrochloride tablet and capsule, ambroxol hydrochloride oral solution agent, ambroxol hydrochloride sustained-release capsule etc., these dosage form biological utilisations are relatively poor, onset is slow, and the more gastrointestinal side effect that occurs, be mainly that stomach is scorching hot, dyspepsia, occur feeling sick once in a while, phenomenon such as vomiting.In order to adapt to needs under the multiple clinically situation, it is prepared into the dosage form of powder pin, the solution that can be made into desired concn during use gets final product.In the ambroxol hydrochloride lyophilized powder of patent CN1820749, except excipient mannitol, added the antioxidant sodium sulfite, the refrigerating process of ambroxol hydrochloride freeze-dried powder injection is: with hydrochloric acid ammonia Australia rope, mannitol is added in the water for injection, stirring down, the adding sodium sulfite makes material dissolution and transfers pH3.5～6.0, the injection-use activated carbon of adding 0.01～0.5%, stirred 15-30 minute, the filtering active carbon, filtrate is packed in the pallet, place freezer dryer, be cooled to-25 ℃～-30 ℃ and keep being cooled to-40 ℃～-45 ℃ again after 2 hours, open vacuum, slowly be warming up to-5 ℃～0 ℃ sublimation drying, stop drying less than 1% to moisture, lyophilization is finished.Even also might there be potential hazard in a spot of absorption body of the antioxidant that adds in this patent to body.Disclose ambroxol hydrochloride combination lyophilized powder among the patent CN1843372, selecting mannitol for use is excipient, also has other active component in addition, as compositions such as antibiotic.In the disclosed ambroxol hydrochloride lyophilized formulations of patent CN1954808, select for use materials such as citric acid, sodium citrate, potassium citrate, phosphoric acid, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, aspartic acid as cosolvent.
In the above-mentioned ambroxol hydrochloride freeze-dried powder injection, because when the adjunct ingredient that is added in the ambroxol hydrochloride principal agent is complicated, stability to principal agent exerts an influence, and might cause unknown side effect, in order to overcome because of the complicated side effect that brings of adjunct ingredient, it is safer that the patient is used, and the inventor provides a kind of prescription simple ambroxol hydrochloride freeze-dried powder injection.
Summary of the invention
One object of the present invention is to provide a kind of ambroxol hydrochloride freeze-dried powder injection, and the composition of this freeze-dried powder is simple, good stability, storage that can the long period.
Another object of the present invention is to provide a kind of preparation method of ambroxol hydrochloride freeze-dried powder injection, and the ambroxol hydrochloride freeze-dried powder injection quality that this method makes is loose, adds can dissolve rapidly behind the water and recover the primary characteristic of medicinal liquid.
The ambroxol hydrochloride freeze-dried powder injection that provides of the present invention is made up of ambroxol hydrochloride, mannitol.
The weight ratio of described ambroxol hydrochloride and mannitol is: 10～20:90～120, the weight ratio of preferred ambroxol hydrochloride and mannitol is 15:100.
The selection of adjuvant is analyzed from prescription, and the principle that the inventor follows is that under the prerequisite of the product that does not influence medicine stability, meets clinical needs, the composition of adjuvant is simple more good more.The composition of adjuvant is simple more, and preparation can be simplified batching step greatly in production technology, simultaneously, can avoid adjuvant to be divided into the side effect that is difficult to expect that complexity is brought, and therefore, the present invention only selects a kind of adjuvant of mannitol for use.
The dissolubility that the record ambroxol hydrochloride is among the patent CN1954808 is smaller, approximately dissolve the 1mg ambroxol hydrochloride in the 70mL water, according to " 2005 editions regulations of Chinese pharmacopoeia to dissolubility, ambroxol hydrochloride belongs to slightly molten thing, be made into every performance injection powder pin up to specification, must add materials such as cosolvent or solubilizing agent.
Mannitol of the present invention is as the adjuvant of freeze-dried powder, ambroxol hydrochloride there is good hydrotropy effect, do not need to add other cosolvents again, avoid introducing more impurity, the affiliation that adds of some inorganic salt cosolvent makes freeze-dried powder volume-diminished, duricrust and crisp phenomenon such as loose occur; Mannitol also has good bulk skeleton function simultaneously, makes prepared ambroxol hydrochloride freeze-dried powder injection keep original volume substantially by adding mannitol, and color and luster is even, is easy to dissolve the clear and bright solution of formation.
