CN107519129A - A kind of ambroxol hydrochloride oral solution and preparation method thereof - Google Patents

A kind of ambroxol hydrochloride oral solution and preparation method thereof Download PDF

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Publication number
CN107519129A
CN107519129A CN201710846759.5A CN201710846759A CN107519129A CN 107519129 A CN107519129 A CN 107519129A CN 201710846759 A CN201710846759 A CN 201710846759A CN 107519129 A CN107519129 A CN 107519129A
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ambroxol hydrochloride
preparation
hydrochloride oral
minutes
oral solution
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Inventor
芦传有
赵冬艳
范宁
魏军旗
郭艳波
刘洋
杜进
张莹
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SANJING PHARMACEUTICAL CO Ltd HAYAO GROUP
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Physiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention is to provide a kind of ambroxol hydrochloride oral solution and preparation method thereof, contain in every 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, the 20g of sodium hydrogensulfite 10, the 300g of sucrose 200, the 2500ml of honey 1500.The pH value of the ambroxol hydrochloride oral solution is 3.5 4.5.The present invention is by optimization formula, in the case where not adding preservative, pH adjusting agent, cosolvent and essence, realize it is stability-enhanced simultaneously, making mouthfeel, more preferably drug effect is stronger.The present invention chooses the honey rational proportion formula clinically to moisten the lung and relieve the cough, realizes super expected effect, avoids the addition of preservative, pH adjusting agent and cosolvent, this product is turned into the oral liquid more healthy to human body, improves core competitiveness.

