CN102716076B - Ambroxol hydrochloride medicine combination for injection - Google Patents
Ambroxol hydrochloride medicine combination for injection Download PDFInfo
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- CN102716076B CN102716076B CN 201210231905 CN201210231905A CN102716076B CN 102716076 B CN102716076 B CN 102716076B CN 201210231905 CN201210231905 CN 201210231905 CN 201210231905 A CN201210231905 A CN 201210231905A CN 102716076 B CN102716076 B CN 102716076B
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- Prior art keywords
- ambroxol hydrochloride
- injection
- acetic acid
- glacial acetic
- water
- Prior art date
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- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 130
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 128
- 238000002347 injection Methods 0.000 title claims abstract description 61
- 239000007924 injection Substances 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 title abstract description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000000243 solution Substances 0.000 claims abstract description 38
- 230000001954 sterilising effect Effects 0.000 claims abstract description 37
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 238000003756 stirring Methods 0.000 claims abstract description 31
- 239000008215 water for injection Substances 0.000 claims abstract description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960000583 acetic acid Drugs 0.000 claims abstract description 26
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 26
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 25
- 239000001632 sodium acetate Substances 0.000 claims abstract description 25
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 25
- 238000007689 inspection Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000003610 charcoal Substances 0.000 claims description 21
- 229940105082 medicinal charcoal Drugs 0.000 claims description 21
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- 238000000967 suction filtration Methods 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 238000012360 testing method Methods 0.000 description 23
- 238000004659 sterilization and disinfection Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 11
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- 206010036790 Productive cough Diseases 0.000 description 9
- 239000013618 particulate matter Substances 0.000 description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 229910000397 disodium phosphate Inorganic materials 0.000 description 8
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- 210000002345 respiratory system Anatomy 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 210000003802 sputum Anatomy 0.000 description 7
- 208000024794 sputum Diseases 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229960005174 ambroxol Drugs 0.000 description 6
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 6
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
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- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an ambroxol hydrochloride medicine combination for injection. The ambroxol hydrochloride injection is composed of ambroxol hydrochloride, sodium chloride, glacial acetic acid and sodium acetate, wherein each ambroxol hydrochloride injection is composed of 15-30mg of ambroxol hydrochloride, 18-36mg of sodium chloride, 10-20mg of glacial acetic acid and 2.52-5.1g of sodium acetate. The preparing method includes: taking 90% of water for injection as the prescription amount; adding the glacial acetic acid and the sodium acetate as the prescription amount for stirring to dissolve the glacial acetic acid and the sodium acetate at the temperature of 55-65 DEG C; adding the ambroxol hydrochloride as the prescription amount, stirring to dissolve the ambroxol hydrochloride, adding the sodium chloride as the prescription amount in the solution, and stirring to totally dissolve the sodium chloride; measuring the initial pH value, regulating the pH value to be within the range of 3.5-4.5 with 10% glacial acetic acid solution; adding 0.05% of medical carbon in the solution, stirring and standing for 30 minutes; performing suction filtration, replenishing injection water to full amount, and evenly mixing; performing fine filtering; filling; sterilizing for 15 minutes under hot pressure at the temperature of 121 DEG C; performing lamp inspection; warehousing; and obtaining the ambroxol hydrochloride injection. The ambroxol hydrochloride medicine combination is good in photo-stability and stability, improves product yield, reduces cost, achieves industrialization, can be better applied to clinical medicine and has obvious advantages.
Description
Technical field
The present invention relates to the medicine in field of medicaments, especially relate to a kind of stablely to light, can not produce particulate matter, ambroxol hydrochloride pharmaceutical composition of the injection of good stability and preparation method thereof.
Background technology
Ambroxol hydrochloride is a kind of glutinous expectorant lytic agent, has another name called AMB, expectorant and improve the characteristics such as the pulmonary function effect is strong and be widely used in clinical.This medicine can act on secretory cell, regulates the secretion of serosity and mucus, and serous secretion is increased, the mucus dissolved dilution, and can strengthen the swing of cilium, and increase the removing ability of mucus transportation system, make sputum be easy to discharge.Ambroxol hydrochloride is also a kind of respiratory system protective agent, has antioxidation, the release of inflammation-inhibiting medium, and lax airway smooth muscle promotes the effects such as synthetic and secretion of pulmonary surfactant.Ambroxol hydrochloride can also increase the drug level of antibiotic in air flue, thereby improves antibiotic curative effect.
