CN101606903A - A kind of atomizing of ambroxol sucks with solution and preparation method thereof - Google Patents
A kind of atomizing of ambroxol sucks with solution and preparation method thereof Download PDFInfo
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- CN101606903A CN101606903A CNA200810110981XA CN200810110981A CN101606903A CN 101606903 A CN101606903 A CN 101606903A CN A200810110981X A CNA200810110981X A CN A200810110981XA CN 200810110981 A CN200810110981 A CN 200810110981A CN 101606903 A CN101606903 A CN 101606903A
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Abstract
The atomizing that the present invention relates to a kind of ambroxol sucks uses pharmaceutical solutions, belongs to the galenic pharmacy field.A kind of atomizing of ambroxol sucks and uses pharmaceutical solutions, comprises ambroxol or its officinal salt of (1) single pharmaceutical dosage; (2) isotonic agent and solvent; (3) buffer; (4) pharmaceutical pack of single dose; In ambroxol, the mass ratio of medicinal ingredient and isotonic agent is 1: 1.1-1: 3.3.Advantage of the present invention is: ambroxol aerosol inhalation solution preparation and the employing that the invention provides single dose blow-irritate-seal the pharmaceutical pack of (BFS) integrated fully-automatic production, and its advantage is to aim at atomizing and sucks and manufacture and design with the patient; Do not contain antiseptic; Disposable single dose uses; Use is convenient, need not dilution, preparation; Can reduce microbial contamination in the use and waste etc. greatly.This pharmaceutical preparation provides the pharmaceutical dosage that a kind of prior art lacked accurate, drug quality high-quality, stable, clinical practice safety, simple and direct treatment medicine and therapeutic scheme.
Description
Technical field
The atomizing that the present invention relates to a kind of ambroxol sucks uses pharmaceutical solutions, belongs to the galenic pharmacy field.
Background technology
Ambroxol is the expectorant of present wide clinical application, is applicable to sticky, the dyspnea of sputum that acute and chronic respiratory system disease (as acute and chronic bronchitis, bronchial asthma, bronchiectasis, chronic obstructive pneumonia, pulmonary tuberculosis, emphysema, pneumoconiosis etc.) causes.Ambroxol also can be used for the perform the operation prophylactic treatment of back pulmonary complication and the treatment of the poverty-stricken disease of infant breathes simultaneously.
Respiratory system disease is one of common frequently-occurring disease, wherein again based on bronchitis, asthma and pneumonia etc.According to statistics, the sickness rate of Chinese acute bronchitis in 2000 is about 1%, and the sickness rate of chronic bronchitis is that the sickness rate of crowd more than 3.8%, 50 years old is up to 15%.Point out have 300,000,000 people to suffer from asthma approximately in the world wide at present according to 2004 " report of global asthma burden ".China resident asthma annual morbidity was 1.2% in 2000, and total number of persons is compared with 1980 1,560 ten thousand people, and total incidence rate has increased by 75%.Have investigation show the northern area of China more than 15 years old crowd's chronic obstructive pneumonia sickness rate be 3.17%.The investigation of Wenzhou City's old people's chronic obstructive pneumonia more than 60 years old shows that smoker's chronic obstructive pneumonia prevalence reaches 15.6%, and the non smoker also reaches 4.6%.Because of reasons such as social development, environmental pollutions, the sickness rate of respiratory system disease is in tangible raising.
Respiratory system disease often shows as cough, expectoration, or with breathing hard, pant etc., and severe patient can concurrent emphysema, pulmonary heart disease etc.; And the breathing heavily of respiratory system disease, cough, expectorant, scorching four diseases is general common symptons, often exist simultaneously, reciprocal causation.
Ambroxol be bromhexine at the intravital active metabolite of people, be mucolytic, act on stronger than bromhexine.Can increase the secretion of respiratory mucosa serous gland, reduce the secretion of mucous gland, the mucopolysaccharide fiber in minimizing and the fracture sputum reduces the sputum viscosity, and the sputum attenuation is easy to expectoration.Ambroxol also can activate the conveying in the alveolar epithelium II type cell synthetic surface respiratory tract, discharges in order to sputum, reaches the effect of cleaning up respiratory mucosa, directly protects pulmonary function.In addition, ambroxol has certain antitussive action, and antitussive effect is equivalent to 1/2nd of codeine.
