CN102058548B - Ambroxol hydrochloride composition for injection and preparation method thereof - Google Patents
Ambroxol hydrochloride composition for injection and preparation method thereof Download PDFInfo
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- CN102058548B CN102058548B CN 201010615049 CN201010615049A CN102058548B CN 102058548 B CN102058548 B CN 102058548B CN 201010615049 CN201010615049 CN 201010615049 CN 201010615049 A CN201010615049 A CN 201010615049A CN 102058548 B CN102058548 B CN 102058548B
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Abstract
The invention relates to an ambroxol hydrochloride composition for injection and a preparation method thereof. The composition contains ambroxol hydrochloride and mannitol. The preparation method comprises the steps of: (1) preparing: placing the ambroxol hydrochloride and the mannitol in a preparation tank according to the proportion of 1:(1-4), adding water for injection, and stirring to ensure that the ambroxol hydrochloride and the mannitol are completely dissolved and uniformly mixed; (2) aseptically filtering, split-charging and plugging half; and (3) freezing and drying in vacuum to obtain the ambroxol hydrochloride composition. The ambroxol hydrochloride composition provided by the invention has the advantages of simple prescription, advanced process, uniform and stable quality, completely moisture dryness and better re-solubility.
Description
Technical field
What the present invention relates to is ambroxol hydrochloride composition of a kind of injection and preparation method thereof; The prophylactic treatment that can be used for the postoperative pulmonary complication through the ambroxol hydrochloride composition of this method preparation; Secrete acute, the chronic respiratory tract disease of undesired and expectoration dysfunction with sputum; The particularly treatment of eliminating the phlegm of chronic bronchitis acute exacerbation and asthmatic bronchitis, and the treatment of premature infant and congenital alveolar dysplasia.
Background technology
The ambroxol hydrochloride chemical name is trans-4-(2-amino-3,5-dibromobenzene methylamino) cyclohexanol hydrochloridumi.
Its structural formula is:
Molecular formula: C
13H
18Br
2N
2OHCl
Molecular weight: 414.58.
Ambroxol hydrochloride (Ambroxol Hydrochloride) is that German Karl Thomae drugmaker produces; The vigorous woods Ge Haimu corporate agent's of the Yin Dynasty of Germany (Boehringer Ingelheim) expelling phlegm drugs of new generation; It is found when research bromine amine (bromhexine hydrochloride Bisolvon); Be bromine one of amine metabolite in vivo, be the derivant of two bromo benzylamines, have the selectivity that promotes the effect that mucus is got rid of and dissolve secretions.Can promote the discharge of thick secretions in the respiratory tract and reduce mucous delay, thereby significantly promote expectoration, improve breath state.When using the ambroxol treatment, the mucous secretion of patient can return to normal condition.Cough and amount of expectoration significantly reduce usually, breathe surfactant on the mucosa thereby the defencive function that can bring into normal play.
The dosage forms that adopt freeze-dried powders when ambroxol hydrochloride poor stability, clinical use more, ambroxol itself is poorly soluble; Therefore clinical preparation uses its hydrochlorate as active component more, and well-known, hydrochloric acid is volatile acid; Highly volatile, under the vacuum condition, evaporable speed is faster.Adopt traditional freeze-dry process; Because part HCl is taken away under high vacuum condition in the ambroxol hydrochloride, causes the ambroxol hydrochloride salify not thorough, the part ambroxol exists with the form of base; Can not dissolve fully during clinical use; Visible foreign matters, particulate matter and the underproof phenomenon of clarity occur, these phenomenons all show, adopt in the hydrochloride for injection ambroxol of traditional lyophilizing prepared to have more molecule.In these granules; Diameter can block blood flow through PC the time at 5～20 microns and above granule; Thereby cause like pulmonary infarction complication even worried dead; Exogenous granule also can form phlebitis in the injection site, possibly cause also that simultaneously vein blood vessel blocks and patient's injury, has bigger clinical safety hidden danger.Press for a kind of hydrochloric acid volatilization of avoiding, improve the technical scheme of ambroxol hydrochloride freeze-dried powder injection agent redissolution performance.
CN02156916.9 discloses a kind of ambroxol hydrochloride injection that contains HP-and preparation method thereof; Solve the dissolubility of ambroxol hydrochloride in high pH value water through adding " 2-HP-"; Owing to need to add extra adjuvant HP-, well do not solve above-mentioned technological deficiency with big clinical side reaction risk.