Ambroxol hydrochloride
English name: Ambroxol Hydrochloride;
Chemical name: Ambroxol Hydrochloride;
Molecular formula: C
13H
18Br
2N
2OHCl;
Structural formula:
Respiratory system disease is one of disease kind of being familiar with of people, such as flu, and cough, bronchitis, bronchial asthma etc. mostly are commonly encountered diseases and frequently-occurring disease.Respiratory system disease occurs in human respiratory tract's (comprising throat, trachea, bronchus and pulmonary), and to cough, expectorant is breathed heavily, and is its common symptom.These symptoms affect patient's rest and health, if do not heal for a long time, also may develop into emphysema, bronchiectasis and pulmonary heart disease etc.When respiratory tract is ill, cough, expectorant and to breathe heavily can be independent appearance, but also exist simultaneously often, and can promote mutually or increase the weight of.For example, expectorant can stimulate respiratory mucosa to cause cough; When abundant expectoration blocks bronchioles, not only cause asthma, can also cause secondary infection, further damage respiratory tract, increase the weight of cough, cough up phlegm and pant.
Sputum is secreted by the body of gland of trachea and bronchus (mucous gland, serous gland) and goblet cell.Under normal circumstances, a small amount of mucus of body of gland and goblet cell secretion is covered in the respiratory mucosa surface, plays protective effect, and the microgranules such as the dust of suction can be sticked by mucus, are discharged by the cilium directed movement simultaneously.In the situation that respiratory inflammation, body of gland and goblet cell hyperplasia are loose, secretions increase, and viscosity increases, ciliated cell pathological changes in addition, ciliary movement goes down, and mucus can not in time be discharged, so expectorant is arranged.But sensor and afferent nerve endings under the sputum irritates nucous membrane increase the weight of or cause cough, also can block respiratory tract, cause out of breathly even to suffocate.The stagnant of sputum created condition for secondary infection again, further damages respiratory tissues, and the symptom that makes cough, coughs up phlegm and pant further increases the weight of, and forms vicious cycle.The important measure of curing the disease to the ill so dispel sputum.
The sickness rate of China's diseases of respiratory system and case fatality rate are all high in recent years, at present, have been China human mortality's the third-largest factor.Therefore, the exploitation for the treatment of medicament for treating respiratory system thing also becomes a pith of drug research.In the situation that respiratory tract infection (as respiratory tract diseases such as chronic bronchitiss), tend to produce a large amount of sputums, respiratory tract is stopped up in the existence of expectorant, easily cause cough, pant, even causing dyspnea, so especially the difficulty of spitting often appears in children's and old man. the application of expectorant is very necessary.Ambroxol hydrochloride series is to act on clinically at present the strongest expectorant, and is very sure to its curative effect both at home and abroad.
The first-elected listing of Germany Boehringer Ingelheim company in 1979, to have toxicity low because of it, expectorant and improve the characteristics such as the pulmonary function effect is strong and be widely used in clinically and successively goes on the market in nearly 20 countries such as Italy, Switzerland, Argentina, Japan, France, Spain, Singapore, Thailand.China is in beginning import in 1991, mainly contains the mucosolvan etc. that German He Su reaches An Pusuo that the pharmaceutical factory produces, German Boehringer Ingelheim company.In recent years, the study hotspot of ambroxol turns to for breast, abdominal postoperative prevention pulmonary infection, pulmonary atelectasis.Particularly before art with chronic bronchitis or the patient of other basic pulmonary disease, after operation, because body fluid reduces, stomach tube keeps, bed, the reasons such as wound pain cause thick sputum to be difficult for expectoration, the serious even threat to life of pulmonary infection that causes.
Application number be CN201110388637.9 disclosure of the invention a kind of Ambroxol hydrochloride liposome injection and method for making thereof.This lipidosome injection is made by ambroxol hydrochloride, cholesterol, soy phosphatidylserine, soyasterol, Tween 80, trehalose and the PVP of specified weight proportioning.Introduce Tween 80 in injection, can cause haemolysis, reliability can not effectively guarantee.
