CN101756948A - Composition of ambroxol hydrochloride and arginine and preparation method thereof - Google Patents
Composition of ambroxol hydrochloride and arginine and preparation method thereof Download PDFInfo
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- CN101756948A CN101756948A CN200910008473A CN200910008473A CN101756948A CN 101756948 A CN101756948 A CN 101756948A CN 200910008473 A CN200910008473 A CN 200910008473A CN 200910008473 A CN200910008473 A CN 200910008473A CN 101756948 A CN101756948 A CN 101756948A
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Abstract
The invention belongs to the technical field of medicine, in particular to a composition of ambroxol hydrochloride and arginine and a preparation method thereof. The weight ratio of the ambroxol hydrochloride and the arginine in the composition is 1:0.01 to 0.8. The invention also provides a preparation method of freeze-dried powder preparation of the composition, and a use of the composition in the preparation of expectorant drugs.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to a kind of ambroxol hydrochloride and arginic composition and method of making the same, and be used for the treatment of purposes in the expelling phlegm drugs in preparation.
2, background technology
Ambroxol (Ambroxol) be bromhexine active metabolite, chemistry is called anti--4-[(2-amino-3, the 5-dibromo phenyl)] Hexalin, be lubricated expectorant of a kind of respiratory tract and mucolytic, have mucus and get rid of the characteristic of facilitation and dissolving secretions, it can promote the eliminating of thick secretions in the respiratory tract and reduce mucous delay, thereby significantly promotes expectoration, improves breath state.Can promote the secretion of pulmonary surfactant, the secretion and the ciliary movement of air flue liquid.Its preparation method and pharmacological action are delivered on U.S. Pat 3536713, and this medicine is used for clinical the form with hydrochlorate in 1984.At present ambroxol hydrochloride is widely used in the treatment respiratory system disease in states such as many countries such as the U.S., Britain, Germany, Japan, and clinical effectiveness is good, and its curative effect and safety have obtained clinical trial and confirmed.Ambroxol hydrochloride can improve the lung functions index, the prevention respiratory tract infection, be widely used in acute, chronic respiratory tract disease clinically with sputum diacrisis and expectoration dysfunction, the for example prophylactic treatment and the auxiliary treatment of acute/chronic bronchitis, bronchiectasis and san bronchial asthma, pulmonary surgery patient's postoperative pulmonary complication, and the treatment of the thick sputum, dys-expectoration, premature infant and the new-born baby respiratory distress syndrome (IRDS) that cause such as pulmonary tuberculosis.
The ambroxol hydrochloride structural formula is as follows:
Ambroxol hydrochloride oral absorbs rapidly, eliminates 2～3 hours half-life.Its toxicity is low, determined curative effect, and phlegm-dispelling functions is stronger than bromhexine.Dosage form mainly contains tablet, slow releasing capsule, solution, syrup, aqueous injection and compound preparation thereof.At present commercially available ambroxol hydrochloride oral preparation is through gastrointestinal absorption, and gastrointestinal upset is often arranged after taking, as burn feeling, feel sick, vomiting, and ambroxol hydrochloride has bitterness, the baby is reluctant to take.For swallowing inconvenient patient and old people, commercially available ambroxol hydrochloride oral preparation is not suitable for them at present.Commercially available liquid drugs injection instability is met light and is easily degraded, and shelf life stability is poor.On the other hand, the dissolubility of ambroxol hydrochloride in water is not ideal, makes its preparation application and clinical practice all be subjected to certain limitation, and has increased the preparation cost.In order to adapt to the needs of multiple situation clinically, it is prepared into the dosage form of powder pin, the solution that can be made into desired concn during use gets final product, and adds the problem that cosolvent solves its poorly water-soluble in preparation.Patent CN1954808 discloses in the ambroxol hydrochloride lyophilized formulations, selects for use materials such as citric acid, sodium citrate, potassium citrate, phosphoric acid, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, aspartic acid as cosolvent.Select for use mannitol as cosolvent among the patent CN101224196, and the ambroxol hydrochloride that adds and the weight ratio of mannitol are 10～20: 90～120.
In the above-mentioned ambroxol hydrochloride freeze-dried powder injection, because when the adjunct ingredient that added is complicated in the ambroxol hydrochloride principal agent, the stability of principal agent is exerted an influence, and the supplementary product consumption that adds might cause unknown side effect when high.In order to overcome because of adjunct ingredient complexity or the high side effect that brings of consumption and ambroxol hydrochloride water solublity and the bad problem of stability, it is safer that the patient is used, cost is lower, and the inventor provides a kind of ambroxol hydrochloride and arginic composition and method of making the same.