CN 200810009183.8 discloses a kind of ambroxol hydrochloride freeze-dried powder injection and preparation method thereof, is made up of ambroxol hydrochloride and mannitol, does not solve above-mentioned technological deficiency.
CN 200610044429.6 discloses a kind of Pharmaceutical composition of treating productive cough; It is an active component by ambroxol hydrochloride, guaifenesin, Levalbuterol; Combine with acceptable accessories, do not solve above-mentioned technological deficiency.
CN 200610066946.3 discloses prescription of a kind of amoxicillin sodium for injection/ambroxol hydrochloride powder pin and preparation method thereof; Dosage form is an injectable powder; Wherein contain Amoxicillin Sodium, ambroxol hydrochloride; Content ratio is 25～100 parts of amoxicillin, 1～5 part of ambroxol hydrochloride, but optimal proportion is 50: 3, and the optimum content formula proportion is 50: 3; The present invention has overcome that Amoxicillin Sodium/ambroxol hydrochloride oral preparation bioavailability is poor, and onset is slow, and the shortcoming that gastrointestinal side effect is many does not solve above-mentioned technological deficiency.
CN 200510073169.0 discloses a kind of amoxicillin of suitable child's application and compound preparation and the prescription and the method for preparing of ambroxol hydrochloride, and dosage form comprises powder and granule, does not solve above-mentioned technological deficiency.
CN 200510118511.4 discloses a kind of high dose Ambroxol hydrochloride freeze-dried preparation and method for preparing, and every bottle of ambroxol-hydrochloride-containing of its lyophilized formulations is up to 500mg; Can dissolve entirely in about 30 seconds behind the adding water for injection, solution is clarified, but needs to add the cosolvent of more amount, the above-mentioned technological deficiency of not good solution.
CN 200710059969.6 discloses a kind of ambroxol hydrochloride injection; With the ambroxol hydrochloride is active component; Stable type pharmaceutical composition with pharmaceutically acceptable carrier composition; These carriers comprise water-soluble filler, pH regulator agent, stabilizing agent, water for injection or osmotic pressure regulator etc., do not solve above-mentioned technological deficiency.
CN 200810010209.0 discloses a kind of method for preparing of ambroxol for injection freeze-dried powder; Behind the aqueous solution of this method configuration ambroxol-hydrochloride-containing; Using sodium hydroxide to transfer pH is 6～8, and it is 5～6 that reuse phosphoric acid is transferred pH, and the packing lyophilization promptly gets; Need to add extra buffer salt, well do not solve above-mentioned technological deficiency.
CN 201010195712.5 discloses injection of a kind of ambroxol and preparation method thereof, needs extra interpolation sodium hydrogen phosphate and citric acid, does not solve above-mentioned technological deficiency.
CN 201010199259.5 discloses a kind of ambroxol hydrochloride composition, needs extra interpolation citric acid, sodium hydrogen phosphate and sodium chloride, does not solve above-mentioned technological deficiency.
Existing known technology is all less than the suggestion that above defective is proposed improve.
Summary of the invention
The objective of the invention is provides ambroxol hydrochloride composition of injection and preparation method thereof to above weak point; This poor stability of ambroxol hydrochloride is needed lyophilizing; Highly volatile HCl dissociate the medicine of indissoluble base again simultaneously; The present invention can significantly reduce even eliminate the phenomenon that HCl is taken away under high vacuum environment, preparation redissolution performance and clinical application safety are more guaranteed.
Inventor of the present invention finds that through research experiment the control through the dryer link to vacuum lyophilization suits stage by stage need not the significant prolongation freeze-drying time, can effectively control the volatilization of HCl, obtains the lyophilized formulations of redissolution function admirable.
At first, reduce products temperature with 10～15 ℃/hour speed, as 40 ℃ of products temperature Di Yu –; Being incubated 60 minutes freezes the ambroxol hydrochloride medicinal liquid fully; Through this process, can be so that the ambroxol hydrochloride medicinal liquid be frozen into framework firmly and stabilization of solid has bigger distillation duct simultaneously; Make moisture to take away by unobstructed quilt, the situation that HCl is pulled away with steam when having reduced distillation.
Secondly, at the intensification sublimation stage, Sheng 25 ℃ of Wen Zhi – for the first time, keeping vacuum through ginseng gas is 5～10Pa; Continue 2 hours, Sheng 15 ℃ of Wen Zhi – for the second time, keeping vacuum through ginseng gas is 10～15Pa; Continue 2 hours, Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa; Continue 2 hours, be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa; Continue 3 hours,, make HCl after temperature raises, also not have tangible volatilization through corresponding especially temperature and vacuum degree control.