Application number is that the invention of CN201110163622.2 belongs to pharmaceutical field, is specifically related to the preparation method of the stable ambroxol hydrochloride injection of a kind of pH value.Concrete: be to guarantee that by adding buffer system solution pH value before and after sterilization is stable, avoid sterilization front and back pH value generation significant change, reduce the generation of impurity, select buffering to the pH stabilizing agent as solution, the buffering that adopts is to being citric acid-sodium hydrogen phosphate, and is a pair of arbitrarily in citric acid-sodium citrate.And select by above-mentioned buffering to the pH scope of the buffer of preparation between 4.5 ~ 5.5.The committed step of preparation method of the present invention is to utilize buffer salt system to guarantee that pH is stable, reduces or avoids the ambroxol hydrochloride degraded to generate impurity B and impurity E, is conducive to medicine performance curative effect, and avoids having side effects because of impurity.
What application number was that the invention of CN201010615049.X relates to is ambroxol hydrochloride composition of a kind of injection and preparation method thereof, said composition contains ambroxol hydrochloride and mannitol, its preparation method is: 1) preparation: ambroxol hydrochloride and mannitol are put in preparing tank for 1:1 ~ 4 by weight proportion, inject water, stir and make it to dissolve fully also mix homogeneously; 2) aseptic filtration, packing are partly jumped a queue; 3) vacuum lyophilization, and get final product.The present invention fills a prescription simply, and technique is advanced, the quality stable homogeneous, and moisture drying is thorough, and the performance of redissolving is better.
application number provides a kind of ambroxol hydrochloride composition for the invention of CN201010199259.5, said composition comprises following composition: ambroxol hydrochloride 14-16 weight portion, citric acid 2.6-3.2 weight portion, sodium hydrogen phosphate 4.8-6.0 weight portion and sodium chloride 13-16 weight portion, the resulting ambroxol hydrochloride injection component of ambroxol hydrochloride injection that also has above-mentioned composition to make is simple, under higher PH (5.5-7.0) condition, the stability of active medicine ambroxol hydrochloride is higher, be more suitable for the human injection, the sense of discomfort of bringing to the patient when reducing injection.
Application number provides injection of a kind of ambroxol and preparation method thereof for the invention of CN201010195712.5, this injection contains ambroxol or its pharmaceutically acceptable salt, sodium hydrogen phosphate and citric acid, wherein, the weight ratio of ambroxol or its pharmaceutically acceptable salt, sodium hydrogen phosphate and citric acid is 1: 0.18-0.22: 0.12-0.16, preferably, the weight ratio of ambroxol or its pharmaceutically acceptable salt, sodium hydrogen phosphate and citric acid is 1: 0.20: 0.14.The pharmaceutically acceptable salt of ambroxol of the present invention is preferably hydrochlorate.The activated carbon dosage that adopts in preparation is 0.2-0.3%.
Application number be CN200910306512.X disclosure of the invention a kind of ambroxol hydrochloride small-volume injection and preparation method thereof of high stability.Ambroxol hydrochloride low capacity intravenous injection of the present invention, wherein the concentration expressed in percentage by weight of ambroxol hydrochloride is 0.3 ~ 4%, wherein ambroxol hydrochloride solution comprises that also can form soda acid cushions right component, and wherein ambroxol hydrochloride solution also comprises carbon dioxide, and the segment space in ampoule is filled with nitrogen.
Application number be CN200910090241.9 the invention discloses a kind of ambroxol hydrochloride liquid preparation and preparation method thereof.The method comprises the steps: ambroxol hydrochloride, stabilizing agent and osmotic pressure regulator are dissolved in water for injection, and mixing obtains solution I, then solution I is filtered, and obtains ambroxol hydrochloride liquid preparation.Do not introduce active carbon in preparation method of the present invention.
application number is that the invention of CN200710059969.6 relates to pharmaceutical preparation, more particularly, relate to a kind of ambroxol hydrochloride injection, it is take ambroxol hydrochloride as active component, stable type pharmaceutical composition with pharmaceutically acceptable carrier composition, these carriers comprise water-soluble filler, pH adjusting agent, stabilizing agent, water for injection or osmotic pressure regulator etc., owing to adopting described carrier to carry out the science preparation, guaranteed freeze-dried powder of the present invention, the drug quality of small injection and primary infusion preparation and drug safety, and can improve the stability of goods in storage process.
The ambroxol hydrochloride injection that prior art is produced has very strict requirement to the requirement of storage, lucifuge, all has inconvenience in use, preservation and transportation.