Description

A kind of ambroxol hydrochloride oral solution and preparation method thereof
Technical field
The present invention relates to pharmaceutical technology field, is to be related to a kind of ambroxol hydrochloride oral solution and preparation method thereof.
Background technology
Ambroxol hydrochloride is metabolite of the bromhexine in human body, is that a kind of new glutinous phlegm dissolves medicine, German Bo Linge Yin Gehan released in 1979.Listed successively in many countries such as France, Italy, Japan, Spain later.Present hydrochloric acid ammonia Bromine rope turns into clinically acts on most strong expectorant, and clinic is extremely affirmed to its curative effect, and its toxic side effect also very little, hydrochloric acid Ambroxol can shorten the treatment time of infection in respiratory system, reduce complication rate and case fatality rate, be applicable age broadness, can be wide It is general to be used for various acute and chronic PUD Ds, ARDS, there is the work for reducing sputum viscosity, improving patient's expectoration function and PFT With curative for effect, patient can generally be resistant to very well
Mucus hypersecretion is the important pathophysiological feature of chronic inflammatory airway disease, can aggravate respiratory tract air flow resistance Plug, accelerates decline in pulmonary function, and the mucus of air flue retention also turns into the good culture medium of bacterial growth, the hair for causing air flue Inner to infect Raw and exacerbation, and infection and follow-up inflammatory products further cause mucus hypersecretion, so as to form vicious circle, increase disease Admission rate and case fatality rate.The viscoelasticity of airway mucus is mainly determined that ambroxol hydrochloride can decompose it by mucin therein In saccharide portion, and increase the secretion of respiratory mucosa slurries body of gland, reduce mucus glandular secretion, so as to reduce sputum viscosity, Promote mucus discharge, the synthesis to alveolar surfactant remarkably promotes effect with secretion, can increase bronchus cilium fortune It is dynamic, play a part of notable expectoration, improve breath state.
Honey is described as in the Nature most perfect nutraceutical, can harmonizing the spleen and stomach;Relieving spasm to stop pain;Moisten the lung and relieve the cough;Ease constipation Defaecation;Moisturizing myogenic;Removing toxic substances.The empty pain of main gastral cavity abdomen;Xeropulmonary cough;Dry constipation of intestines;Hot eyes;Aphtha;Unhealing ulcer;Rubella itch; Scald;Brothers' (army's skin) are split.《Prescriptions worth thousand gold》In be used for control cough, pant, there is thing, spitting blood in larynx.Honey as flavouring, Stabilizer, strengthen the effect of drug effect with collaboration.Honey rational proportion formula, realizes super expected effect, avoids anti- The addition of rotten agent, pH adjusting agent and cosolvent, this product is turned into the ambroxol hydrochloride oral solution more healthy to human body, there is core Heart competitiveness.
For ambroxol hydrochloride as oral administration solution, technique is simple, and cost is low, convenient to take, particularly suitable for the elderly and children, Medicine is scattered in medium with molecular forms, and decentralization is big, absorbs fast, the relatively rapid performance curative effect of energy, raising bioavilability. But in existing ambroxol hydrochloride oral solution, preservative, cosolvent, pH adjusting agent, essence etc. are mostly added, in treatment The material factor unfavorable to body is have also been introduced simultaneously, mouthfeel is also poor, and patient medication biddability is not naturally high.
The content of the invention
The defects of in order to overcome ambroxol hydrochloride oral solution prior art, the invention provides a kind of salt being completely newly formulated Sour ambroxol oral liquid, preservative, pH adjusting agent are avoided, the addition of cosolvent and essence, this product is turned into human body more The ambroxol hydrochloride oral solution of health, patient take compliance height.
The invention provides a kind of compound method of ambroxol hydrochloride oral solution, this method technique simple possible, saves, Key factor is controllable, and the product stability of production is high.
Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 10-20g, sucrose 200-300g, honey 1500-2500ml, the pH value of oral administration solution are controlled in 3.5-4.5;The sodium hydrogensulfite is anti-oxidant Agent, sucrose are flavouring, and honey strengthens the effect of drug effect with collaboration as flavouring, stabilizer.
Step is as follows:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in 8-12 times of purified water of its weight (55~65 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in 25-35 times of purified water of its weight (45~55 DEG C), it is standby.
(3) the purified water for volume 25%~50% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 15~20 Minute to being completely dissolved.It is cooled to 45~55 DEG C, adds the solution of sodium bisulfite dissolved in advance, stir 15~20 minutes, most The ambroxol hydrochloride solution dissolved in advance and honey are added afterwards, and stir about filters for 15~20 minutes to whole dissolvings.(the mistake Filter as one or both of 0.1-1 μm of miillpore filter, 0.1-1 μm of stud, clarification plate, 0.1-1 μm of clay rod combination of the above).
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
With reference to instantiation, the present invention is described in further detail:
Embodiment 1:Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 10g, sucrose 200g, honey 1500ml;
Step is as follows:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in 8 times of purified waters of its weight (55 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in 25 times of purified waters of its weight (45 DEG C), it is standby.
(3) the purified water for volume 25% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 15 minutes to complete Dissolving.45 DEG C are cooled to, adds the solution of sodium bisulfite dissolved in advance, stirs 15 minutes, is eventually adding the salt dissolved in advance Sour ambroxol solution and honey, stir about 15 minutes to whole dissolvings, 1 μm of stud, 0.1 μm of filtering with microporous membrane.
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
Embodiment 2:Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 20g, sucrose 300g, honey 2500ml;
