CN107233311A - It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof - Google Patents
It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof.The invention further relates to application of the glycopyrronium bromide in terms of Afromoterol aqueous stability is improved.The present invention using glycopyrronium bromide while Afromoterol physical stability is improved, and the two can produce synergy pharmacologically again, and then improve lung's local therapeutic effects.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of using Afromoterol and glycopyrronium bromide as the mist of active component
Agent and preparation method thereof.The invention further relates to application of the glycopyrronium bromide in terms of Afromoterol aqueous stability is improved.
Background technology
In recent years due to atmosphere pollution, smoking, aging population and other factorses, the chronic respiratory disease incidence of disease,
Fatal rate substantially increases.Common chronic respiratory disease includes COPD (Chronic obstructive
Pulmonary disease, COPD, abbreviation chronic obstructive pulmonary disease), bronchial astehma, pulmonary infection and lung cancer etc..Wherein chronic obstructive pulmonary disease is in
State's incidence of disease is up to 8.2%, and in the U.S., the incidence of disease is up to 14%.Chronic obstructive pulmonary disease is the disease being characterized with chronic progressive airflow obstruction
Disease, mainly including chronic bronchitis, chronic obstructive emphysema, its Symptoms is that cough, expectoration, shortness of breath or breathing are tired
It is difficult, pant with it is uncomfortable in chest etc..As the high breathing problem of fatal rate of disabling, chronic obstructive pulmonary disease often causes chronic pulmonary heart
Disease and right heart failure, respiratory failure, sleep disordered breathing etc., have a strong impact on patients ' life quality, harm patient vitals' safety.
In view of the particularity of disease, COPD patient needs long-term prescription.Durative action preparation helps to reduce times for spraying, carries
The compliance of high patient, quality of making the life better.
In terms of the selection of medicine, the effect of being greatly improved to chronic obstructive pulmonary disease of beta receptor activator.They mainly pass through excitement
In the beta receptor of respiratory tract, activated adenyl cyclase, activated cell atriphos (Adenosine triphosphate,
ATP formation CAMPs, activated protein kinase A increases Na+、K+、Ca2+Intraor extracellular is exchanged, and reduces the Ca of endocellular liberation2 +, so that relaxation, diastole bronchial smooth muscle, play antiasthmatic effect.Allergic mediators can be reduced simultaneously particularly loose from cell
Discharged in cell.
Afromoterol (Arformoterol), also known as (R, R)-Formoterol, are that the single optics of racemization Formoterol is different
Structure body, its structural formula is as follows.Afromoterol belongs to long-acting beta2Receptor stimulating agent, can be clinically used for the treatment of chronic pulmonary obstruction.
The Formoterol listed at present contains R, R and S, two kinds of configurations of S.Research shows the biology of Afromoterol ((R, R)-Formoterol)
Activity is more than 1000 times of (S, S)-Formoterol configuration, and Afromoterol is strengthened acetylcholine without (S, S)-Formoterol and drawn
Play the side effect of bronchoconstriction reaction.
Afromoterol foreign countries' commercialized product is poor (the HPLC surveys of suction liquid, trade name Brovana, but the stability of solution
Determine the Afromoterol in Foradil Aerolizer formoterol fumarate, Miao Xu West China pharmaceutical journal, 2011.03).The A of CN 1333682 (entitled " can
Storage the active substance concentrate containing Formoterol ") in point out that Formoterol can not be stored substantially stably in the solution, with
Cause can not ensure drug quality of the preparation in prolonged storage, therefore Formoterol is only limited to carry out for sucking with powder
Therapy.Based on this, the A of CN 1333682 provide the concentration of the liquid or form of suspension of a kind of material containing formoterol active
Liquid.However, the concentration of active material is too high in the concentrate, so that corresponding solution or suspension are under not diluted, it is impossible to
It is used to treat for suction.
MAChR antagonist can suppress its work by the combination of blockage of acetylcholine and acceptor
With.Glycopyrronium bromide (Glycopyrronium Bromide) is a kind of new anticholinergic agent, and its structural formula is as follows.Ge Long
Bromine ammonium can forcefully selective exclusion M3 acceptors (M-ChR), more longlasting bronchus protection and bronchus can be produced
Dilating effect, works rapid, bronchiectatic activity continues more than 24h.Glycopyrronium bromide action speed is rapid-action compared with Tiotropium Bromide
About 3-5 times, there is good tolerance with respect to Tiotropium Bromide.However, glycopyrronium bromide can not be mixed with alkaline drug, pH>Ester when 6
Base is easily hydrolyzed, and the amino of high degree of polarization limits it and passes through lipid film in glycopyrronium bromide, is unfavorable for and pneumonocyte film surface
Acceptor, which is combined, plays drug effect, and this also limits the performance of glycopyrronium bromide drug effect to a certain extent.