In the ambroxol hydrochloride freeze-dried powder injection of the present invention, the consumption of its adjuvant mannitol is more higher than the mannitol consumption in the ambroxol hydrochloride in the prior art comparatively speaking, but can not cause adverse effect to human body, the consumption of mannitol uses by body weight 0.25～2g/kg for child when injection, drug effect is just arranged during mannitol, and the mannitol in every ambroxol hydrochloride powder of the present invention pin at most only contains 120mg, is not have side effect to human body.
The character of the technology of frozen preparation, the quality of product and drug solution has substantial connection, freezing dry process is the process of a dynamic change, different drug solutions need improve accordingly to three processes of refrigerating process, dry run, vacuum control of refrigerating process, just can draw standard compliant product.To this, the inventor has paid all effort, has obtained following technology.
For realizing that another object of the present invention prepares a kind of ambroxol hydrochloride freeze-dried powder injection, the technical scheme of employing is:
(1) ambroxol hydrochloride with recipe quantity joins in the water for injection, is heated to 60 ℃ and makes it dissolving, adds mannitol then in above-mentioned solution, stirring and dissolving, and regulator solution pH adds sterilized water for injection to full dose;
(2) in the solution that step (1) is prepared, add active carbon, filter;
(3) the filtrate lyophilization that step (2) is obtained is in aseptic condition lower cover, aluminum envelope, promptly;
It is characterized in that, in the described freezing dry process, filtrate placed lower the temperature in-18～-20 ℃ household freezer, preliminary freezing 3 hours, and then it is dropped to about-45 ℃ evacuation, in 10～12 hours, be warming up to-10～-5 ℃, the time of keeping-10～-5 ℃ is 6 hours, is warming up to 20～25 ℃ again in 6～9 hours, and the time of keeping 20～25 ℃ is 6 hours.
In the heating for dissolving process described in the above-mentioned steps (1), at first ambroxol hydrochloride is fully dissolved at 60 ℃, after adding mannitol again, both are uniform distribution in solution, the solubility of the lyophilisation product that obtains at last is good, the definite principle inventor does not also learn as yet, infer possible former should be, when temperature is 60 ℃, abundant dissolved ambroxol hydrochloride can form more stable soluble complexes or solubility organic molecule complex with mannitol, and the screening test of temperature is seen experimental example 1.
During regulator solution PH described in the above-mentioned steps (1), used PH regulator is that concentration is hydrochloric acid and the 0.1mol/L sodium hydroxide solution of 0.1mol/L.
The described solution PH of above-mentioned steps (1) is adjusted to 4.8～5.1, and they are preferred 5.0 years old.
The water solublity of ambroxol hydrochloride under acid condition is better, so when the dissolving ambroxol hydrochloride, the PH of solution is adjusted to 4.8～5.1.
The consumption of active carbon is 0.1% (g/ml) of join liquor capacity in the above-mentioned steps (2).
The consumption of active carbon is to the influence of product, if activated carbon dosage is too many, can cause the active component in the adsorbent solution, the productive rate of its product is reduced, if activated carbon dosage is very little, can not be fully with solution decolouring, the source of reducing phlegm and internal heat, the removal of impurity, and then influence the performance such as quality, purity of product.So the selection to the consumption of active carbon should be taken all factors into consideration.
The inventor finds, in ambroxol hydrochloride solution, the active carbon that adds 0.1% (g/mL), this moment, there was adsorption in active carbon hardly to the principal agent ambroxol hydrochloride, solution colour is a colorless cleared solution after filtering, and the ambroxol hydrochloride after activated carbon adsorption carries out the detection of related substance, and its total impurities is below 0.8%, maximum contaminant is below 0.2%, and bacterial endotoxin is up to specification.See experimental example 2 for details.
In the above-mentioned steps (2), add after the active carbon, stirred 10～14 minutes.
In the above-mentioned steps (3), freezing dry process divides three phases, freezing, distillation, dry run.
1, freezing
In the freezing dry process of ambroxol hydrochloride freeze-dried powder injection of the present invention, the refrigerating process of ambroxol hydrochloride solution is finished in two steps.Take all factors into consideration the mode of appearance of frozen product dry run, product and the content of moisture, earlier with its quick freezing to eutectic point, and, it is tentatively freezed keeping a period of time in temperature.With ambroxol hydrochloride solution fast cooling to-18～-20 ℃ the time because the control of thermograde and cooling rate, the ice crystal of formation can be very not little, dried layer resistance is big when dry, distillation is slow, can not make shortcomings such as ice crystal is very big, and product appearance is coarse, and dissolution velocity is slow yet.