The atomizing inhalation is used for the treatment of respiratory system diseases such as asthma, chronic obstructive pulmonary disease, tracheitis and pneumonia and has advantage easy and simple to handle, that local drug concentration is high and side effect is little, thereby is subjected to clinician and patient's welcome deeply.Ambroxol is widely used clinically at present expectorant, has the glutinous expectorant effect of dissolving, makes sputum be beneficial to expectoration.Because the ambroxol effect is rapid, toleration is good, but and prolonged application, be considered to the ideal good medicine that eliminates the phlegm.
In the ambroxol description and the medication in the relevant pharmacopeia be oral or intravenously administrable, still do not have the single dose atomized inhalation both at home and abroad so far and emerge.Domestic many clinicians are used for the atomization inspiration treatment respiratory system disease with the ambroxol injection, but only are given for intravenous injection in its description, and how are effectiveness that atomizing sucks and safety, lack the system evaluation of relevant evidence at present.At first, be dosage (concentration) problem.Document [Huang Ping, Luo Shesheng, Wang Tianlin etc., " the mucosolvan atomizing sucks the auxiliary treatment infantile pneumonia ", Fudan Journal (medical science version), 2001; 28 (5): 453-454] report: with the concentration atomization inspiration treatment infantile pneumonia of minimum 0.36mg/ml, and document (Wang Suxiang, Zheng Zhongshi, " atomizing of ambroxol hydrochloride injection liquid pump sucks assistant and controls pneumonia of newborn 86 examples ", Strait Pharmaceutical Journal, 2003; 15 (3): 58-59) report: with the concentration treatment pneumonia of newborn of 5mg/ml, both concentration differ about 14 times.Secondly, be the problem course of treatment.Searching document the shortest known course of treatment is 3 days, and be 10 days the course of treatment the longest, differs more than 3 times.Whether exist reciprocal action all to need further research between the suitableeest course of treatment and dosage and they.Once more, be safety issue.Fog inhalation therapy sucks respiratory system with medicine after atomizing, be gathered into higher concentration in the part, and directly acts on the sensor of airway surface or target receptor and play a role, and can directly absorb from air flue mucosa and pulmonary, brings into play pharmacological action rapidly.Exactly because the fog inhalation therapy effect directly, rapidly, thereby especially should note the safety of inhalable aerosol drug.Document (Merkus P, Classification of cilioinhibiting effects of nasal drugs, Laryngoscope, 2001; 111 (4 Pt 1): 595-602) report: the main component in the via intranasal application drug-delivery preparation, antiseptic and additive (as solubilizing agent, short absorbent) all produce certain irritation to nasal cavity, some material even can suppress nose cilium induction system causes the motionless disease of cilium.Although being arranged, multinomial research do not find all that during treating the suction of ambroxol injection night fog has the generation of untoward reaction, but all lack the course of treatment of all researchs (≤10 days), and all follow up a case by regular visits to, so the ambroxol injection also lacks effective evidences to the safety of nasal cavity and whole respiratory system.
The multiple dose that the aerosol inhalation solution that gone on the market mostly adopts is write out a prescription and is brought problems to clinical use.At first, the aerosol inhalation solution product that gone on the market has adopted 20-250 milliliter packing specification more, even bigger.This makes the single access times reach 20-200 time, even more.The clinical use repeatedly that causes has thus increased the probability of microbial contamination in the use greatly and has ensured the difficulty of liquid preparation quality stability, thereby has largely increased the risk of patient's inhaled medication.Secondly, heavy dose of atomizing sucks the use of preparation, usually all can in prescription, use antiseptic and additive, as Benzalkonii Chloridum (Benzalkoniumchlodie), the probability that this clinical adverse that will increase inhaled medication takes place, and existing studies confirm that this type of antiseptic can influence the effect of ciliated cell, will largely influence the curative effect of atomization inspiration treatment.For these reasons, be limited in this type of antiseptic of use in the medicine in the strictness of a lot of countries of European Union.In addition, because the prescribed dose of multiple dose suction preparation is excessive, will bring unnecessary waste to the patient; And need the doctor to dilute preparation, bring many inconvenience to clinical application.
Chinese patent application 200510018727.3 discloses a kind of suction aerosol of ambroxol, it is characterized in that it is made up of feed liquid and propellant.Feed liquid is made up of ambroxol hydrochloride, common solvent, surfactant and additive.Because suction is all adopted propellant such as freon with aerosol and powder inhalant, can cause certain destruction to environment, and contain the suction drug product quality control complexity of casting system in recent years, dosage accuracy and quality stability are difficult to guarantee.