The inventor is through studying for a long period of time, the unexpected discovery used special adjuvant, the ambroxol hydrochloride pharmaceutical composition of special process preparation, light resistance is good, be difficult for to produce particulate matter, good stability has not only successfully solved the problem of the poor stability of ambroxol hydrochloride, reduce production costs, easy to implement, can realize industrialization, remarkable in economical benefits.
Summary of the invention
The first purpose of the present invention is to provide a kind of ambroxol hydrochloride pharmaceutical composition of injection, this ambroxol hydrochloride injection is stable to light, be difficult for producing particulate matter, good stability, to improving product yield, reduce costs, realize industrialization, better be applied to clinically, have more obvious advantage.
The second purpose of the present invention is to provide a kind of preparation method of ambroxol hydrochloride pharmaceutical composition of injection, and the method is simple, prepared ambroxol hydrochloride pharmaceutical composition, stable to light, be difficult for producing particulate matter, clarity is good, good stability.
For realizing the first purpose of the present invention, the present invention adopts following technical scheme:
A kind of ambroxol hydrochloride pharmaceutical composition of injection, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 15-30g
Sodium chloride 18-36g
Glacial acetic acid 10-20g
Sodium acetate 2.52-5.1g
Water for injection adds to 2L or 4L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 15g
Sodium chloride 18g
Glacial acetic acid 10g
Sodium acetate 2.52g
Water for injection adds to 2L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 4L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 2L.
Ambroxol hydrochloride pharmaceutical composition of the present invention is to adopt following method preparation:
Get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal, stir, place; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; Sterilization; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
In the present invention, the consumption of described medicinal charcoal is 0.05-0.1%.
In the present invention, described stirring is to stir 30 minutes under 55-65 ℃.
In the present invention, described sterilization is at 121 ℃ of pressure sterilizing 15-20 minutes, is preferably 121 ℃ of pressure sterilizings 15 minutes.
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of ambroxol hydrochloride pharmaceutical composition of the present invention, wherein, the method comprises the steps:
Get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal, stir, place; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; Sterilization; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
According to aforesaid preparation method, wherein, the consumption of described medicinal charcoal is 0.05-0.1%.
According to aforesaid preparation method, wherein, described stirring is to stir 30 minutes under 55-65 ℃.
According to aforesaid preparation method, wherein, described sterilization is at 121 ℃ of pressure sterilizing 15-20 minutes, is preferably 121 ℃ of pressure sterilizings 15 minutes.
Below to the more detailed elaboration of the present invention:
One aspect of the present invention provides a kind of ambroxol hydrochloride pharmaceutical composition of injection, every 1000 described ambroxol hydrochloride pharmaceutical compositions, and its formula consists of:
Ambroxol hydrochloride 15-30g
Sodium chloride 18-36g
Glacial acetic acid 10-20g
Sodium acetate 2.52-5.1g
Water for injection adds to 2L or 4L.
Traditional ambroxol hydrochloride injection, photostability is poor, and easily degraded, separate out, and quality can't guarantee.
In the present invention, in the stability study process to ambroxol hydrochloride injection light, a certain amount of cysteine hydrochloride is selected in discovery, after the pH value of first regulator solution, dissolve again ambroxol hydrochloride, add a certain proportion of sodium chloride, can effectively improve said preparation to the stability of light, also make it be difficult for separating out, related substance is unchanged.Through the screening of the test recipes of tens of times and the summary of test data, optimized its recipe quantity, not only solved the poor problem of photostability, and made the product clarity good, constant product quality.
The ambroxol hydrochloride pharmaceutical composition of a kind of injection of the present invention, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 15-30g
Sodium chloride 18-36g
Glacial acetic acid 10-20g
Sodium acetate 2.52-5.1g
Water for injection adds to 2L or 4L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 15g
Sodium chloride 18g
Glacial acetic acid 10g
Sodium acetate 2.52g
Water for injection adds to 2L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 4L.
Preferably, every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 2L.
The inventor finds through a large amount of experimental study, when the ambroxol hydrochloride pharmaceutical composition of counting is above-mentioned when more apolegamy side being arranged, and described injection the best in quality, stable best.
Another aspect of the present invention provides the preparation method of ambroxol hydrochloride injection of the present invention, and the method is simple, and prepared ambroxol hydrochloride injection is stable to light, is difficult for producing particulate matter, and clarity is good, good stability.