WO2016/170518 A1 disclose a kind of pharmaceutical composition including Afromoterol or its salt and glycopyrronium bromide, should
Pharmaceutical composition is suspension or solution form, wherein comprising propellant, being administered with aerosol form.
US2011/0150782 A1 disclose a kind of aerosol for being applied to that COPD patient is administered by pressurised metered device
Agent, includes glycopyrronium bromide and Formoterol.
US2011/0150784 A1 and CN 102665678 discloses the aerosol comprising glycopyrronium chloride and Formoterol,
Wherein propellant is hydrofluoroalkane (Hydrofluoroalkane, HFA).
WO2013/021199 A2 disclose a kind of pharmaceutical composition of the two class pharmacologically active principles for COPD, tool
Body employs eutectiferous technology.
CN 104257610 discloses a kind of method for being used to prepare the carrier granular used in inhalable dry powder, is directed to lead to
The available carrier granular of methods described and its powdered drug preparation are crossed, Formoterol or glycopyrronium bromide is contained.
Document Aclidinium bromide and formoterolfumarateas a fixed-dose
combination in COPD:pooledanalysis of symptoms and exacerbations fromtwo six-
Month, multicentre, randomised studies (ACLIFORM and AUGMENT) disclose a kind of aclidinium bromide
Combined with the fixed dosage of formoterol fumarate, it is preferred that emphasis is investigate the pharmacology index of the combination.
The pharmaceutical dosage form for the treatment of chronic obstructive pulmonary disease is generally dry powder doses or aerosol in the market.However, due to the spy of aerosol
Very high, it is necessary to which health care professional is instructed application method is required to the fitness of patient in different property, administration process, it is desirable to
Patient synchronously sucks, and otherwise can largely influence therapeutic effect, especially for ability to accept slightly weak old man and child,
It is possible to administering effect unsatisfactory.In addition, aerosol or this kind of formulation of dry powder doses require patient when in use forced suction,
Hold one's breath, this is for patient with PUD D itself, and its PFT has been affected, and is extremely difficult to such formulation medicine
Thing plays the throughput needed for preferable drug effect.
Moreover, EP 1157689 and CN 102665679 mention formoterol fumarate aerosol be it is relatively unstable,
Significantly degraded under high temperature, super-humid conditions.
In addition, there is zoopery to show, after dry powder insulin agent medication is given for a long time, the incidence of disease of lung cancer significantly increases
Plus.Although can't determine it is drug-induced at present, formulation (the Cui Ying insulin caused of pulmonary administration in itself
The Central-South pharmacy of retrospective analysis [J] of Foradil Aerolizer formoterol fumarate Exubera documents, 2009:7(10).).
By contrast, Alevaire avoids the negative effect that may be brought without micronization step；Match somebody with somebody without patient is special
Close, operate relatively simple, the normal breathing state of holding, and then avoid the problem of respiratory promoter is uncoordinated；And may be used also
Avoid the problems such as propellant in medicine and aerosol is incompatible.
However, the Afromoterol aqueous solution is more unstable, for example, tartaric acid Afromoterol is in acid, alkali, high temperature, illumination, oxidation
Under the conditions of produce obvious degradation, there is obvious catabolite.Therefore, rarely have in the prior art be related to Afromoterol with water
For the Alevaire of solvent.
In consideration of it, there is demand to the Alevaire for developing simple to operate, use, stable Afromoterol.
The content of the invention
In order to solve Afromoterol, stability is poor in aqueous, problem of easy degradation, it is an object of the invention to provide
A kind of Alevaire, it is using Afromoterol and glycopyrronium bromide as active component, using water as solvent.
Further, the Afromoterol in Alevaire of the present invention is to exist in a salt form, including but not limited to tartaric acid
Salt, fumarate, hydrochloride, sulfate, benzene sulfonate, succinate, preferably tartrate.
Further, in Alevaire of the present invention Afromoterol and the mol ratio of glycopyrronium bromide is 1:10-10:1, preferably rub
You are than being 1:2.