Arginine is a kind of double-basis aminoacid, and natural arginine is the L-type, and it is water-soluble, and is nontoxic, and nonirritant is a kind of good adjuvant.The present invention is by the surprised discovery of a large amount of experiments, ambroxol hydrochloride and arginine have solved its water solublity problem fully with after the certain proportion combination, make ambroxol hydrochloride can with the alkalescent medicine compatibility, make things convenient for clinical application, and stability, dissolution velocity increases all.
3, summary of the invention
The purpose of this invention is to provide and contain ambroxol hydrochloride and arginic compositions.
Another object of the present invention provides the freeze-dried powder that contains ambroxol hydrochloride and arginic compositions, and the water solublity of this freeze-dried powder and good stability can be stored the long period.
A further object of the present invention provides the preparation method of the freeze-dried powder that contains ambroxol hydrochloride and arginic compositions, the ambroxol hydrochloride freeze-dried powder injection quality that this method makes is loose, add and can dissolve rapidly behind the water and recover the primary characteristic of medicinal liquid, and preparation cost is low, quality controllable.
An also purpose of the present invention provides and contains ambroxol hydrochloride and arginic compositions and be used for the treatment of application in the expectorant medicine in preparation.
The invention provides and contain ambroxol hydrochloride and arginic composition and method of making the same, technical scheme is as follows:
Ambroxol hydrochloride and the arginic compositions of containing provided by the invention, it is characterized in that: described ambroxol hydrochloride and arginic weight ratio are 1: 0.01～0.8.
Described ambroxol hydrochloride and the arginic compositions of containing is characterized in that: described ambroxol hydrochloride and arginic weight ratio be preferably 1: 0.05～and 0.5.
Described ambroxol hydrochloride and the arginic compositions of containing is characterized in that: described ambroxol hydrochloride and arginic weight ratio more preferably 1: 0.1～0.3.
Described ambroxol hydrochloride and the arginic compositions of containing is characterized in that: a step is preferably 1: 0.2 again for described ambroxol hydrochloride and arginic weight ratio.
Described ambroxol hydrochloride and the arginic compositions of containing is characterized in that: describedly contain ambroxol hydrochloride and arginic compositions is a freeze-dried powder.
When the preparation lyophilized formulations, in order to obtain full outward appearance and to regulate the composite osmotic pressure of solution afterwards, the normal excipient that adds adds mannitol, lactose, sorbitol, glucose, xylitol, fructose, maltose or sodium chloride, more preferably mannitol or lactose in the freeze-drying prods of the present invention.
The selection of adjuvant is analyzed from prescription, and the principle that the inventor follows is, under the prerequisite of the product that does not influence medicine stability, meets clinical needs, the composition of adjuvant is simple more, and consumption is few more good more.The composition of adjuvant is simple more, and preparation can be simplified batching step greatly in production technology, simultaneously, and the side effect that is difficult to expect that can avoid the adjunct ingredient complexity to bring; Supplementary product consumption is few more, easy more carrying out in the production technology, and cost is relatively low.Therefore, the present invention only selects for use arginine and mannitol or arginine and lactose as adjuvant.
The dissolubility of record ambroxol hydrochloride is smaller among the patent CN1954808, 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.
The arginine that the present invention adds has good hydrotropy effect to ambroxol hydrochloride, has solved the problem of its poorly water-soluble, avoids introducing too much impurity, and the affiliation that adds of some inorganic salt cosolvent makes freeze-dried powder volume-diminished, duricrust and crisp phenomenon such as loose occur; Arginine also has good bulk skeleton function simultaneously, makes prepared ambroxol hydrochloride freeze-dried powder injection keep original volume substantially by adding arginine, and color and luster is even, is easy to dissolve the clear and bright solution of formation.
The described freeze-dried powder that contains ambroxol hydrochloride and arginic compositions is characterized in that: the described preparation method that contains the freeze-dried powder of ambroxol hydrochloride and arginine composition is:
(1) ambroxol hydrochloride and the arginine with recipe quantity joins in the water for injection, after stirring is dissolved it fully, adds the mannitol of recipe quantity, stirring and dissolving, and benefit adds to the full amount of water for injection;
(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.
The described freeze-dried powder that contains ambroxol hydrochloride and arginine composition is characterized in that, the consumption of active carbon is 0.1% of a liquor capacity in the described step (2).