Once more, because the process of front has been accomplished dryer basically, water content seldom in the goods; Most of HCl is connected with very firm chemical bond with ambroxol, and the evaporable risk of HCl is extremely low, so the 5th time is warming up to 25 ℃; Do not control vacuum; Continue 3 hours, accomplished drying in the short period of time, make that freeze-drying time can significant prolongation residual moisture.
At last, the final drying temperature of goods is 35 ℃, continues 4～6 hours, in close after the case vacuum does not have significant change before the valve; Tamponade, outlet, with plastic-aluminum composite cover tying, packing after quality inspection is qualified; Promptly get, in this process, only have the adsorbed water of minute quantity to exist; HCl can volatilize hardly, and higher baking temperature can guarantee that product dried is more thorough, thereby has better stability.
Can significantly reduce even eliminate the phenomenon that HCl is taken away through said method under high vacuum environment, preparation redissolution performance and clinical application safety are more guaranteed.
The ambroxol hydrochloride composition of injection provided by the invention, specific as follows:
A kind of ambroxol hydrochloride composition of injection contains ambroxol hydrochloride and mannitol, prepares according to following method:
1) preparation: ambroxol hydrochloride and mannitol are put in the preparing tank for 1:1～4 by weight proportion, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
2) aseptic filtration, packing: the step is gathered 1) the ambroxol hydrochloride solution that obtains to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
3) vacuum lyophilization:
A, pre-freeze: the step is gathered 2) divide the ambroxol hydrochloride medicinal liquid that installs to put in the freeze dryer, reduce products temperature with 10～15 ℃/hour speed, when products temperature hangs down in 40 ℃ of –, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4～6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets.
A kind of method for preparing of ambroxol hydrochloride composition of injection is:
1) preparation: ambroxol hydrochloride and mannitol are put in the preparing tank for 1:1～4 by weight proportion, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
2) aseptic filtration, packing: the step is gathered 1) the ambroxol hydrochloride solution that obtains to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
3) vacuum lyophilization:
A, pre-freeze: the step is gathered 2) divide the ambroxol hydrochloride medicinal liquid that installs to put in the freeze dryer, reduce products temperature with 10～15 ℃/hour speed, when products temperature hangs down in 40 ℃ of –, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4～6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets.
Only ambroxol-hydrochloride-containing, mannitol and pH regulator agent in freeze dried product, in the finished product in component and the raw material ratio do not have substantial variation.
Ambroxol hydrochloride composition of injection of the present invention and preparation method thereof; This poor stability of ambroxol hydrochloride is needed lyophilizing; Highly volatile HCl dissociate the medicine of indissoluble base again simultaneously; Can significantly reduce even eliminate the phenomenon that HCl is taken away under high vacuum environment, preparation redissolution performance and clinical application safety are more guaranteed.The present invention has improved the redissolution performance of the ambroxol hydrochloride composition of injection greatly, the ambroxol hydrochloride composition quality stable homogeneous of the injection of preparation, and content is evenly accurate, and moisture drying is thorough, and the stability in transportation and storage process is better.Preparation technology of the present invention is simple, and is convenient feasible, good reproducibility, and production cost is lower, is easy to realize industrialized great production, thereby can produce considerable economic and social benefit.
The specific embodiment
Further specify the present invention through embodiment below.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the present invention and requires the scope protected.
Be guarantee test result's concordance, the embodiment of the invention has been used identical raw material, adjuvant, cillin bottle and plug.
Embodiment 1:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 150g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, products temperature is fallen low, be incubated to the ambroxol hydrochloride medicinal liquid and freeze fully to 40 ℃ of –;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up, the final drying temperature is 35 ℃; Continue 4 hours, in close after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, after quality inspection is qualified, pack, promptly get the ambroxol hydrochloride composition of injection.
Embodiment 2:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 600g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, products temperature is fallen low, be incubated to the ambroxol hydrochloride medicinal liquid and freeze fully to 40 ℃ of –;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up, the final drying temperature is 35 ℃; Continue 6 hours, in close after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, after quality inspection is qualified, pack, promptly get the ambroxol hydrochloride composition of injection.
Embodiment 3:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 300g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, products temperature is fallen low, be incubated to the ambroxol hydrochloride medicinal liquid and freeze fully to 40 ℃ of –;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up, the final drying temperature is 35 ℃; Continue 5 hours, in close after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, after quality inspection is qualified, pack, promptly get the ambroxol hydrochloride composition of injection.