Preparation method provided by the present invention comprises: get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal, stir, place; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; Sterilization; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
The ambroxol hydrochloride injection that makes according to the inventive method proves that through industrial amplification production machine study on the stability product is stable, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
In preparation method of the present invention, the consumption of described medicinal charcoal is 0.05-0.1%.
In preparation method of the present invention, described stirring is to stir 30 minutes under 55-65 ℃.
Add appropriate medicinal charcoal can improve the clarity of solution, can adsorb thermal source, pigment again, medicinal charcoal there is no absorption to ambroxol hydrochloride, the inventor adopts UV-VIS spectrophotometry to measure the content of ambroxol hydrochloride, investigated medicinal charcoal, temperature, adsorption time to the impact of ambroxol hydrochloride content in injection.Result shows, the medicinal charcoal consumption is at 0.05-0.1%, and adsorption time is at 30 minutes, and adsorption temp is at 55-65 ℃, best results.
In preparation method of the present invention, described sterilization is at 121 ℃ of pressure sterilizing 15-20 minutes, is preferably 121 ℃ of pressure sterilizings 15 minutes.
Product of the present invention is the sterile water solution of ambroxol hydrochloride, and sterilising conditions is very crucial, should reach sterilization effect, can not destroy solution again, and the inventor investigates sterilising conditions, sees test example 4 for details.Result shows, at 121 ℃ of pressure sterilizing 15-20 minutes, and wherein 121 ℃ of pressure sterilizings 15 minutes, best results.
Compared with prior art, the present invention has following advantage:
1) new ambroxol hydrochloride composition provided by the present invention has thoroughly solved the stability problem of ambroxol hydrochloride to light.
2) ambroxol hydrochloride injection provided by the present invention is for the market risk of the yield that improves this product, reduction product, and better being applied to clinical treatment has very large help.
3) new ambroxol hydrochloride composition provided by the present invention through industrialized great production and study on the stability, proves constant product quality, through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
4) preparation method of new ambroxol hydrochloride composition provided by the present invention, the method is simple, and prepared ambroxol hydrochloride injection is stable to light, can not separate out, and clarity is good, good stability.
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail
Embodiment 1
Every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 15g
Sodium chloride 18g
Glacial acetic acid 10g
Sodium acetate 2.52g
Water for injection adds to 2L.
Preparation technology: get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal 0.05%, stir, placed 30 minutes; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; 121 ℃ of pressure sterilizings 15 minutes; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
Embodiment 2
Every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 4L.
Preparation technology: get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal 0.05%, stir, placed 30 minutes; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; 121 ℃ of pressure sterilizings 15 minutes; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
Embodiment 3
Every 1000 described ambroxol hydrochloride pharmaceutical compositions, its formula consists of:
Ambroxol hydrochloride 30g
Sodium chloride 36g
Glacial acetic acid 20g
Sodium acetate 5.1g
Water for injection adds to 2L.
Preparation technology: get recipe quantity water for injection 90%, temperature adds glacial acetic acid and the sodium acetate of recipe quantity, after stirring and dissolving at 55-65 ℃; The ambroxol hydrochloride that adds recipe quantity after being stirred to dissolving, adds the sodium chloride of recipe quantity in the solution again, is stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; To adding medicinal charcoal 0.05%, stir, placed 30 minutes; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; 121 ℃ of pressure sterilizings 15 minutes; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
Comparing embodiment 1
CN20101019929.5 embodiment 1
Prescription: 1000 components
Ambroxol hydrochloride 16g
Citric acid 2.8g
Sodium hydrogen phosphate 4.9g
Sodium chloride 15g
Water for injection 1800mL.
Preparation method: recipe quantity ambroxol hydrochloride, citric acid, sodium hydrogen phosphate, sodium chloride are dissolved in water for injection, wherein the total amount of water for injection is 70% of total water amount, stirring makes its dissolving record pH between 5.5, then add active carbon 0.02%, at room temperature stir about is 10 minutes, remove by filter active carbon, then add to the full amount of water for injection, carry out again afterwards fine straining, embedding, sterilization.
Comparing embodiment 2
CN201010195712.5
Ambroxol hydrochloride 15g
Sodium hydrogen phosphate 3.3g
Citric acid 2.4g
Sodium chloride 13.6g
Nitrogen is appropriate
Water for injection adds to 2000mL.