The consumption of needle-use activated carbon in the also claimed described preparation method of the present invention.The consumption of active carbon influences 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, after filtering is colorless cleared solution, and the ambroxol hydrochloride after activated carbon adsorption carries out the detection of related substance, and its total impurities is below 0.6%, maximum contaminant is below 0.2%, and bacterial endotoxin is up to specification.See experimental example 1 for details.
Described ambroxol hydrochloride and the arginic compositions of containing is characterized in that being used for the treatment of application in the expelling phlegm drugs in preparation.Ambroxol hydrochloride of the present invention and arginic compositions, mainly be applicable to acute, the chronic respiratory tract disease of and expectoration dysfunction undesired with the sputum secretion, the postoperative pulmonary complication, the thick sputum that poverty-stricken syndrome of motherhood youngster and newborn respiration road (IRDS) and pulmonary tuberculosis etc. cause, the treatment of dys-expectoration.
The inventor investigates with regard to stable aspect ambroxol hydrochloride freeze-dried powder injection and the freeze-dried powder that contains ambroxol hydrochloride and arginine composition of the present invention of patent CN1954808, sees experimental example 2 for details.
The ambroxol hydrochloride that contains of the present invention is compared with immediate existing close technology with arginic composition and method of making the same, has the following advantages:
The present invention has improved the water solublity of ambroxol hydrochloride freeze-dried powder injection by adding arginine, can with the alkalescent medicine compatibility, make things convenient for clinical application; Because adjuvant is simple, consumption is few, 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 ambroxol hydrochloride prescription and freeze-dry process the quality of prepared ambroxol hydrochloride lyophilized powder is loose, adds can dissolve rapidly behind the water and recover the primary characteristic of medicinal liquid and the raising of the stability of ambroxol hydrochloride.Simultaneously, make products obtained therefrom rapid-action, the bioavailability height; Dose controlled, good appearance; Packaging volume is little, and packaging material require low, have reduced packing cost and cost of transportation.
4, the specific embodiment
With the specific embodiment of experimental example form, foregoing of the present invention is described in further detail by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Ambroxol hydrochloride 15g
Arginine 0.15g
Lactose 70g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 0.15g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, the lactose that adds 70g, stirring and dissolving, add water for injection to 2000mL, the injection active carbon of adding 0.1% (g/mL) also stirred 30 minutes, through the buchner funnel filtering decarbonization, No. 4 the incipient fusion filter bulb filters, 0.22 μ m membrane filtration is to clear and bright, by the loading amount fill of every bottle of 2mL in antibiotic glass bottle, butyl rubber bung beyond the Great Wall partly, sabot is sent into and is done the pre-freeze processing in the pre-freeze case.Below temperature of charge is reduced to eutectic point, 10～20 ℃ the time, take out sample rapidly, close freeze drying box, open vacuum pump, material is slowly heated to freeze drying box, lyophilization, tamponade fully, the jewelling lid takes out material, check, printing package.
Embodiment 2
Ambroxol hydrochloride 15g
Arginine 0.15g
Mannitol 70g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 0.15g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 70g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 3
Ambroxol hydrochloride 15g
Arginine 0.75g
Lactose 70g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 0.75g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 70g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 4
Ambroxol hydrochloride 15g
Arginine 0.75g
Mannitol 70g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 0.75g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 70g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 5
Ambroxol hydrochloride 15g
Arginine 1.5g
Lactose 69g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 1.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 69g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 6
Ambroxol hydrochloride 15g
Arginine 1.5g
Mannitol 69g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 1.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 69g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 7
Ambroxol hydrochloride 15g
Arginase 12 g
Lactose 68g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 2g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 68g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 8
Ambroxol hydrochloride 15g
Arginase 12 g
Mannitol 68g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 2g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 68g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 9
Ambroxol hydrochloride 15g
Arginine 3g
Lactose 67g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 3g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 67g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 10
Ambroxol hydrochloride 15g
Arginine 3g
Mannitol 67g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 3g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 67g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 11
Ambroxol hydrochloride 15g
Arginine 4g
Lactose 66g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 4g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 66g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 12
Ambroxol hydrochloride 15g
Arginine 4g
Mannitol 66g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 4g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 66g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 13
Ambroxol hydrochloride 15g
Arginine 4.5g
Lactose 65g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 4.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 65g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 14
Ambroxol hydrochloride 15g
Arginine 4.5g
Mannitol 65g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 4.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 65g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 15
Ambroxol hydrochloride 15g
Arginine 7.5g