Further, the consumption of the Afromoterol in Alevaire of the present invention is 0.17-22.98 μ g/mL, preferably 7.66 μ
g/mL。
Further, the consumption of the glycopyrronium bromide in Alevaire of the present invention is 0.4-54 μ g/mL, preferably 18 μ g/mL.
In the preferred scheme of the present invention, the Afromoterol in Alevaire of the present invention is present in the form of tartrate,
The consumption of its mesotartaric acid Afromoterol is 0.25-33 μ g/mL, preferably 11 μ g/mL.
In the preferred scheme of the present invention, nonionic surface active agent is also included in Alevaire of the invention.
Further, the nonionic surface active agent in Alevaire of the present invention include but is not limited to tween, it is sapn, polynary
Alcohol, poloxamer, preferably Tween 80.
Further, the consumption of the nonionic surface active agent in Alevaire of the present invention is 50-400mg/L, preferably
100mg/L。
In the preferred scheme of the present invention, pH buffer solutions are also included in Alevaire of the invention.
Further, the pH buffer solutions in Alevaire of the present invention include Acetic acid-sodium acetate, phosphoric acid-sodium phosphate, citric acid-
Sodium citrate, preferably citric acid-sodium citrate.
In the preferred scheme of the present invention, the pH value of Alevaire of the invention is 4.0-6.0, preferably 4.5.
In the preferred scheme of the present invention, osmotic pressure regulator is also included in Alevaire of the invention.
Further, the osmotic pressure regulator in Alevaire of the present invention includes sodium chloride, glucose, propane diols, glycerine, excellent
Select sodium chloride.
Further, the consumption of the osmotic pressure regulator in Alevaire of the present invention is 8-10mg/mL, preferably 9mg/mL.
In the preferred scheme of the present invention, complexing agent is also included in Alevaire of the invention.
Further, the complexing agent in Alevaire of the present invention is EDTA or its salt, preferably EDTA-2Na.
Further, the consumption of the complexing agent in Alevaire of the present invention is 50-500mg/L, preferably 300mg/L.
Present invention also offers the method for preparing Alevaire of the present invention, methods described includes：
Osmotic pressure regulator is dissolved in the water of proper volume, after stirring and dissolving, tartaric acid Afromoterol and lattice are added
Grand bromine ammonium, stirring is added water to full dose to dissolving, and is added pH buffer solutions regulation pH, is produced.
In the preferred scheme of the present invention, the method for preparing Alevaire includes：
Osmotic pressure regulator, complexing agent are dissolved in the water of proper volume, after stirring and dissolving, tartaric acid A Fute is added
Sieve and glycopyrronium bromide, stirring to dissolving；The water of proper volume is added into nonionic surface active agent, is stood to scattered equal
It is even, it is added in above-mentioned solution, is sufficiently stirred for, add water to full dose, adds pH buffer solutions regulation pH, produce.
Prepared present invention also offers the combination of Afromoterol and glycopyrronium bromide for treating chronic respiratory disease
Alevaire in purposes.
In the preferred scheme of the present invention, the chronic respiratory disease includes COPD, bronchus
Asthma, pulmonary infection.
It is surprisingly found by the inventors that, glycopyrronium bromide is added in Alevaire of the invention, is not only strengthened from physicochemical property angle
The stability of Afromoterol, and the two pharmacologically has synergy, and be favorably improved Afromoterol control curative effect
Really.
The Alevaire of the present invention, without dilution, can directly utilize air compression, ultrasonic atomizatio, vibratory sieve using water as solvent
Atomized medicine introducing is realized etc. technology.
Brought by force in addition, adding nonionic surface active agent in the Alevaire of the present invention and overcoming glycopyrronium bromide polarity
The defect for being not easily accessible alveolar cell, from suitable nonionic surface active agent extend lung's holdup time, promote medicine
The pulmonary absorption of thing, and then improve lung's local therapeutic effects.The present invention is by selecting suitable pH scopes and complexing agent to enter
One step lifts the stability of Afromoterol.By adding osmotic pressure regulator, the osmotic pressure of Alevaire is adjusted, enters its atomization
The stimulation to lung tissue is reduced after lung.
Brief description of the drawings
Fig. 1 is the HPLC spectrograms of the mesotartaric acid Afromoterol contrast solution of embodiment 4.
Fig. 2 is the HPLC spectrograms after the mesotartaric acid Afromoterol of embodiment 4 is degraded in acid condition.