Find the clinical ambroxol fog inhalation therapy of needing badly, but the at present domestic proprietary dosage form listing that do not atomize by investigation to hospital and doctor.Hospital adopts injection usually, but many risks such as this type of usage has indication medicine for external use, research data to lack and usage and dosage is indeterminate, therefore, the atomizing of ambroxol sucks can satisfy the intensive demand of clinical application with pharmaceutical solutions.
Summary of the invention
The atomizing that the technical problem to be solved in the present invention provides a kind of safe, effective, good quality sucks uses the ambroxol special product.
For achieving the above object, the present invention by the following technical solutions.
A kind of atomizing of ambroxol sucks and uses pharmaceutical solutions, comprising:
1) ambroxol of single pharmaceutical dosage or its officinal salt;
2) isotonic agent and solvent;
3) buffer;
4) pharmaceutical pack of single dose.
In ambroxol, the mass ratio of medicinal ingredient and isotonic agent is 1: 1.1-1: 3.3.
Described single dose atomizing sucks ambroxol, ambroxol hydrochloride, tartaric acid ambroxol, hydrobromic acid ambroxol and other officinal salt that preparation comprises 5-60 milligram pharmaceutical dosage.
Described single dose atomizing sucks preparation and comprises 7.5,15.0,22.5,30.0,37.5,45.0,52.5,60.0 milligrams ambroxol hydrochloride.
Described single dose atomizing sucks preparation and comprises 7.5,15.0,30.0,45.0 milligrams ambroxol hydrochloride.
Described isotonic agent is sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, sorbitol.
Described buffer is a citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, sodium hydrogen phosphate-potassium dihydrogen phosphate, acetic acid-sodium acetate, citric acid-sodium hydroxide-hydrochloric acid.
Described buffer is citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, sodium hydrogen phosphate-potassium dihydrogen phosphate, citric acid-sodium hydroxide-hydrochloric acid.
The pH value of aerosol inhalation solution is stable at 3.0-6.0.
The pH value of aerosol inhalation solution is stable at 5.0-6.0.
Described specification is every 1.0-20.0 milliliter.
Described specification is 1.0,2.0,3.0,4.0,5.0,6.0,8.0,10.0 milliliters every.
Single dose ambroxol atomizing provided by the invention sucks uses solution, comprises ambroxol or its officinal salt, medicinal isotonic agent, solvent, buffer and the single dose pharmaceutical pack of pharmaceutical dosage.
Medicinal active ingredient in the single dose ambroxol aerosol inhalation solution provided by the invention is ambroxol, ambroxol hydrochloride, tartaric acid ambroxol or other officinal salt, is more preferably ambroxol hydrochloride.
Single dose ambroxol aerosol inhalation solution provided by the invention adopts single dose of drug compositions and pharmaceutical pack thereof.Described single dose is meant that the single atomizing sucks the dosage of employed medicinal active ingredient.Avoided exactly because determined the dosage of single medication that the big packaging solution of multiple dose caused measure repeatedly, dilution preparation repeatedly, the inaccurate shortcoming of dosage.Particularly, the pharmaceutical dosage of ambroxol hydrochloride is between the 5-60 milligram, and preferred single dosage is 7.5,15.0,22.5,30.0,45.0,52.5,60 milligrams, and 7.5,15.0,30.0,45.0 milligrams ambroxol hydrochloride most preferably.
Single dose ambroxol aerosol inhalation solution provided by the invention adopts single dose independent packaging and prescription thereof.In the prior art, atomized inhalation is made with ambroxol hydrochloride by existing external producer, but adopt be the multiple dose prescription, owing to packing dosage is bigger, in the prescription use of adjuvant different with the present invention, be compared as follows:
In the multiple dose prescription, owing to consider clinical use repeatedly, added the antiseptic benzalkonium chloride, to guarantee the stability of medicine, but add antiseptic as everyone knows and can improve the probability that untoward reaction takes place, and existing studies confirm that this type of antiseptic can influence the effect of ciliated cell, the curative effect of atomization inspiration treatment will largely be influenced, the unit dose package that the present invention adopts has solved this problem, especially using asepticize to blow-irritate-inside back cover unification technique (Blow/Fill/Seal, BFS) single dose is independent canned, after sealing, adding preservative agent can not guaranteed the stability of medicine yet, and realized that further ingredient is single, greatly reduce and suck in the medicinal liquid antiseptic patient's potential hazard.
When carrying out the atomizing effect relative analysis, find that the adding of benzalkonium chloride has also influenced the surface tension of suction preparation, thereby increased the particle diameter of atomized particles, reduced to suck microgranule, reduce the curative effect of atomization inspiration treatment.Concrete experimental data is seen embodiment 12.