After tentatively freezing ambroxol hydrochloride, further with its cooling, it is freezed fully again, if medicinal liquid does not freeze fully, when vacuum sublimation was dry, liquid boiling caused spray bottle phenomenon.
In the freezing dry process of ambroxol hydrochloride freeze-dried powder injection of the present invention, because when drying, the temperature and time control of water sublimed, moisture more than 90% is removed, afterwards, it is dry to heat up, and the moisture of ambroxol hydrochloride freeze-dried powder injection can be lower than 0.8%, and the stability of active medicine improves.
2, distillation
After medicine freezes, start the vacuum machine and be evacuated to 10Pa, close fridge, heat up to make to medicine and freeze the product temperature and rise to-10～-5 ℃; Insulation then.
The choice relation of sublimation temperature is to the speed of distillation, why select-10～-5 ℃, rather than it is higher more near eutectic point, be because when distillation, the upper materials drying that will take the lead in, if it is too fast that its temperature rises, might reach the temperature of caving in (or being referred to as the disintegrate temperature), porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause solubility, stability and clarity is variation simultaneously.
In addition, temperature retention time is unsuitable long, this is because the small crystals that medicinal liquid quick freezing of the present invention produces has very high surface energy, when heating recrystallize might take place; mutually combining between the little ice crystal forms big ice crystal; make its surface to volume ratio reach minimum, and big ice crystal makes the dried frozen aquatic products outward appearance bad, solubility is poor.
Therefore, excessive temperature or after distillation for a long time or insulation all has adverse effect to the present invention, through a large amount of experiment screenings, can be referring to experimental example 3, and being elevated temperature is-10～-5 ℃, temperature retention time is 6 hours.
Pressure during the distillation is 10Pa, rather than lower, though this is because the low distillation that helps ice in the product of pressure, because pressure is unfavorable to conducting heat when too low, product is difficult for the acquisition heat, and rate of sublimation reduces on the contrary.But when pressure was too high, the rate of sublimation of ice slowed down in the product, and minimizing falls in the product caloric receptivity.So the temperature of product self rises, when being higher than temperature of eutectic point, product will melt, and cause the lyophilizing failure.Therefore, pressure is set at 10Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation.
3, drying
Promptly remove the process of bound water at dry period, behind sublimation drying, also remaining a part of adsorbed water and bound water, these water are not frozen, can not remove in primary drying.The present invention was warming up to 20～25 ℃ with temperature in 6～9 hours behind sublimation drying, the time of keeping 20～25 ℃ is 6 hours, and the moisture of obtained freeze-drying product is lower than 0.8%, and is as well known to those skilled in the art, and the moisture of freeze-drying prods is low more, and its stability is good more.
Freeze drying process preferred version of the present invention is: filtrate is placed lower the temperature in-20 ℃ household freezer, preliminary freezing 3 hours, and then it is dropped to about-45 ℃, evacuation, in 11 hours, be warming up to-8～-6 ℃, the time of keeping-8～-6 ℃ is 6 hours, is warming up to 22～23 ℃ again in 7～7.5 hours, and the time of keeping 22～23 ℃ is 6 hours.
In the ambroxol hydrochloride freeze-dried powder injection of the present invention, except mannitol, do not add other compositions, the inventor investigates with regard to stable aspect ambroxol hydrochloride freeze-dried powder injection and the ambroxol hydrochloride freeze-dried powder injection of the present invention of patent CN1954808, sees the result of the test of experimental example 4.
By using a kind of adjuvant mannitol, the stability of the principal agent of the ambroxol hydrochloride powder pin of this simple component is high among the present invention because adjuvant is simple, can maximum possible avoid the negative effect of interaction between the adjuvant or adjuvant to medicine, human body; The present invention makes that by the improvement to the freeze-dry process of ambroxol hydrochloride the quality of prepared ambroxol hydrochloride lyophilized powder is loose, add can dissolve rapidly behind the water and recover the primary characteristic of medicinal liquid, and the stability of ambroxol hydrochloride improves.Simultaneously, make the products obtained therefrom dose controlled, good appearance; Packaging volume is little, and packaging material require low, have reduced packing cost and cost of transportation.