Fig. 3 is the HPLC spectrograms after the mesotartaric acid Afromoterol of embodiment 4 is degraded in the basic conditions.
Fig. 4 is the HPLC spectrograms after the mesotartaric acid Afromoterol of embodiment 4 is degraded under the high temperature conditions.
Fig. 5 is the HPLC spectrograms after the mesotartaric acid Afromoterol of embodiment 4 is degraded under the conditions of actinic.
Fig. 6 is the HPLC spectrograms after the mesotartaric acid Afromoterol of embodiment 4 is degraded under oxidative conditions.
Embodiment
The above of the present invention is described in further detail below with reference to the drawings and specific embodiments.But this
Art personnel are it should be appreciated that protection scope of the present invention is not limited thereto.
Embodiment
Raw material tartaric acid Afromoterol (AF) producer used in the embodiment of the present invention is MSN Laboratories
Private Limited, lot number is AFS/C062/3/01；Glycopyrronium bromide (GB) producer is M/S.HARMAN FINOCHEM
LTD, lot number is GCP/006/2014-2015.
The preparation of the tartaric acid Afromoterol folk prescription Alevaire of embodiment 1 and glycopyrronium bromide folk prescription Alevaire
Tartaric acid Afromoterol folk prescription Alevaire and glycopyrronium bromide folk prescription Alevaire are prepared respectively by table 1.
Table 1
Preparation method：
Weigh recipe quantity sodium chloride to be dissolved in the water of proper volume after (about 700ml), stirring and dissolving, add recipe quantity wine
Stone acid Afromoterol or glycopyrronium bromide, stirring are added water to full dose to dissolving, and add citric acid-sodium citrate buffer regulation
PH, is produced.
The preparation of the tartaric acid Afromoterol of embodiment 2 and glycopyrronium bromide compound Alevaire
Tartaric acid Afromoterol and glycopyrronium bromide compound Alevaire are prepared by table 2.
Table 2
Preparation method：
Weigh recipe quantity sodium chloride to be dissolved in the water of proper volume after (about 700ml), stirring and dissolving, add recipe quantity wine
Stone acid Afromoterol and glycopyrronium bromide, stirring are added water to full dose to dissolving, and add citric acid-sodium citrate buffer regulation
PH, is produced.
The consumption of the compound Alevaire mesotartaric acid Afromoterol of embodiment 3 and glycopyrronium bromide is investigated
The tartaric acid Afromoterol that preparation method according to embodiment 2 is prepared in table 3 below is atomized with glycopyrronium bromide compound
Agent.
Table 3
Take respectively the five kinds of tartaric acid Afromoterols and the glycopyrronium bromide compound Alevaire that are prepared by table 3 in 40 DEG C ± 2 DEG C/
Placed 1 month under the conditions of 75%RH ± 5%RH, drug content is measured by sampling (with T0Content is as 100%).40℃±2℃/
75%RH ± 5%RH conditions accelerated test measurement result of 1 month is as shown in table 4 below.
Table 4
As a result show, in tartaric acid Afromoterol of the invention and glycopyrronium bromide compound Alevaire, tartaric acid Afromoterol
Preferable amount be 11 μ g/mL, the preferable amount of glycopyrronium bromide is 18 μ g/mL.
The stability study of the Afromoterol of embodiment 4 and glycopyrronium bromide
The measure of tartaric acid Afromoterol forced degradation is using high performance liquid chromatograph Agilent1100, HPLC condition：
Chromatographic column：C18 posts (150mm × 4.6mm, 5 μm)
Mobile phase：23.9mmol/L the volume ratio of biphosphate sodium water solution-acetonitrile, biphosphate sodium water solution and acetonitrile
For 85:15
Flow velocity：1mL/min
Detection wavelength：214nm
Column temperature：40℃
Sampling volume：20μl.
The measure of glycopyrronium bromide forced degradation is using high performance liquid chromatograph Agilent1100, HPLC condition：
Chromatographic column：C18 posts (150mm × 4.6mm, 5 μm)
Mobile phase：The volume ratio of 23.9mmol/L biphosphates sodium water solution-acetonitrile, biphosphate sodium water solution and acetonitrile
For 75:25
Flow velocity：1mL/min
Detection wavelength：214nm
Column temperature：40℃
Sampling volume：20μl.
1. the forced degradation of glycopyrronium bromide
Glycopyrronium bromide (1mg/mL) 24h under acid, high temperature, oxidation drastic conditions does not produce obvious degradation material, in 1M
2h degradeds about 28% under NaOH alkalescence conditions.