Lactose 63g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 7.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 63g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 16
Ambroxol hydrochloride 15g
Arginine 7.5g
Mannitol 63g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 15g ambroxol hydrochloride and 7.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 63g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 17
Ambroxol hydrochloride 30g
Arginine 0.3g
Mannitol 140g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 0.3g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 140g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 18
Ambroxol hydrochloride 30g
Arginine 1.5g
Lactose 140g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 1.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 140g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 19
Ambroxol hydrochloride 30g
Arginine 1.5g
Mannitol 140g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 1.5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 140g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 20
Ambroxol hydrochloride 30g
Arginine 3g
Mannitol 137g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 3g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 137g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 21
Ambroxol hydrochloride 30g
Arginine 5g
Mannitol 135g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 135g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 22
Ambroxol hydrochloride 30g
Arginine 5g
Mannitol 135g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 5g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 135g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 23
Ambroxol hydrochloride 30g
Arginine 6g
Mannitol 134g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 6g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 134g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 24
Ambroxol hydrochloride 30g
Arginine 6g
Lactose 134g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 6g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 134g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 25
Ambroxol hydrochloride 30g
Arginine 8g
Mannitol 132g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 8g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 132g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 26
Ambroxol hydrochloride 30g
Arginine 8g
Lactose 132g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 8g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 132g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 27
Ambroxol hydrochloride 30g
Arginine 9g
Mannitol 131g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 9g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 131g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 28
Ambroxol hydrochloride 30g
Arginine 9g
Lactose 131g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 9g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 131g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 29
Ambroxol hydrochloride 30g
Arginine 15g
Mannitol 125
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 15g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the mannitol of 125g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Embodiment 30
Ambroxol hydrochloride 30g
Arginine 15g
Lactose 125g
Water for injection adds to 2000mL
Make 1000 bottles altogether
Take by weighing 30g ambroxol hydrochloride and 15g arginine, place appropriate vessel, add the about 1500mL of injection water, after stirring is dissolved it fully, add the lactose of 125g, stirring and dissolving adds water for injection to 2000mL, and is remaining with embodiment 1.
Experimental example 1
This experimental example is the screening experiment of concentration of activated carbon.Selecting for use the injection active carbon of variable concentrations to adsorb respectively, serves as to investigate index with clarity, the content that filters the front and back ambroxol hydrochloride, the consumption of screening active carbon.The inspection employing of clarity " two clarity inspection techniques of Chinese Pharmacopoeia version in 2005, concrete experimental technique and result are as follows:
1) experimental technique:
The prescription preparation ambroxol hydrochloride of employing embodiment 10 and arginic compositions are with the solution 400mL of mannitol, form the turbid white liquid of microemulsion, solution is divided into 4 parts, every part of about 100mL, the active carbon that adds 0.05%, 0.1%, 0.15%, 0.2% (g/mL) respectively, stir 20 minutes after-filtration and take off charcoal, get achromatism and clarity solution.
2) experimental result:
Table 1 active carbon is to the influence of content
By result shown in the above chart as can be seen: activated carbon dosage is 0.05% o'clock, the color of solution does not change basically, the principal agent of solution is adsorbed bigger when consumption is 0.15%, 0.2%, have only that solution is achromatism and clarity solution when consumption is 0.1%, and principal agent is adsorbed less, therefore, select for use 0.1% active carbon as adsorbent.
Experimental example 2
This experimental example is to utilize the freeze-dried powder of prepared ambroxol hydrochloride of the present invention and arginic compositions and patent CN101224196 ambroxol hydrochloride freeze-dried powder injection product to carry out stability test, the stability that compares both according to conventional accelerated test, the freeze-dried powder of ambroxol hydrochloride of the present invention and arginic compositions adopts the method preparation of embodiment 10, the ambroxol hydrochloride freeze-dried powder injection of patent CN101224196 adopts the method preparation of embodiment 3, and result of the test sees the following form.
The stability of table 2 the present invention and patent CN101224196 ambroxol hydrochloride freeze-dried powder injection relatively
By table 2 result as seen, under different time, the freeze-dried powder stability that contains ambroxol hydrochloride and arginine composition of the present invention better, the preparation more stable with respect to patent CN101224196 is more suitable for long term storage, is adapted to more that industry is big produces.
Experimental example 3
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 " two ones of Chinese pharmacopoeia versions in 2005 the results are shown in following table:
The Performance Detection of table 3 ambroxol hydrochloride freeze-dried powder injection of the present invention
Can learn that every performance of gained ambroxol hydrochloride freeze-dried powder injection of the present invention is all qualified, and the content of related substance, moisture improve than prior art all.