Embodiment 4:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 150g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 10 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 5:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 300g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 15 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 5.5 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 6:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 450g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 13 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4.5 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 7:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 600g
Water for injection adds to 20Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 12 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 5 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 8:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 600g
Water for injection adds to 30Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 14 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 9:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 150g
Water for injection adds to 25Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 15 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 5 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 10:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 300g
Water for injection adds to 40Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 10 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 11:
Prescription:
Ambroxol hydrochloride 150g
Mannitol 450g
Water for injection adds to 30Kg
Preparation:
Ambroxol hydrochloride and mannitol are put in the preparing tank, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
Aseptic filtration, packing:
The ambroxol hydrochloride solution that preparation is obtained to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
Vacuum lyophilization:
A, pre-freeze: the ambroxol hydrochloride medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature,, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully when products temperature hangs down in 40 ℃ of – with 12 ℃/hour speed;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through ginseng gas is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through ginseng gas is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through ginseng gas is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets the ambroxol hydrochloride composition of injection.
Embodiment 12:
Each prepares the ambroxol hydrochloride composition of injection respectively by embodiment 1～11, checks pH value, solubility, visible foreign matters, clarity and capacitive microgranule not more respectively, and its result sees table 1:
?
Can find out from table 1; Technical scheme of the present invention (embodiment 4～11) compares with prior art (embodiment 1～3); Significantly improved the redissolution performance of ambroxol hydrochloride composition, at pH value, visible foreign matters, clarity and do not have clear superiority on the quality control level of capacitive microgranule.
Claims (2)
1. the ambroxol hydrochloride composition of an injection is characterized in that containing ambroxol hydrochloride and mannitol, prepares according to following method:
1) preparation: ambroxol hydrochloride and mannitol are put in the preparing tank for 1:1～4 by weight proportion, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
2) aseptic filtration, packing: the step is gathered 1) the ambroxol hydrochloride solution that obtains to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
3) vacuum lyophilization:
A, pre-freeze: the step is gathered 2) divide the ambroxol hydrochloride medicinal liquid that installs to put in the freeze dryer, reduce products temperature with 10～15 ℃/hour speed, when products temperature hangs down in 40 ℃ of –, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through aeration is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through aeration is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through aeration is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through aeration is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4～6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets.
2. the method for preparing of the ambroxol hydrochloride composition of the described injection of claim 1 is characterized in that method for preparing is:
1) preparation: ambroxol hydrochloride and mannitol are put in the preparing tank for 1:1～4 by weight proportion, added the injection water, stir and make it to dissolve fully also mix homogeneously, and regulate pH value to 5.3 with the hydrochloric acid of 0.1mol/L and the sodium hydroxide solution of 0.1mol/L;
2) aseptic filtration, packing: the step is gathered 1) the ambroxol hydrochloride solution that obtains to sterilizing room, is sub-packed in the cillin bottle false add plug through filtering with microporous membrane;
3) vacuum lyophilization:
A, pre-freeze: the step is gathered 2) divide the ambroxol hydrochloride medicinal liquid that installs to put in the freeze dryer, reduce products temperature with 10～15 ℃/hour speed, when products temperature hangs down in 40 ℃ of –, be incubated 60 minutes the ambroxol hydrochloride medicinal liquid is freezed fully;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, drying: the open vacuum pump with at a distance from valve, begin the sublimation drying that heats up,
Sheng for the first time 25 ℃ of Wen Zhi –, keeping vacuum through aeration is 5～10Pa, continues 2 hours,
Sheng for the second time 15 ℃ of Wen Zhi –, keeping vacuum through aeration is 10～15Pa, continues 2 hours,
Sheng 5 ℃ of Wen Zhi – for the third time, keeping vacuum through aeration is 15～20Pa, continues 2 hours,
Be warming up to 5 ℃ the 4th time, keeping vacuum through aeration is 20～30Pa, continues 3 hours,
Be warming up to 25 ℃ the 5th time, do not control vacuum, continue 3 hours,
The final drying temperature is 35 ℃, continues 4～6 hours, in close after the case vacuum does not have significant change before the valve, tamponade, outlet with plastic-aluminum composite cover tying, is packed after quality inspection is qualified, promptly gets.
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| CN106511283B (en) * | 2016-12-02 | 2019-09-24 | 苏州天马医药集团天吉生物制药有限公司 | A kind of lyophilized technique of clindamycin phosphate for injection |
| 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 |
| 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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