The specific embodiment
The preparation of embodiment 1 every bottle of ambroxol-hydrochloride-containing 15mg lyophilized powder, totally 1000 bottles.
The composition of the lyophilized powder of every bottle of ambroxol-hydrochloride-containing 15mg:
Ambroxol hydrochloride 15g is dissolved in the sterile water for injection, stirring makes its dissolving, taking by weighing 100g mannitol adds in the above-mentioned solution, stirring makes dissolving, be heated to 60 ℃, stir and make its dissolving, with the pH to 4.9 of 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution regulator solution, add sterilized water for injection to 2000mL, add the active carbon of 0.1% (g/mL), stirred 14 minutes, medicinal liquid is again through the 0.22um membrane filtration, filtrate is divided in the cillin bottle, place to be cooled to-20 ℃ freezer dryer, and keep-20 ℃ freezing 3 hours, and then it is dropped to-45 ℃, evacuation, be warming up to-7 ℃ in 11 hours, the time of keeping-7 ℃ is 6 hours, continues to be warming up to 20 ℃ again in 8 hours, the time of keeping 20 ℃ is 6 hours, obtain the freeze-dried powder of every bottle of ambroxol-hydrochloride-containing 15mg, moisture is 0.7%, adds the water for injection of 2mL in this lyophilized powder, about 20 seconds are promptly molten entirely, the solution water white transparency.
The preparation of embodiment 2 every bottle of ambroxol-hydrochloride-containing 15mg lyophilized powders, totally 1000 bottles.
The composition of the lyophilized powder of every bottle of ambroxol-hydrochloride-containing 15mg:
Ambroxol hydrochloride 15g is dissolved in the sterile water for injection, stirring makes its dissolving, taking by weighing 150g mannitol adds in the above-mentioned solution, stirring makes dissolving, be heated to 60 ℃, stir and make its dissolving, with the pH to 5.1 of 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution regulator solution, add sterilized water for injection to 2000mL, add the active carbon of 0.1% (g/mL), stirred 12 minutes, medicinal liquid is again through the 0.22um membrane filtration, filtrate is divided in the cillin bottle, place to be cooled to-18 ℃ freezer dryer, and keep-18 ℃ freezing 3 hours, and then it is dropped to-45 ℃, evacuation, be warming up to-10 ℃ in 12 hours, the time of keeping-10 ℃ is 6 hours, continues to be warming up to 22 ℃ again in 9 hours, the time of keeping 22 ℃ is 6 hours, obtain the freeze-dried powder of every bottle of ambroxol-hydrochloride-containing 15mg, moisture is 0.68%, adds the water for injection of 2mL in this lyophilized powder, about 18 seconds are promptly molten entirely, the solution water white transparency.
The preparation of embodiment 3 every bottle of ambroxol-hydrochloride-containing 15mg lyophilized powders, totally 1000 bottles.
The composition of the lyophilized powder of every bottle of ambroxol-hydrochloride-containing 15mg:
Ambroxol hydrochloride 15g is dissolved in the sterile water for injection, stirring makes its dissolving, taking by weighing 68g mannitol adds in the above-mentioned solution, stirring makes dissolving, be heated to 60 ℃, stir and make its dissolving, with the pH to 4.8 of 0.1mol/L hydrochloric acid solution and 0.1mo1/L sodium hydroxide solution regulator solution, add sterilized water for injection to 2000mL, add the active carbon of 0.1% (g/mL), stirred 10 minutes, medicinal liquid is again through the 0.22um membrane filtration, filtrate is divided in the cillin bottle, place to be cooled to-20 ℃ freezer dryer, and keep-20 ℃ freezing 3 hours, and then it is dropped to about-45 ℃, evacuation, be warming up to-10 ℃ in 10 hours, the time of keeping-10 ℃ is 6 hours, continues to be warming up to 23 ℃ again in 7 hours, the time of keeping 23 ℃ is 6 hours, obtain the freeze-dried powder of every bottle of ambroxol-hydrochloride-containing 15mg, moisture is 0.74%, adds the water for injection of 2mL in this lyophilized powder, about 22 seconds are promptly molten entirely, the solution water white transparency.
The preparation of embodiment 4 every bottle of ambroxol-hydrochloride-containing 10mg lyophilized powders, totally 1000 bottles.