2. the forced degradation of tartaric acid Afromoterol
Tartaric acid Afromoterol (1mg/mL) produces obvious degradation under acid, alkali, high temperature, illumination, oxidizing condition, occurs
Obvious catabolite.Specifically it is shown in Table 5.
Table 5
The HPLC spectrograms of tartaric acid Afromoterol contrast solution without forced degradation are referring to Fig. 1, tartaric acid Afromoterol
HPLC spectrograms after being degraded under the conditions of above-mentioned forced degradation are referring to Fig. 2 to Fig. 6.
The comparison of the tartaric acid Afromoterol of embodiment 5, glycopyrronium bromide list compound Alevaire
Compared by single compound, investigate interaction that may be present between tartaric acid Afromoterol and glycopyrronium bromide.
The tartaric acid Afromoterol that Example 2 is prepared respectively is made with glycopyrronium bromide compound Alevaire and embodiment 1
Standby obtained tartaric acid Afromoterol folk prescription Alevaire and glycopyrronium bromide folk prescription Alevaire are in 40 DEG C of ± 2 DEG C/75%RH ± 5%RH
Under the conditions of place 2 months, be measured by sampling drug content (with T0Content is as 100%).
Content detection uses high performance liquid chromatograph Waters 2690, and HPLC conditions are：
Chromatographic column：C18 posts (150mm × 4.6mm, 5 μm)
Mobile phase：The volume ratio of 23.9mmol/L biphosphates sodium water solution-acetonitrile, biphosphate sodium water solution and acetonitrile
For 75:25
Flow velocity：1mL/min
Detection wavelength：214nm
Column temperature：40℃
Sampling volume：20μl.
40 DEG C of ± 2 DEG C/75%RH ± 5%RH conditions accelerated test measurement results of 2 months are as shown in table 6 below.
Table 6
| AF (%) | GB (%) | |
| Tartaric acid Afromoterol (AF) folk prescription | 10.33 | N/A |
| Glycopyrronium bromide (GB) folk prescription | N/A | 4.44 |
| Tartaric acid Afromoterol (AF) and glycopyrronium bromide (GB) compound | 29.73 | 10.44 |
As a result show, the content of tartaric acid Afromoterol folk prescription mesotartaric acid Afromoterol is 10.33%, glycopyrronium bromide list
The content of glycopyrronium bromide is 4.44% in side, and tartaric acid Afromoterol and glycopyrronium bromide compound mesotartaric acid Afromoterol and lattice
The content of grand bromine ammonium is respectively 29.73% and 10.44%.Compared with respective folk prescription, with significant difference (P<0.05).It can be seen that,
For tartaric acid Afromoterol folk prescription Alevaire, the addition of glycopyrronium bromide significantly improves the steady of tartaric acid Afromoterol
It is qualitative.From the two chemical structure analysis, it may be possible to contain hydroxyl and ester group in glycopyrronium bromide molecule, they can be with tartaric acid
The groups such as hydroxyl, carboxyl in Afromoterol formation hydrogen bond so that the stability enhancing of tartaric acid Afromoterol.
Embodiment 6 investigates influences of the pH to Alevaire stability of the present invention
Forced degradation experiment (embodiment 4) display of early stage, tartaric acid Afromoterol can degrade in acid condition.
Based on this, the compound Alevaire that pH is 4.5,5.0 and 5.5 is prepared respectively and is studied.
Tartaric acid Afromoterol and glycopyrronium bromide compound are prepared by the raw material dosage of table 7 according to the preparation method of embodiment 2
Alevaire.
Table 7
Take respectively the three kinds of tartaric acid Afromoterols and the glycopyrronium bromide compound Alevaire that are prepared by table 7 in 40 DEG C ± 2 DEG C/
Placed 1 month under the conditions of 75%RH ± 5%RH, drug content is measured by sampling (with T0Content is as 100%).40℃±2℃/
75%RH ± 5%RH conditions accelerated test measurement result of 1 month is as shown in table 8 below.
Table 8
| AF (%) | GB (%) | |
| Compound Alevaire 1 (pH4.5) | 48.11 | 15.86 |
| Compound Alevaire 2 (pH5.0) | 51.64 | 30.32 |
| Compound Alevaire 3 (pH5.5) | 40.11 | 19.81 |
The stability of tartaric acid Afromoterol and glycopyrronium bromide compound Alevaire and tartaric acid Afromoterol folk prescription Alevaire
Comparative study
In order to carry out comparative study, the tartaric acid Afromoterol folk prescription Alevaire that pH is 4.5,5.0 and 5.5 is prepared respectively.