Described isotonic agent comprises sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, sorbitol.Used solvent is medicinal purified water or water for injection.
Buffer purpose on the galenic pharmacy that the present invention adopts is to keep the stability of ambroxol solution, specifically is meant with buffer solution as the pH regulator agent.Used buffer solution includes but not limited to citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, sodium hydrogen phosphate-potassium dihydrogen phosphate, acetic acid-sodium acetate, citric acid-sodium hydroxide-hydrochloric acid.Preferred buffer is citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, citric acid-sodium hydroxide-hydrochloric acid.Further, pH regulator agent of the present invention specifically is meant to be regulated the pH value of single dose ambroxol aerosol inhalation solution and be stable between the 3.0-6.0, and preferred pH value interval is 5.0-6.0.
What ambroxol aerosol inhalation solution provided by the invention adopted is unit dose package, definite is meant: for fear of atomizing suck medicine produce and the preservation process in microbial contamination, and the steady quality that ensures medicine adopts the packing of the active component that independently contains the single dosage and pharmaceutic adjuvant, solvent.Be meant the pharmacy of adopting novel asepticize, canned and seal production technology more accurately.Include but not limited to: blow-irritate-the inside back cover unification technique (Blow/Fill/Seal, BFS).The independent advantage canned, sealing tech of the single dose of asepticize comprises: the medicine inherent quality is high and stability is reliable, need not wash bottle, the conserve water and the energy.Further, single dose ambroxol aerosol inhalation solution packing specification provided by the invention is the 1.0-20.0 milliliter, more preferably 1.0,2.0,3.0,4.0,5.0,6.0,8.0,10.0 milliliters.The formulation samples that adopts the preparation of BFS technology is referring to accompanying drawing 1, accompanying drawing 2.
According to the present invention, ambroxol hydrochloride sucks solution through the nebulizer inhalation, and its irritation test shows rabbit respiratory mucosa nonirritant and cilium toxicity.
Term " isotonic agent " is the Essential Terms of this area, also is referred to as " isosmotic solution ", is meant the solution that equates with plasma osmotic pressure, belongs to the physical chemistry notion.Term " buffer " is the Essential Terms of this area, also is referred to as " buffer agent " or " pH regulator agent ".
Term " pharmaceutical dosage " is the Essential Terms of this area, be meant with the treatment of diseases to be the dosage of the medicine that uses of purpose, as disclosed general knowledge, the pharmaceutical dosage of ambroxol is a prior art, concrete dosage, can be with reference to the pharmacy quick-reference book, for example " new pharmacology ", " newly organized hospital medicine complete works ", " clinical application guide ", " the two-way guide of clinical application ", " clinical practice new drug handbook, " new drug clinical practice handbook, " newly organized clinical application handbook etc.Term " single dose " is the Essential Terms of this area, is meant the dosage of a drug.
Advantage of the present invention is: the invention provides the atomizing of a kind of single dose and suck and use ambroxol pharmaceutical solutions, said preparation to can be used for expectorant as a kind of novel suction that sputum that acute and chronic respiratory system disease causes is sticky, dyspnea.Also can be used for simultaneously the perform the operation prophylactic treatment of back pulmonary complication and the treatment of the poverty-stricken disease of infant breathes.The invention provides a kind of ambroxol solution that sucks the treatment design that aims at, be gathered into higher concentration in the part, and directly act on the sensor of airway surface or target receptor and play a role, and can directly absorb from air flue mucosa and pulmonary, bring into play pharmacological action rapidly.This sucks with pharmaceutical solutions and has remedied blank on the present domestic market, can stop for want of to suck the special-purpose preparation medicine of treatment, uses ambroxol injection to substitute to be used to suck treatment and the safety hidden danger that produces.Suction provided by the invention ambroxol pharmaceutical solutions refers in particular to the ambroxol aerosol inhalation solution preparation of single dose, preferred adopt blow-irritate-seal the pharmaceutical pack of (BFS) integrated fully-automatic production, its advantage is: aiming at the suction that atomizes and manufacturing and designing with the patient; Do not contain antiseptic; Disposable single dose uses; Use is convenient, need not dilution, preparation; Can reduce microbial contamination and waste in the use greatly, and reduce the zest that antiseptic brings, improve the safety of medication.This pharmaceutical preparation provides the pharmaceutical dosage that a kind of prior art lacked accurate, drug quality high-quality, stable, clinical practice safety, simple and direct treatment medicine and therapeutic scheme.