The composition of the lyophilized powder of every bottle of ambroxol-hydrochloride-containing 10mg:
Ambroxol hydrochloride 10g is dissolved in the sterile water for injection, stirring makes its dissolving, taking by weighing 75g mannitol adds in the above-mentioned solution, stirring makes dissolving, be heated to 60 ℃, stir and make its dissolving, with the pH to 4.9 of 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution regulator solution, add sterilized water for injection to 2000mL, add the active carbon of 0.1% (g/mL), stirred 13 minutes, medicinal liquid is again through the 0.22um membrane filtration, filtrate is divided in the cillin bottle, place to be cooled to-20 ℃ freezer dryer, and keep-20 ℃ freezing 3 hours, and then it is dropped to about-45 ℃, evacuation, be warming up to-7 ℃ in 10 hours, the time of keeping-7 ℃ is 6 hours, continues to be warming up to 20 ℃ again in 9 hours, the time of keeping 20 ℃ is 6 hours, obtain the freeze-dried powder of every bottle of ambroxol-hydrochloride-containing 15mg, moisture is 0.77%, adds the water for injection of 2mL in this lyophilized powder, about 24 seconds are promptly molten entirely, the solution water white transparency.
The preparation of embodiment 5 every bottle of ambroxol-hydrochloride-containing 20mg lyophilized powders, totally 1000 bottles.
The composition of the lyophilized powder of every bottle of ambroxol-hydrochloride-containing 20mg:
Ambroxol hydrochloride 20g is dissolved in the sterile water for injection, stirring makes its dissolving, taking by weighing 120g mannitol adds in the above-mentioned solution, stirring makes dissolving, be heated to 60 ℃, stir and make its dissolving, with the pH to 5.1 of 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution regulator solution, add sterilized water for injection to 2000mL, add the active carbon of 0.1% (g/mL), stirred 14 minutes, medicinal liquid is again through the 0.22um membrane filtration, filtrate is divided in the cillin bottle, place to be cooled to-18 ℃ freezer dryer, and keep-18 ℃ freezing 3 hours, and then it is dropped to about-45 ℃, evacuation, be warming up to-8 ℃ in 11 hours, the time of keeping-8 ℃ is 6 hours, continues to be warming up to 25 ℃ again in 7 hours, the time of keeping 25 ℃ is 6 hours, obtain the freeze-dried powder of every bottle of ambroxol-hydrochloride-containing 15mg, moisture is 0.75%, adds the water for injection of 2mL in this lyophilized powder, about 22 seconds are promptly molten entirely, the solution water white transparency.
Experimental example 1
This experimental example is screening experiment, other parameters and the technology reference example 1 of temperature when ambroxol hydrochloride and mannitol are dissolved in water for injection.
The screening test of solution temperature during table 1 dissolving
| Temperature (℃) | 25 | 35 | 50 | 60 | 70 | 80 |
| Clarity | Muddy | Opalescence | Clear and bright | Clear and bright | Clear and bright | Opalescence |
| Dissolution velocity (s) | 35 | 20 | 27 | |||
| Related substance | 2.3％ | 1.9％ | 1.5％ | 0.7％ | 1.7％ | 2.7％ |
Experimental data can draw from table, and when aqueous solution was 60 ℃, the performance of obtained freeze-drying powder pin was best, and in this temperature, ambroxol hydrochloride and mannitol form stable soluble complexes or soluble complex etc.
Experimental example 2
This experimental example is the screening experiment of activated carbon concentration.Other component technological parameter selects for use the injection active carbon of variable concentrations to adsorb respectively all with embodiment 1, serves as to investigate index with ambroxol hydrochloride content, clarity, the consumption of screening active carbon.The inspection employing of clarity " two clarity inspection techniques of Chinese pharmacopoeia version in 2000 the results are shown in Table 2:
Table 2 activated carbon dosage screening test
| Concentration of activated carbon (%) | Ambroxol hydrochloride content (%) | Clarity |
| 0.2 | 97.8 | Up to specification |
| 0.1 | 99.0 | Up to specification |
| 0.05 | 99.5 | Opalescence is arranged |
| 0.03 | 99.5 | Opalescence is arranged, muddiness |
| 0 | 100.0 | Opalescence is arranged, muddiness |
By drawing in the table, 0.1% active carbon can make the clarity of lyophilizing liquid qualified, and is less to principal agent absorption, and pollutes minimumly, is that the active carbon of 0.1% (g/ml) adsorbs so select concentration for use.