Tartaric acid Afromoterol folk prescription Alevaire is prepared by the raw material dosage of table 9 according to the preparation method of embodiment 1.
Table 9
The three kinds of tartaric acid Afromoterol folk prescription Alevaires prepared by table 9 are taken respectively in 40 DEG C of ± 2 DEG C/75%RH ± 5%
Placed 1 month under the conditions of RH, drug content is measured by sampling (with T0Content is as 100%).40 DEG C of ± 2 DEG C/75%RH ± 5%RH
The condition accelerated test measurement result of 1 month is as shown in table 10 below.
Table 10
| AF (%) | |
| AF folk prescriptions Alevaire 1 (pH4.5) | 37.11 |
| AF folk prescriptions Alevaire 2 (pH5.0) | 50.04 |
| AF folk prescriptions Alevaire 3 (pH5.5) | 30.60 |
As a result show, when compound Alevaire pH of the invention is 4.5-5.0, the grand bromine of tartaric acid Afromoterol dative therein
Higher (the P of content of ammonium<0.05), that is to say, that more stablize when compound Alevaire pH of the invention is 4.5-5.0.It is another
Aspect, no matter the pH of Alevaire is 4.5,5.0 or 5.5, and the content of the tartaric acid Afromoterol in compound Alevaire is above wine
The content of tartaric acid Afromoterol in stone acid Afromoterol folk prescription Alevaire, the addition of this explanation glycopyrronium bromide causes tartaric acid
The stability enhancing of Afromoterol.
Embodiment 7 investigates influence of the protective agent to compound Alevaire stability of the present invention
The protective agent investigated in the present embodiment is nonionic surfactant and complexing agent.
Tartaric acid Afromoterol and glycopyrronium bromide compound Alevaire are prepared by the raw material dosage of table 11.
Table 11
Preparation method：
Weigh recipe quantity sodium chloride, EDTA-2Na (situation for being directed to compound Alevaire 2 and 4) and be dissolved in the water of proper volume
In (about 700ml), after stirring and dissolving, add recipe quantity tartaric acid Afromoterol, glycopyrronium bromide, stirring is to dissolving.Separately to prescription
Measure in Tween 80 (being directed to the situation of compound Alevaire 3 and 4) and add suitable quantity of water (about 20ml), stand to being uniformly dispersed, be added to
In above-mentioned solution, it is sufficiently stirred for, adds water to full dose, adds citric acid-sodium citrate buffer regulation pH, produce.
Take respectively the four kinds of tartaric acid Afromoterols and the glycopyrronium bromide compound Alevaire that are prepared by table 11 in 40 DEG C ± 2 DEG C/
Placed 2 months under the conditions of 75%RH ± 5%RH, drug content is measured by sampling (with T0Content is as 100%).40℃±2℃/
75%RH ± 5%RH conditions accelerated test measurement result of 2 months is as shown in table 12 below.
Table 12
| AF (%) | GB (%) | |
| Compound Alevaire 1 (pH4.5, no EDTA-2Na/Tween 80) | 29.73 | 10.44 |
| Compound Alevaire 2 (pH4.5 has EDTA-2Na) | 73.34 | 77.58 |
| Compound Alevaire 3 (pH4.5 has Tween 80) | 45.06 | 28.74 |
| Compound Alevaire 4 (pH4.5 has EDTA-2Na/Tween 80) | 71.96 | 75.25 |
In addition, take respectively the four kinds of tartaric acid Afromoterols and the glycopyrronium bromide compound Alevaire that are prepared by table 11 in 40 DEG C ±
Placed 1 month under the conditions of 2 DEG C/75%RH ± 5%RH, drug content is measured by sampling (with T0Content is as 100%).40℃±2
DEG C/75%RH ± 5%RH conditions accelerated test measurement result of 1 month is as shown in table 13 below.