The present invention will be further described below in conjunction with concrete the drawings and specific embodiments, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
Description of drawings
Fig. 1 packs diagram for single dose sucks with the ambroxol solution example
Fig. 2 sucks with ambroxol solution example assembly packaging diagram for single dose
The specific embodiment
The consumption of the preparation process of following pharmaceutical preparation embodiment and used material of preparation or the used material of preparation is not limited to character express; all formulation methods that contains pharmaceutical composition provided by the invention; all belong to protection scope of the present invention, but concrete experimental technique reference drug preparation quick-reference book.
Embodiment 1: prepare 30 milligrams/2 milliliters single dose ambroxol aerosol inhalation solutions (1000)
Prescription:
Ambroxol hydrochloride 30.0g
Sodium chloride 30.0g
Citric acid 1.80g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 2000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 1600ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 100ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulates pH to 4.5-5.5; Gained solution adds purified water to 2000ml, fill, seals, and every 2ml, leak detection, quality inspection, packing promptly gets 30mg/ (2ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 2: preparation 30mg/2ml single dose ambroxol aerosol inhalation solution (10000)
Prescription:
Ambroxol hydrochloride 300g
Sodium chloride 300g
Citric acid 18.0g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 20000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 16000ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 1000ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulates pH to 4.5-5.5; Gained solution adds purified water to 20000ml, and adopt the blowing-irritates of asepticize-inside back cover unification technique (BFS) fill, seal, every 2ml, leak detection, quality inspection is packed, and promptly gets 30mg/ (2ml/ props up), totally 10000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 3: preparation 30mg/4ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 30.0g
Sodium chloride 48.0g
Citric acid 2.22g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 4000ml
Preparation method:
Take by weighing ambroxol hydrochloride and sodium chloride by recipe quantity, add the 2000ml purified water dissolve solution 1; The citric acid that other gets recipe quantity is dissolved in the 1000ml purified water, gets solution 2; Two kinds of solution are merged, stir solution 3, it is an amount of to take by weighing sodium hydrogen phosphate again, add the solution that the injection water is mixed with 0.4mol/L, stir and slowly join in the solution 3 adjusting pH to 5.5-6.0, add 0.2% activated carbon and boiled 30 minutes, filter decarburization, add purified water to 4000ml in the gained solution through the sand filtration rod, fill, seal every 4ml, leak detection, quality inspection, packing promptly gets 30mg/ (4ml/ props up), totally 1000.
The major technique test rating:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 5.5-6.0
Embodiment 4: preparation 30mg/8ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 30.0g
Sodium chloride 66.0g
Citric acid 2.70g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 8000ml
Preparation method:
Take by weighing ambroxol hydrochloride and sodium chloride by recipe quantity, add the 4000ml purified water dissolve solution 1; The citric acid that other gets recipe quantity is dissolved in the 2000ml purified water, gets solution 2; Two kinds of solution are merged, stir solution 3, it is an amount of to take by weighing sodium hydrogen phosphate again, add the solution that the injection water is mixed with 0.4mol/L, stir and slowly join in the solution 3 adjusting pH to 4.5-5.5, add 0.2% activated carbon and boiled 30 minutes, filter decarburization, add purified water to 8000ml in the gained solution through the sand filtration rod, fill, seal every 8ml, leak detection, quality inspection, packing promptly gets 30mg/ (8ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 5: preparation 7.5mg/1ml milliliter single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 7.5g
Sodium chloride 11.3g
Citric acid 0.38g
Sodium citrate (0.2mol/l) is an amount of
Purified water adds to 1000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 500ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 100ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium citrate again, adds the solution that the injection water is mixed with 0.2mol/L, stirs slowly to join in the solution 3, regulates pH to 4.5-5.5; Gained solution adds purified water to 1000ml, fill, seals, and every 1ml, leak detection, quality inspection, packing promptly gets 7.5mg/ (1ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 6: preparation 15mg/2ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 15.0g
Sodium chloride 18.0g
Citric acid 0.84g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 2000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 1600ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 100ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulates pH to 5.0-5.5; Gained solution adds purified water to 2000ml, fill, seals, and every 2ml, leak detection, quality inspection, packing promptly gets 15mg/ (2ml/ props up), totally 1000.
The major technique test rating:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 5.0-5.5
Embodiment 7: preparation 15mg/2ml single dose ambroxol aerosol inhalation solution (10000)
Prescription:
Ambroxol hydrochloride 150.0g
Sodium chloride 172.0g
Citric acid 8.4g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 20000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 16000ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 1000ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulates pH to 5.0-5.5; Gained solution adds purified water to 20000ml, and adopt the blowing-irritates of asepticize-inside back cover unification technique (BFS) fill, seal, every 2ml, leak detection, quality inspection is packed, and promptly gets 15mg/ (2ml/ props up), totally 10000.