Step is as follows:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in about 12 times of purified waters of its weight (65 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in about 35 times of purified waters of its weight (55 DEG C), it is standby.
(3) the purified water for volume 50% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 20 minutes to complete Dissolving.55 DEG C are cooled to, adds the solution of sodium bisulfite dissolved in advance, stirs 20 minutes, is eventually adding the salt dissolved in advance Sour ambroxol solution and honey, stir about 20 minutes to whole dissolvings, 1 μm of stud, 0.22 μm of filtering with microporous membrane.
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
Embodiment 3:Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 15g, sucrose 250g, honey 2000ml;
Step is as follows:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in 10 times of purified waters of its weight (60 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in 30 times of purified waters of its weight (50 DEG C), it is standby.
(3) the purified water for volume 40% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 18 minutes to complete Dissolving.50 DEG C are cooled to, adds the solution of sodium bisulfite dissolved in advance, stirs 18 minutes, is eventually adding the salt dissolved in advance Sour ambroxol solution and honey, stir about 1 μm of stud, clarify plate, 0.1 μm of filtering with microporous membrane in 17 minutes to whole dissolvings.
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
Embodiment 4:Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 20g, sucrose 200g, honey 1500ml;
Step is as follows:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in 12 times of purified waters of its weight (65 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in 35 times of purified waters of its weight (55 DEG C), it is standby.
(3) the purified water for volume 50% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 20 minutes to complete Dissolving.55 DEG C are cooled to, adds the solution of sodium bisulfite dissolved in advance, stirs 20 minutes, is eventually adding the salt dissolved in advance Sour ambroxol solution and honey, stir about 20 minutes to whole dissolvings, 1 μm of clay rod, 0.22 μm of filtering with microporous membrane.
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
Embodiment 5:Contain in per 10000mL ambroxol hydrochloride oral solutions:Ambroxol hydrochloride 31g, sodium hydrogensulfite 10, Sucrose 250, honey 2000ml;
The compound method of above-mentioned ambroxol hydrochloride oral solution, the preparation method comprise the following steps:
(1) the sodium hydrogensulfite of recipe quantity is dissolved in 8 times of purified waters of its weight (55 DEG C), it is standby.
(2) the ambroxol hydrochloride of recipe quantity is dissolved in 25 times of purified waters of its weight (45 DEG C), it is standby.
(3) the purified water for volume 25% of about making up a prescription is heated to boiling, adds the sucrose of recipe quantity, boil 15 minutes to complete Dissolving.45 DEG C are cooled to, adds the solution of sodium bisulfite dissolved in advance, stirs 15 minutes, is eventually adding the salt dissolved in advance Sour ambroxol solution and honey, stir about clarify plate, the filtering of 1um studs in 15 minutes to whole dissolvings.
(4) purified water is added in the concentrated wiring liquid after (3) filtering, and is settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH (3.5-4.5), relative density (1.090-1.200), clarity, qualified rear decoction carry out refined filtration, medicine with hyperfiltration technique Liquid embedding, sterilizing.
For above example, pilot scale sample preparation has been carried out respectively, and ambroxol hydrochloride oral solution is carried out respectively Quality testing.Testing result such as following table:
Detection project Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Content (mg/10ml) 30.4 30.2 30.1 30.3 30.5
Character Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
pH 4.1 3.8 4.0 3.7 3.9
Relative density 1.098 1.156 1.103 1.162 1.137
Impurity A (%) 0.016 0.023 0.018 0.022 0.021
Other impurities (%) 0.015 0.015 0.015 0.016 0.014
Total impurities (%) 0.031 0.038 0.033 0.038 0.035
Any one has carried out clinical experimental study in selection above example, as a result as follows:
Cough, expectoration are its common clinical symptoms in respiratory disease, to the not smooth respiratory disease of expectoration , cough therapeutic effect.
Method:Glue and be not easy using the cough caused by the various acute and chronic respiratory systems of ambroxol hydrochloride oral solution treatment, phlegm 120 patients of expectoration patient, are randomly divided into ambroxol hydrochloride group and bisolvon group.To improve patient's cough, expectoration easy degree And amount of expectoration is index.
As a result:
1. to the effective percentage of expectoration easy degree and amount of expectoration
To the effective percentage of expectoration easy degree and amount of expectoration in ambroxol group 60:Effective 38, effective 21, invalid 1, Total effective rate is 98.3%;To the effective percentage of expectoration easy degree and amount of expectoration in bisolvon group 60, wherein effective 22, effectively 25, invalid 13, total effective rate 78.3%, ambroxol group total effective rate is apparently higher than bisolvon group (P<0.05)
2. control rate and obvious effective rate are faced to cough:
Ambroxol hydrochloride oral solution is respectively 31.0% and 40.2% to face the control rate and obvious effective rate of cough, hence it is evident that is higher than Bisolvon (being respectively 10.8% and 18.7%) (P<0.05).
Ambroxol hydrochloride oral solution of the present invention is a kind of highly effective eliminating the phlegm, cough suppressing medicine.
Results of stability:
(1) influence factor is tested
1. illumination factor
2. temperature 60 C
(2) low temperature freezing and thawing test:
Low-temperature circulating is tested:Circulation three times, is placed 2 days under the conditions of circulating in 4 DEG C every time, is then transferred to 40 DEG C of condition decentralizations Put 2 days, detected.
Freeze-thaw cycle experiment:Circulation three times, is placed 2 days at -10 DEG C~-20 DEG C every time, is then transferred to 40 DEG C of condition decentralizations Put 2 days, detected.
(3) accelerated test
(4) long term test
Stability test conclusion:Tested by series of stable, as a result prove that the ambroxol hydrochloride oral of the present invention is molten Liquid has good stability.