Experimental example 4
This experimental example is to utilize the freeze-dried powder of prepared ambroxol hydrochloride of the present invention and arginic compositions and patent CN101224196 ambroxol hydrochloride freeze-dried powder injection product to carry out dissolution velocity comparative study.The freeze-dried powder of ambroxol hydrochloride of the present invention and arginic compositions adopts the method preparation of embodiment 10, and the ambroxol hydrochloride freeze-dried powder injection of patent CN101224196 adopts the method preparation of embodiment 3.Press the pH assay method of ambroxol hydrochloride among the European Pharmacopoeia EP2001, measure the pH value of the present invention and patent CN101224196 respectively.Measure its fusing point by the requirement of Chinese Pharmacopoeia version appendix in 2005.Get 1g respectively, add 100mL water, its dissolution velocity is measured in jolting gently.Comparative determination result such as following table:
The dissolution velocity of table 4 the present invention and patent CN101224196 ambroxol hydrochloride
The result shows: the dissolution velocity that the present invention makes freeze-dried powder makes the dissolution velocity of freeze-dried powder far away faster than patent CN101224196.
Claims (10)
1. one kind contains ambroxol hydrochloride and arginic compositions, it is characterized in that: described ambroxol hydrochloride and arginic weight ratio are 1: 0.01～0.8.
2. ambroxol hydrochloride and the arginic compositions of containing as claimed in claim 1, it is characterized in that: described ambroxol hydrochloride and arginic weight ratio are 1: 0.05～0.5.
3. ambroxol hydrochloride and the arginic compositions of containing as claimed in claim 2, it is characterized in that: described ambroxol hydrochloride and arginic weight ratio are 1: 0.1～0.3.
4. ambroxol hydrochloride and the arginic compositions of containing as claimed in claim 3, it is characterized in that: described ambroxol hydrochloride and arginic weight ratio are 1: 0.2.
5. as described ambroxol hydrochloride and the arginic compositions of containing of each claim of claim 1～4, it is characterized in that: describedly contain ambroxol hydrochloride and arginic compositions is a freeze-dried powder.
6. the freeze-dried powder that contains ambroxol hydrochloride and arginic compositions as claimed in claim 5, it is characterized in that: its freeze-dried powder adds excipient, and described excipient is selected from mannitol, lactose, sorbitol, glucose, xylitol, lactose, fructose, maltose or sodium chloride.
7. the freeze-dried powder that contains ambroxol hydrochloride and arginic compositions as claimed in claim 6 is characterized in that: described excipient is selected from mannitol or lactose.
8. as the described freeze-dried powder that contains ambroxol hydrochloride and arginic compositions of each claim of claim 6～7, it is characterized in that: the described preparation method that contains the freeze-dried powder of ambroxol hydrochloride and arginine composition is:
(1) ambroxol hydrochloride and the arginine with recipe quantity joins in the water for injection, after stirring is dissolved it fully, adds the mannitol of recipe quantity, stirring and dissolving, and benefit adds to the full amount of water for injection;
(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.
9. the freeze-dried powder that contains ambroxol hydrochloride and arginine composition as claimed in claim 8 is characterized in that: the consumption of active carbon is 0.1% of a liquor capacity in the described step (2).
10. as described ambroxol hydrochloride and the arginic compositions of containing of each claim of claim 1～4, it is characterized in that being used for the treatment of application in the expelling phlegm drugs in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910008473A CN101756948A (en) | 2008-11-20 | 2009-02-03 | Composition of ambroxol hydrochloride and arginine and preparation method thereof |
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| CN200810180022.5 | 2008-11-20 | ||
| CN200910008473A CN101756948A (en) | 2008-11-20 | 2009-02-03 | Composition of ambroxol hydrochloride and arginine and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860461A (en) * | 2012-12-17 | 2014-06-18 | 长春海悦药业有限公司 | Medicinal composition containing active component ambroxol hydrochloride |
| CN107213123A (en) * | 2017-07-23 | 2017-09-29 | 南京正宽医药科技有限公司 | A kind of Ambroxol Hydrochloride for Injection and preparation method thereof |
-
2009
- 2009-02-03 CN CN200910008473A patent/CN101756948A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860461A (en) * | 2012-12-17 | 2014-06-18 | 长春海悦药业有限公司 | Medicinal composition containing active component ambroxol hydrochloride |
| CN103860461B (en) * | 2012-12-17 | 2016-04-13 | 长春海悦药业有限公司 | A kind of pharmaceutical composition containing active ingredient hydrochloric acid ambroxol |
| CN107213123A (en) * | 2017-07-23 | 2017-09-29 | 南京正宽医药科技有限公司 | A kind of Ambroxol Hydrochloride for Injection and preparation method thereof |
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