Experimental example 3
This experimental example is the screening experiment of sublimation temperature and time.
Table 3 is screening tests that ambroxol hydrochloride freezes sublimation temperature in the product freezing dry process, and table 4 ambroxol hydrochloride freezes the screening test of distillation time in the product freezing dry process.Other parameter is with embodiment 1.
The screening experiment of table 3 sublimation temperature and time
| Parameter | First | Second batch | The 3rd batch | The 4th batch | The 5th batch |
| Sublimation temperature (℃) | -15 | -10 | -5 | -3 | 0 |
| Moisture (%) | 1.4 | 0.82 | 0.74 | 0.92 | 1.5 |
| Related substance (%) | 0.6 | 0.7 | 0.6 | 0.7 | 0.7 |
| Clarity | Qualified | Qualified | Qualified | Opalescence | Muddy |
| Character | Off-white color is loose block | Off-white color is loose block | Off-white color is loose block | Layering | Layering |
The screening of table 4 distillation time
| First | Second batch | The 3rd batch | The 4th batch | The 5th batch | |
| Time (h) | 10 | 14 | 16 | 18 | 20 |
| Moisture (%) | 1.7 | 0.9 | 0.74 | 0.7 | 0.7 |
| Related substance (%) | 0.6 | 0.7 | 0.6 | 0.7 | 0.7 |
According to table 3, table 4 test result analysis, at sublimation stage, temperature is controlled at-10～-5 ℃, time at 16～18 hours, all good from every index of final products, though cooling time is prolonging, the performance of product is significantly influence not, but considers that from energy consumption angle aspect freezing 18 hours is maximum.
Experimental example 4
This experimental example is to utilize prepared ambroxol hydrochloride freeze-dried powder injection of the present invention and patent CN1954808 ambroxol hydrochloride freeze-dried powder injection product to carry out stability test, the stability that compares two kinds of ambroxol hydrochloride freeze-dried powder injections according to conventional accelerated test, ambroxol hydrochloride freeze-dried powder injection of the present invention adopts the method preparation of embodiment 1, the ambroxol hydrochloride freeze-dried powder injection of patent CN1954808 adopts the method preparation of embodiment 8, and result of the test sees the following form.
The stability of table 5 the present invention and patent CN1954808 ambroxol hydrochloride freeze-dried powder injection relatively
| Sample | Purity after January | Purity after February | Purity after March | Purity after June |
| The present invention | 99.6％ | 99.5％ | 99.3％ | 98.8％ |
| CN1954808 | 99.5％ | 98.6％ | 98.2％ | 97.3％ |
Experimental example 5
This experimental example is to five batches of ambroxol hydrochloride freeze-dried powder injection Performance Detection of the present invention, concrete detection method all according to " 2000 editions second one of Chinese pharmacopoeia the results are shown in following table:
The Performance Detection of table 6 ambroxol hydrochloride freeze-dried powder injection of the present invention
| Batch | Clarity | Related substance | Drug content | Moisture | Aseptic | Bacterial endotoxin |
| First | Clear and bright | 0.6％ | 99.8％ | 0.78％ | Up to specification | Up to specification |
| Second batch | Clear and bright | 0.5％ | 99.6％ | 0.81％ | Up to specification | Up to specification |
| The 3rd batch | Clear and bright | 0.6％ | 99.7％ | 0.80％ | Up to specification | Up to specification |
| The 4th batch | Clear and bright | 0.7％ | 100.2％ | 0.72％ | Up to specification | Up to specification |
| The 5th batch | Clear and bright | 0.7％ | 99.8％ | 0.74％ | Up to specification | Up to specification |
Kind can learn that every performance of gained ambroxol hydrochloride freeze-dried powder injection of the present invention is all qualified at table 6, and the content of related substance, moisture improve than prior art all.