Table 13
| AF (%) | GB (%) | |
| Compound Alevaire 1 (pH4.5, no EDTA-2Na/Tween 80) | 48.11 | 15.86 |
| Compound Alevaire 2 (pH4.5 has EDTA-2Na) | 93.36 | 98.5 |
| Compound Alevaire 3 (pH4.5 has Tween 80) | 69.02 | 60.28 |
| Compound Alevaire 4 (pH4.5 has EDTA-2Na/Tween 80) | 90.58 | 95.0 |
The stability of tartaric acid Afromoterol and glycopyrronium bromide compound Alevaire and tartaric acid Afromoterol folk prescription Alevaire
Comparative study
In order to carry out comparative study, tartaric acid Afromoterol folk prescription Alevaire is prepared by the raw material dosage of table 14.
Table 14
Preparation method：
Weigh recipe quantity sodium chloride, EDTA-2Na (situation for being directed to folk prescription Alevaire 2 and 4) and be dissolved in the water of proper volume
In (about 700ml), after stirring and dissolving, add recipe quantity tartaric acid Afromoterol, stirring is to dissolving.Separately to recipe quantity Tween 80
Suitable quantity of water (about 20ml) is added in (being directed to the situation of folk prescription Alevaire 3 and 4), stands to being uniformly dispersed, is added to above-mentioned solution
In, it is sufficiently stirred for, adds water to full dose, adds citric acid-sodium citrate buffer regulation pH, produce.
The four kinds of tartaric acid Afromoterol folk prescription Alevaires prepared by table 14 are taken respectively in 40 DEG C of ± 2 DEG C/75%RH ± 5%
Placed 1 month under the conditions of RH, drug content is measured by sampling (with T0Content is as 100%).40 DEG C of ± 2 DEG C/75%RH ± 5%RH
The condition accelerated test measurement result of 1 month is as shown in table 15 below.
Table 15
| AF (%) | |
| AF folk prescriptions Alevaire 1 (pH4.5, no EDTA-2Na/Tween 80) | 37.11 |
| AF folk prescriptions Alevaire 2 (pH4.5 has EDTA-2Na) | 95.94 |
| AF folk prescriptions Alevaire 3 (pH4.5 has Tween 80) | 60.78 |
| AF folk prescriptions Alevaire 4 (pH4.5 has EDTA-2Na/Tween 80) | 93.72 |
As a result show, complexing agent is contained in compound Alevaire of the invention or contains complexing agent and non-ionic surface active
During agent, tartaric acid Afromoterol therein and the very high (P of glycopyrronium bromide content<0.05).On the other hand, glycopyrronium bromide is added
The content of tartaric acid Afromoterol can be improved, its stability lifting effect is slightly weaker than addition protective agent, but is protected compared to only adding
Protect for stability of the agent to lift tartaric acid Afromoterol, the addition of glycopyrronium bromide causes while exciting beta receptor, block
M receptor, can play synergy pharmacologically, and Cooperative Relaxation airway smooth muscle improves therapeutic effect.
The optimizing research of 8 pairs of embodiment tartaric acid Afromoterol of the invention and glycopyrronium bromide compound Alevaire
Tartaric acid Afromoterol and glycopyrronium bromide compound Alevaire are prepared by table 16.
Table 16
Preparation method：
Recipe quantity sodium chloride, EDTA-2Na is weighed to be dissolved in the water of proper volume after (about 700ml), stirring and dissolving, plus
Enter recipe quantity tartaric acid Afromoterol, glycopyrronium bromide, stirring to dissolving；Separately suitable quantity of water is added into recipe quantity Tween 80 (about
20ml), stand to being uniformly dispersed, be added in above-mentioned solution, be sufficiently stirred for, add water to full dose, add citric acid-citric acid
Sodium buffer solution adjusts pH, produces.
Take the tartaric acid Afromoterol prepared with glycopyrronium bromide compound Alevaire in 4 DEG C, 25 DEG C ± 2 DEG C, 40 DEG C ± 2
Placed 2 months under the conditions of DEG C, drug content is measured by sampling (with T0Content is as 100%).
The measurement result that 2 months are placed under the conditions of 4 DEG C, 25 DEG C ± 2 DEG C, 40 DEG C ± 2 DEG C is as shown in table 17 below.
Table 17
| AF (%) | GB (%) | |
| 4℃ | 80.07 | 78.43 |
| 25℃±2℃ | 77.49 | 77.39 |
| 40℃±2℃ | 71.96 | 75.25 |
As a result show, the tartaric acid Afromoterol is with glycopyrronium bromide compound Alevaire in 4 DEG C, 25 DEG C ± 2 DEG C, 40 DEG C ± 2
The content of tartaric acid Afromoterol and glycopyrronium bromide is very high after being placed 2 months under the conditions of DEG C, and is placed 2 months in 4 DEG C
When the equal highest of the content of tartaric acid Afromoterol and glycopyrronium bromide, 80% or so.