Claims (6)

1. a kind of ambroxol hydrochloride oral solution and preparation method thereof, it is characterized in that:Per 10000mL ambroxol hydrochloride oral solutions In contain:Ambroxol hydrochloride 31g, sodium hydrogensulfite 10-20g, sucrose 200-300g, honey 1500-2500ml, oral administration solution PH value is controlled in 3.5-4.5;The sodium hydrogensulfite is antioxidant, and sucrose is flavouring, honey as flavouring, stably Agent, strengthen the effect of drug effect with collaboration.
A kind of 2. ambroxol hydrochloride oral solution according to claim 1 and preparation method thereof, it is characterised in that:
2.1 are dissolved in the sodium hydrogensulfite of recipe quantity in 8-12 times of purified water of its weight, standby;
2.2 are dissolved in the ambroxol hydrochloride of recipe quantity in 25-35 times of purified water of its weight, standby;
The purified water for volume 25%~50% of about making up a prescription is heated to boiling by 2.3, adds the sucrose of recipe quantity, is boiled 15~20 minutes To being completely dissolved.45~55 DEG C are cooled to, adds 2.1 solution dissolved in advance, is stirred 15~20 minutes, is eventually adding molten in advance 2.2 solution and honey of solution, stir about filter for 15~20 minutes to whole dissolvings;
2.4 purified waters are added in the concentrated wiring liquid after 2.3 filterings, are settled to recipe quantity, circulation stirring 30 minutes, sampling and measuring contains Amount, pH, relative density, clarity, qualified rear decoction carry out refined filtration, embedding, sterilizing with hyperfiltration technique.
3. a kind of ambroxol hydrochloride oral solution according to claim 2.1 and preparation method thereof, it is characterized in that:Purified water Temperature is 55~65 DEG C.
4. a kind of ambroxol hydrochloride oral solution according to claim 2.2 and preparation method thereof, it is characterized in that:Purified water Temperature is 45~55 DEG C.
5. a kind of ambroxol hydrochloride oral solution according to claim 2.3 and preparation method thereof, it is characterized in that:The mistake Filter as one or both of 0.1-1 μm of miillpore filter, 0.1-1 μm of stud, clarification plate, 0.1-1 μm of clay rod and combination of the above.
6. a kind of ambroxol hydrochloride oral solution according to claim 2.4 and preparation method thereof, it is characterized in that:PH value control System is in 3.5-4.5;Relative density is 1.090-1.200.
CN201710846759.5A 2017-09-19 2017-09-19 A kind of ambroxol hydrochloride oral solution and preparation method thereof Pending CN107519129A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1628647A (en) * 2004-10-11 2005-06-22 成都拜特尔药业有限公司 Ambroxol hydrochloride granule
CN1836654A (en) * 2005-03-25 2006-09-27 天津药物研究院 Pharmaceutical composition for stabilizing ambroxol hydrochloride granula
CN101352417A (en) * 2008-08-29 2009-01-28 扬州市三药制药有限公司 Ambroxol hydrochloride oral solution and preparation method thereof
CN101961307A (en) * 2010-09-14 2011-02-02 武汉人福药业有限责任公司 Oral liquid for treating respiratory disease and preparation method thereof
CN102309442A (en) * 2010-07-07 2012-01-11 澳美制药厂 Ambroxol hydrochloride oral aqueous composition and preparation method thereof
CN104027326A (en) * 2013-03-04 2014-09-10 天津康鸿医药科技发展有限公司 Ambroxol hydrochloride atomization inhalant, and preparation method and application thereof
CN105055385A (en) * 2015-08-19 2015-11-18 上海华源安徽锦辉制药有限公司 Composition injection containing ambroxol hydrochloride compound and preparation method thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1628647A (en) * 2004-10-11 2005-06-22 成都拜特尔药业有限公司 Ambroxol hydrochloride granule
CN1836654A (en) * 2005-03-25 2006-09-27 天津药物研究院 Pharmaceutical composition for stabilizing ambroxol hydrochloride granula
CN101352417A (en) * 2008-08-29 2009-01-28 扬州市三药制药有限公司 Ambroxol hydrochloride oral solution and preparation method thereof
CN102309442A (en) * 2010-07-07 2012-01-11 澳美制药厂 Ambroxol hydrochloride oral aqueous composition and preparation method thereof
CN101961307A (en) * 2010-09-14 2011-02-02 武汉人福药业有限责任公司 Oral liquid for treating respiratory disease and preparation method thereof
CN104027326A (en) * 2013-03-04 2014-09-10 天津康鸿医药科技发展有限公司 Ambroxol hydrochloride atomization inhalant, and preparation method and application thereof
CN105055385A (en) * 2015-08-19 2015-11-18 上海华源安徽锦辉制药有限公司 Composition injection containing ambroxol hydrochloride compound and preparation method thereof

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