The major technique test rating:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 5.0-5.5
Embodiment 8: preparation 15mg/4ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 15.0g
Sodium chloride 27.0g
Citric acid 1.08g
Sodium citrate (0.2mol/l) is an amount of
Purified water adds to 4000ml
Preparation method:
Take by weighing ambroxol hydrochloride and sodium chloride by recipe quantity, add the 1000ml purified water dissolve solution 1; The citric acid that other gets recipe quantity is dissolved in the 2000ml purified water, gets solution 2; Two kinds of solution are merged, stir solution 3; It is an amount of to take by weighing sodium citrate again, adds the solution that the injection water is mixed with 0.2mol/L, stirs slowly to join in the solution 3, regulate pH to 4.5-5.5, add 0.2% activated carbon and boiled 30 minutes, filter decarburization through the sand filtration rod, add purified water to 4000ml in the gained solution, fill, seal every 4ml, leak detection, quality inspection, packing promptly gets 15mg/ (4ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 9: preparation 15mg/ (5ml/ props up) single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 15.0g
Sodium chloride 30.0g
Citric acid 1.29g
Disodium phosphate soln (0.4mol/l) is an amount of
Purified water adds to 5000ml
Preparation method:
Take by weighing ambroxol hydrochloride and sodium chloride by recipe quantity, add the 2000ml purified water dissolve solution 1; The citric acid that other gets recipe quantity is dissolved in the 2000ml purified water, gets solution 2; Two kinds of solution are merged, stir solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulate pH to 5.5-6.0, add 0.2% activated carbon and boiled 30 minutes, filter decarburization through the sand filtration rod, add purified water to 5000ml in the gained solution, fill, seal every 5ml, leak detection, quality inspection, packing promptly gets 15mg/ (5ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 5.5-6.0
Embodiment 10: preparation 15mg/10ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 15.0g
Sodium chloride 45.0g
Citric acid 1.80g
Sodium citrate (0.2mol/l) is an amount of
Purified water adds 10000ml
Preparation method:
Take by weighing ambroxol hydrochloride by recipe quantity, join in the water for injection of 8000ml, stirring and dissolving is complete, gets solution 1; Other gets recipe quantity citric acid and sodium chloride, adds 500ml water for injection, after the stirring and dissolving, gets solution 2; Two kinds of solution are merged, stir, get solution 3; It is an amount of to take by weighing sodium citrate again, adds the solution that the injection water is mixed with 0.2mol/L, stirs slowly to join in the solution 3, regulates pH to 4.5-5.5; Gained solution adds purified water to 10000ml, fill, seals, and every 10ml, leak detection, quality inspection, packing promptly gets 15mg/ (10ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 11: preparation 15mg/6ml single dose ambroxol aerosol inhalation solution (1000)
Prescription:
Ambroxol hydrochloride 15.0g
Sodium chloride 36.0g
Citric acid 1.38g
Sodium hydrogen phosphate (0.4mol/l) is an amount of
Purified water adds to 6000ml
Preparation method:
Take by weighing ambroxol hydrochloride and sodium chloride by recipe quantity, add the 3000ml purified water dissolve solution 1; The citric acid that other gets recipe quantity is dissolved in the 2000ml purified water, gets solution 2; Two kinds of solution are merged, stir solution 3; It is an amount of to take by weighing sodium hydrogen phosphate again, adds the solution that the injection water is mixed with 0.4mol/L, stirs slowly to join in the solution 3, regulate pH to 4.5-5.5, add 0.2% activated carbon and boiled 30 minutes, filter decarburization through the sand filtration rod, add purified water to 6000ml in the gained solution, fill, seal every 6ml, leak detection, quality inspection, packing promptly gets 15mg/ (6ml/ props up), totally 1000.
The key technical indexes check:
Character: colourless or almost colourless clear liquid
Content: ambroxol-hydrochloride-containing (C
13H
18Br
2N
2OHCl) should be the 90.0%-110.0% of labelled amount
Related substance: less than 1%
Sterility test: qualified
PH value: 4.5-5.5
Embodiment 12: the atomizing effect of atomized inhalation of the present invention and multiple dose propellant and the test of parameter
Atomizing effect to ambroxol single dose atomized inhalation provided by the invention and multiple dose atomized inhalation compares, and whether possesses technical advantage with reflection single dose atomized inhalation.