Claims (3)
1, a kind of ambroxol hydrochloride freeze-dried powder injection, it is characterized in that, described ambroxol hydrochloride freeze-dried powder injection is made up of ambroxol hydrochloride and mannitol, and the weight ratio of ambroxol hydrochloride and mannitol is 10～20:90～120, and described ambroxol hydrochloride freeze-dried powder injection is prepared by following steps:
(1) ambroxol hydrochloride with recipe quantity joins in the water for injection, is heated to 60 ℃ and makes it dissolving, adds mannitol then in above-mentioned solution, stirring and dissolving, and regulator solution pH adds sterilized water for injection to full dose;
(2) add active carbon in the solution that step (1) is prepared, the consumption of active carbon is the 0.1%g/mL of liquor capacity, filters;
(3) filtrate that step (2) is obtained places and lowers the temperature in-20 ℃ household freezer, preliminary freezing 3 hours, and then it is dropped to-45 ℃, evacuation, be warming up to-8～-6 ℃ in 11 hours, the time of keeping-8～-6 ℃ is 6 hours, is warming up to 22～23 ℃ again in 7～7.5 hours, the time of keeping 22～23 ℃ is 6 hours, promptly obtains ambroxol hydrochloride freeze-dried powder injection.
2, ambroxol hydrochloride freeze-dried powder injection according to claim 1 is characterized in that, the weight ratio of described ambroxol hydrochloride and mannitol is 15:100.
3, the preparation method of a kind of claim 1 or 2 described ambroxol hydrochloride freeze-dried powder injections comprises the steps:
(1) ambroxol hydrochloride with recipe quantity joins in the water for injection, is heated to 60 ℃ and makes it dissolving, adds mannitol then in above-mentioned solution, stirring and dissolving, and regulator solution pH adds sterilized water for injection to full dose;
(2) add active carbon in the solution that step (1) is prepared, the consumption of active carbon is the 0.1%g/mL of liquor capacity, filters;
(3) filtrate that step (2) is obtained places and lowers the temperature in-20 ℃ household freezer, preliminary freezing 3 hours, and then it is dropped to-45 ℃, evacuation, be warming up to-8～-6 ℃ in 11 hours, the time of keeping-8～-6 ℃ is 6 hours, is warming up to 22～23 ℃ again in 7～7.5 hours, the time of keeping 22～23 ℃ is 6 hours, promptly obtains ambroxol hydrochloride freeze-dried powder injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100091838A CN100506217C (en) | 2007-08-14 | 2008-02-04 | Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710016390 | 2007-08-14 | ||
| CN200710016390.1 | 2007-08-14 | ||
| CNB2008100091838A CN100506217C (en) | 2007-08-14 | 2008-02-04 | Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof |
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| CN101627967B (en) * | 2009-08-03 | 2011-12-28 | 上海华源药业（宁夏）沙赛制药有限公司 | Ambroxol hydrochloride liquid preparation and preparation method thereof |
| CN102058548B (en) * | 2010-12-30 | 2012-05-23 | 江苏奥赛康药业股份有限公司 | Ambroxol hydrochloride composition for injection and preparation method thereof |
| CN102670607A (en) * | 2012-05-28 | 2012-09-19 | 海南卫康制药(潜山)有限公司 | Compound ambroxol hydrochloride composition and preparation method thereof |
| CN102670608A (en) * | 2012-05-28 | 2012-09-19 | 海南卫康制药(潜山)有限公司 | Ambroxol hydrochloride freeze-dried powder composite used for injection and preparation method thereof |
| CN102872462B (en) * | 2012-10-26 | 2013-04-17 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride composition and preparation thereof |
| CN103301117A (en) * | 2013-06-27 | 2013-09-18 | 海南卫康制药(潜山)有限公司 | Ambroxol hydrochloride composition for injection |
| CN103536562A (en) * | 2013-10-15 | 2014-01-29 | 海南卫康制药(潜山)有限公司 | Ambroxol hydrochloride composition freeze-dried powder for injection |
| CN105997902A (en) * | 2015-05-15 | 2016-10-12 | 苗怡文 | Ambroxol hydrochloride composition serving as medicine for treating respiratory system diseases |
| CN105147623A (en) * | 2015-09-30 | 2015-12-16 | 合肥华方医药科技有限公司 | Oral lactulose lyophilized powder and preparation method thereof |
| CN105147625A (en) * | 2015-09-30 | 2015-12-16 | 合肥华方医药科技有限公司 | Oral phenobarbital freeze-dried powder preparation and preparation method thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
| CN110075074A (en) * | 2019-06-18 | 2019-08-02 | 南京致中生物科技有限公司 | A kind of Ambroxol Hydrochloride for Injection freeze drying powder injection and its preparation process |
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