Preparation method: take sodium hydrogen phosphate, citric acid, inject water appropriate, make dissolving; Add ambroxol hydrochloride, stirring and dissolving; Add sodium chloride, dissolving.Add 0.3%(W/V) active carbon, stirred 20 minutes, filter.The inflated with nitrogen embedding is in 2ml brown glass ampoule.The sterilization leak detection (121 ℃, 15min), the visible foreign matters passed examination, and get final product.
Test example 1
This test example is for the situation that affects of clarity, particulate matter and the precipitation of the stability of solution of investigating prescription and buffer system recipe quantity and solution.
Prescription forms
| Prescription | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Ambroxol hydrochloride | 15g | 15g | 15g | 15g |
| Sodium chloride | 18g | 18g | 18g | 18g |
| Glacial acetic acid | —— | 40g | 20g | 10g |
| Sodium acetate | —— | 10.2g | 5.1g | 2.52g |
| Water for injection | Add to 2L | Add to 2L | Add to 2L | Add to 2L |
| Make | 1000 | 1000 | 1000 | 1000 |
The 1-that will write out a prescription prescription 4 is placed in the illumination 72 hours of 4500LX ± 500LX, respectively at 0 day, 10 days, its character, pH value and related substance is checked.The results are shown in following table:
Above result of the test shows, prescription 2-prescription 4 is placed in the illumination 72 hours of 4500LX ± 500LX, every inspection all meets up to specification, and 72 hours each indexs of illumination that comparative example 1 and comparative example 2 are placed in 4500LX ± 500LX change not quite, but particulate matter is defective.
Test example 2
This test example is to investigate medicinal charcoal consumption, temperature, adsorption time to the impact of ambroxol hydrochloride content in injection.
The preparation of 1 ambroxol hydrochloride sample solution: according to embodiment 1 preparation 3L.
The impact of 2 different time different amounts medicinal charcoal on ambroxol hydrochloride absorption: get respectively reserve liquid 100ml25 part, every 5 parts is one group, add respectively medicinal charcoal 0,0.05,0.1,0.15,0.2g, worked overtime 15,20,25,30,35 minutes in 60 ℃ of thermostat water baths respectively for 5 parts in every group, be cooled to room temperature, get subsequent filtrate and measure trap according to containing under quantifier, calculate content, the results are shown in Table:
Medicinal charcoal different amounts and difference stir you to the impact of ambroxol hydrochloride content
From showing and can find out, the consumption of medicinal charcoal was greater than 0.15 o'clock, and the content of ambroxol hydrochloride obviously descends, and adsorption time is longer, and content descends more obvious, and therefore the medicinal charcoal consumption is 0.05 in preparation process, and adsorption time was at 30 minutes.
Test example 3
This test example is to investigate the stability of ambroxol hydrochloride composition provided by the present invention.
The accelerated test of ambroxol hydrochloride injection
Method according to the embodiment of the present invention 1 prepares three batches of ambroxol hydrochloride injections (lot number is respectively MT1001001, MT1001002, MT1001003) according to commercially available back, at 40 ℃ ± 2 ℃, the condition of RH75% ± 5% was placed 6 months, during this time respectively at sampling in the 1st, 2,3,6 month, detect according to stable inspection item, and compare with 0 day data.
1, investigation project
High spot reviews: character, pH value, visible foreign matters, osmotic pressure molar density, related substance and content.
2, test data sees the following form
Above conclusion (of pressure testing) can be found out: this product is placed 6 months every detection indexs and was compared no significant difference with 0 month under the accelerated test condition, and stability is measured.
Test example 4
This test example is to investigate the impact of temperature on ambroxol hydrochloride injection content under sterilising conditions:
This product is the sterile water solution of ambroxol hydrochloride, sterilising conditions is very crucial, should reach sterilization effect, can not destroy solution again, the inventor investigates sterilising conditions, after the ambroxol hydrochloride solution by prescription preparation certain volume, be packaged in ampoule bottle respectively at 115 ℃ 30 minutes, 121 ℃ 20 minutes, 121 ℃ 15 minutes
,121 ℃ of sterilizations in 20 minutes, observe after sterilization in solution drug content following table as a result:
The impact of sterilising conditions on ambroxol hydrochloride injection content
| Sterilising conditions | Stock solution | 115 ℃ 30 minutes | 121 ℃ 8 minutes | 121 ℃ 15 minutes | 121 ℃ 20 minutes |
| Content (%) | 100.5 | 96.3 | 100.2 | 100.0 | 97.6 |
As can be seen from the above tests: the sterilising temp condition is little on this product impact, selects 121 ℃ 15 minutes, F0〉12, reach sterilization effect, on solution content almost without affecting.