Prior art and document confirm: suck the curative effect that pH value, osmotic pressure, Dynamic Viscosity, the surface tension of preparation and the diameter of particle (DD) that enters the mouth after the atomizer atomizing all can influence atomization inspiration treatment.The diameter of particle that human body can suck should be and can suck particle diameter (RD) less than 5 microns (μ m), and sucks the particle diameter that preparation pH value, osmotic pressure, Dynamic Viscosity, surface tension all may influence atomized particles.Particle diameter can characterize external atomizing effect less than 5 microns microgranule ratio, is defined as: RF (RespirableFraction)=RD/DD * 100%, and the RF value is big more, and the curative effect of atomization inspiration treatment may be good more.
Adopt the embodiment of the invention 7 described ambroxol single dose atomized inhalation samples and external listing ambroxol multiple dose atomized inhalation product (Mucosolvan inhalations), use PARI
Instruments such as atomizing inhalation machine (hospital with) are tested.
Known that by last watch test result the surface tension of single dose atomized inhalation is greater than the surface tension of multiple dose atomized inhalation, analyzing main cause is to have added antiseptic in the multiple dose atomized inhalation: benzalkonium chloride.
Utilize atomizer that diameter of particle data such as following table are measured in above-mentioned test specimen atomizing back:
Embodiment 13: the atomizing effect of atomized inhalation of the present invention and injection and the comparison of parameter
Atomizing effect to ambroxol single dose atomized inhalation provided by the invention and injection compares, and whether possesses technical advantage with reflection single dose atomized inhalation.
Adopt the embodiment of the invention 7 described ambroxol single dose atomized inhalation samples and China's listing ambroxol injection (Ambroxol injection 15mg/2ml), use PARI
Instruments such as atomizing inhalation machine (child with) are tested.
Utilize atomizer that diameter of particle data such as following table are measured in above-mentioned test specimen atomizing back:
Claims (12)
1. the atomizing of an ambroxol sucks and uses pharmaceutical solutions, comprising:
1) ambroxol of single pharmaceutical dosage or its officinal salt;
2) isotonic agent and solvent;
3) buffer;
4) pharmaceutical pack of single dose.
In ambroxol, the mass ratio of medicinal ingredient and isotonic agent is 1: 1.1-1: 3.3.
2. according to the single dose aerosol inhalation solution preparation described in the claim 1, it is characterized in that: described single dose atomizing sucks ambroxol, ambroxol hydrochloride, tartaric acid ambroxol, hydrobromic acid ambroxol and other officinal salt that preparation comprises 5-60 milligram pharmaceutical dosage.
3. according to the single dose aerosol inhalation solution preparation described in the claim 2, it is characterized in that: described single dose atomizing sucks preparation and comprises 7.5,15.0,22.5,30.0,37.5,45.0,52.5,60.0 milligrams ambroxol hydrochloride.
4. according to the single dose aerosol inhalation solution preparation described in the claim 3, it is characterized in that: described single dose atomizing sucks preparation and comprises 7.5,15.0,30.0,45.0 milligrams ambroxol hydrochloride.
5. according to the single dose aerosol inhalation solution preparation described in the claim 1, it is characterized in that: described isotonic agent is sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, sorbitol.
6. according to claim a kind of described single dose aerosol inhalation solution preparation, it is characterized in that: described buffer is a citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, sodium hydrogen phosphate-potassium dihydrogen phosphate, acetic acid-sodium acetate, citric acid-sodium hydroxide-hydrochloric acid.
7. according to claim 6 kind of described single dose aerosol inhalation solution preparation, it is characterized in that: described buffer is a citric acid-sodium citrate, citric acid-sodium hydrogen phosphate, sodium hydrogen phosphate-potassium dihydrogen phosphate, citric acid-sodium hydroxide-hydrochloric acid.
8. single dose aerosol inhalation solution preparation according to claim 1, it is characterized in that: the pH value of aerosol inhalation solution is stable at 3.0-6.0.
9. single dose aerosol inhalation solution preparation according to claim 8, it is characterized in that: the pH value of aerosol inhalation solution is stable at 5.0-6.0.
10. single dose atomizing according to claim 1 sucks uses pharmaceutical solutions, and it is characterized in that: specification is every 1.0-20.0 milliliter.
Use pharmaceutical solutions 11. single dose atomizing according to claim 10 sucks, it is characterized in that: specification is 1.0,2.0,3.0,4.0,5.0,6.0,8.0,10.0 milliliters every.
12. described single dose atomizing sucks and uses pharmaceutical solutions according to claim 1 to 11, it is characterized in that: described single dose atomizing sucks preparation, and the packing of single dose adopts asepticize to blow-irritate-the inside back cover unification technique.