Comparative test example 1, comparative test example 2 and embodiment 1 are placed in respectively the calorstat 10 days of the illumination of 4500LX ± 500LX, 60 ℃ ± 2 ℃ of high temperature, respectively at 0 day, 10 days, its character, pH value, related substance, content, visible foreign matters and particulate matter are checked.The results are shown in following table:
Comparative test example 1
According to result of the test as can be known, embodiment 1 and comparative example placed 10 days in the calorstat of illumination and high temperature, embodiment 1 is under different condition, each check item has no significant change, the comparative example is all comparatively responsive to light, heat, content reduces obviously, and particulate matter is defective, brings the very big factors of instability for clinical middle drug safety.
Claims (2)
1. the ambroxol hydrochloride pharmaceutical composition of an injection, is characterized in that, every 1000 pharmaceutical compositions, and its formula consists of:
Its preparation method is as follows:
Get water for injection 90%, temperature adds glacial acetic acid and sodium acetate, after stirring and dissolving at 55-65 ℃; Add ambroxol hydrochloride, after being stirred to dissolving, add again sodium chloride in solution, be stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; Add medicinal charcoal 0.05%, stir, placed 30 minutes; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; 121 ℃ of pressure sterilizings 15 minutes; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
2. the ambroxol hydrochloride pharmaceutical composition of an injection, is characterized in that, every 1000 pharmaceutical compositions, and its formula consists of:
Its preparation method is as follows:
Get water for injection 90%, temperature adds glacial acetic acid and sodium acetate, after stirring and dissolving at 55-65 ℃; Add ambroxol hydrochloride, after being stirred to dissolving, add again sodium chloride in solution, be stirred to dissolve complete; Record original ph, according to original ph, regulate the pH value scope at 3.5-4.5 with 10% acetum or 10% sodium hydroxide solution; Add medicinal charcoal 0.05%, stir, placed 30 minutes; Sucking filtration, supplementary injection water be to full dose, mix homogeneously; Fine straining; Fill; 121 ℃ of pressure sterilizings 15 minutes; Lamp inspection; Warehouse-in; Namely get ambroxol hydrochloride injection.
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| CN102988281A (en) * | 2012-12-11 | 2013-03-27 | 辽宁科泰生物基因制药股份有限公司 | Injection of ambroxol hydrochloride and preparation method thereof |
| CN104771358A (en) * | 2014-01-14 | 2015-07-15 | 江苏柯菲平医药股份有限公司 | Acebrophylline injection and preparation method thereof |
| CN105675523A (en) * | 2014-11-17 | 2016-06-15 | 蚌埠丰原涂山制药有限公司 | Ambroxol content UV spectrophotometric test method |
| CN107320445B (en) * | 2017-07-14 | 2020-10-09 | 峨眉山通惠制药有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
| CN109662943A (en) * | 2018-12-25 | 2019-04-23 | 石家庄鹏海制药股份有限公司 | The preparation method of ambroxol hydrochloride injection |
| CN113004157A (en) * | 2019-12-20 | 2021-06-22 | 康普药业股份有限公司 | Preparation method of ambroxol hydrochloride |
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| CN101836953A (en) * | 2010-06-12 | 2010-09-22 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride composition injection |
| CN101836952A (en) * | 2010-06-09 | 2010-09-22 | 云南龙海天然植物药业有限公司 | Ambroxol injection and preparation method thereof |
| CN102225049A (en) * | 2011-06-17 | 2011-10-26 | 成都金典药物科技开发有限公司 | Preparation method of ambroxol hydrochloride injection with stable pH value |
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| CN101836952A (en) * | 2010-06-09 | 2010-09-22 | 云南龙海天然植物药业有限公司 | Ambroxol injection and preparation method thereof |
| CN101836953A (en) * | 2010-06-12 | 2010-09-22 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride composition injection |
| CN102225049A (en) * | 2011-06-17 | 2011-10-26 | 成都金典药物科技开发有限公司 | Preparation method of ambroxol hydrochloride injection with stable pH value |
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