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| CNA200810110981XA CN101606903A (en) | 2008-06-19 | 2008-06-19 | A kind of atomizing of ambroxol sucks with solution and preparation method thereof |
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| CNA200810110981XA CN101606903A (en) | 2008-06-19 | 2008-06-19 | A kind of atomizing of ambroxol sucks with solution and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924302A (en) * | 2012-11-07 | 2013-02-13 | 陕西合成药业有限公司 | Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride |
| CN103462942A (en) * | 2013-08-20 | 2013-12-25 | 湖南赛隆药业有限公司 | Suction-type ambroxol hydrochloride solution |
| US20140066518A1 (en) * | 2011-03-14 | 2014-03-06 | Boehringer Ingelheim International Gmbh | Use of a sprayable composition comprising ambroxol |
| 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 |
| CN105250216A (en) * | 2015-09-28 | 2016-01-20 | 成都天台山制药有限公司 | Ambroxol hydrochloride injection suitable for aerosol inhalation |
| CN106727321A (en) * | 2017-02-14 | 2017-05-31 | 杭州百诚医药科技股份有限公司 | A kind of suction ambroxol hydrochloride solution |
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| CN110179772A (en) * | 2018-07-16 | 2019-08-30 | 北京海浈医药科技有限公司 | A kind of ambroxol hydrochloride preparation and preparation method thereof for Neulized inhalation |
| CN110200905A (en) * | 2019-07-01 | 2019-09-06 | 黑龙江珍宝岛药业股份有限公司 | A kind of ambroxol hydrochloride composition and its injection and application |
| CN111110662A (en) * | 2018-10-30 | 2020-05-08 | 北京盈科瑞创新药物研究有限公司 | Method for preparing solution preparation for inhalation |
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| US20140066518A1 (en) * | 2011-03-14 | 2014-03-06 | Boehringer Ingelheim International Gmbh | Use of a sprayable composition comprising ambroxol |
| US10959964B2 (en) * | 2011-03-14 | 2021-03-30 | Sanofi-Aventis Deutschland Gmbh | Use of a sprayable composition comprising ambroxol |
| CN102924302A (en) * | 2012-11-07 | 2013-02-13 | 陕西合成药业有限公司 | Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride |
| CN104027326B (en) * | 2013-03-04 | 2017-09-01 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride atomized inhalation and its preparation method and application |
| 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 |
| CN103462942A (en) * | 2013-08-20 | 2013-12-25 | 湖南赛隆药业有限公司 | Suction-type ambroxol hydrochloride solution |
| CN105250216A (en) * | 2015-09-28 | 2016-01-20 | 成都天台山制药有限公司 | Ambroxol hydrochloride injection suitable for aerosol inhalation |
| CN105250216B (en) * | 2015-09-28 | 2018-07-31 | 成都天台山制药有限公司 | Suitable for the ambroxol hydrochloride injection of Neulized inhalation |
| CN106975045A (en) * | 2016-01-15 | 2017-07-25 | 北京盈科瑞药物研究院有限公司 | A kind of antiviral Neulized inhalation pharmaceutical solutions and preparation method thereof |
| CN113368208A (en) * | 2016-01-15 | 2021-09-10 | 盈科瑞（横琴）药物研究院有限公司 | Antiviral aerosol inhalation solution preparation and preparation method thereof |
| CN106727321A (en) * | 2017-02-14 | 2017-05-31 | 杭州百诚医药科技股份有限公司 | A kind of suction ambroxol hydrochloride solution |
| CN110179772A (en) * | 2018-07-16 | 2019-08-30 | 北京海浈医药科技有限公司 | A kind of ambroxol hydrochloride preparation and preparation method thereof for Neulized inhalation |
| CN111110662A (en) * | 2018-10-30 | 2020-05-08 | 北京盈科瑞创新药物研究有限公司 | Method for preparing solution preparation for inhalation |
| CN110200905A (en) * | 2019-07-01 | 2019-09-06 | 黑龙江珍宝岛药业股份有限公司 | A kind of ambroxol hydrochloride composition and its injection and application |
| CN110200905B (en) * | 2019-07-01 | 2022-03-25 | 黑龙江珍宝岛药业股份有限公司 | Ambroxol hydrochloride composition, injection and application thereof |
| CN114269369A (en) * | 2019-07-03 | 2022-04-01 | 艾伊拉米治疗有限公司 | Exenatide compositions for pulmonary administration and uses thereof |
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