Claims (16)
1. a kind of Alevaire, it is using Afromoterol and glycopyrronium bromide as active component, using water as solvent.
2. Alevaire according to claim 1, wherein the Afromoterol is to exist in a salt form, the salt includes wine
Stone hydrochlorate, fumarate, hydrochloride, sulfate, benzene sulfonate, succinate, preferably tartrate.
3. Alevaire according to claim 1 or 2, wherein the mol ratio of the Afromoterol and glycopyrronium bromide is 1: 10-
10: 1, preferred molar ratio is 1: 2.
4. Alevaire according to claim 1 or 2, wherein the consumption of the Afromoterol is 0.17-22.98 μ g/mL, it is excellent
Elect 7.66 μ g/mL as；Preferably, the Afromoterol is present in the form of tartrate, its mesotartaric acid Afromoterol
Consumption is 0.25-33 μ g/mL, preferably 11 μ g/mL；The consumption of the glycopyrronium bromide is 0.4-54 μ g/mL, preferably 18 μ g/
mL。
5. Alevaire according to claim 1 or 2, wherein the Alevaire also includes nonionic surface active agent.
6. Alevaire according to claim 5, wherein the nonionic surface active agent include tween, it is sapn, polynary
The consumption of alcohol, poloxamer, preferably Tween 80, wherein nonionic surface active agent is 50-400mg/L, preferably 100mg/L.
7. Alevaire according to claim 1 or 2, wherein the Alevaire also includes pH buffer solutions.
8. Alevaire according to claim 7, wherein the pH buffer solutions include Acetic acid-sodium acetate, phosphoric acid-sodium phosphate,
Citric acid-sodium citrate, the pH value of preferably citric acid-sodium citrate, wherein Alevaire is 4.0-6.0, preferably 4.5.
9. Alevaire according to claim 1 or 2, wherein the Alevaire also includes osmotic pressure regulator.
10. Alevaire according to claim 9, wherein the osmotic pressure regulator includes sodium chloride, glucose, the third two
The consumption of alcohol, glycerine, preferably sodium chloride, wherein osmotic pressure regulator is 8-10mg/mL, preferably 9mg/mL.
11. Alevaire according to claim 1 or 2, wherein the Alevaire also includes complexing agent.
12. Alevaire according to claim 11, wherein the complexing agent is EDTA or its salt, preferably EDTA-2Na, its
Described in complexing agent consumption be 50-500mg/L, preferably 300mg/L.
13. a kind of method for preparing the Alevaire as any one of claim 1-12, methods described includes：
Osmotic pressure regulator is dissolved in the water of proper volume, after stirring and dissolving, Afromoterol and glycopyrronium bromide, stirring is added
To dissolving, add water to full dose, add pH buffer solutions regulation pH, produce.
14. the combination of Afromoterol and glycopyrronium bromide is preparing the use in being used to treat the Alevaire of chronic respiratory disease
On the way.
15. purposes according to claim 14, wherein the chronic respiratory disease include COPD,
Bronchial astehma, pulmonary infection.
16. the purposes according to claims 14 or 15, wherein the Alevaire is used cooperatively with atomizer.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112804991A (en) * | 2019-06-27 | 2021-05-14 | 上海谷森医药有限公司 | Inhalable solution formulations containing formoterol fumarate and aclidinium bromide |
| CN112972384A (en) * | 2019-12-02 | 2021-06-18 | 长风药业股份有限公司 | Preparation method of glycopyrronium bromide and indacaterol bulk drug micro-powder mixture |
| CN114924020A (en) * | 2022-05-30 | 2022-08-19 | 上海奥科达生物医药科技有限公司 | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution |
| CN115267024A (en) * | 2022-07-31 | 2022-11-01 | 浙江知一药业有限责任公司 | Pharmaceutical composition for treating respiratory system diseases and detection method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101394835A (en) * | 2006-03-01 | 2009-03-25 | 呼吸有限公司 | Nebulizer formulation and production method thereof |
| CN101657191A (en) * | 2007-04-19 | 2010-02-24 | 奇斯药制品公司 | Use of a composition comprising formoterol and beclomethasone dipropionate for the prevention or treatment of an acute condition of asthma |
| CN102665678A (en) * | 2009-12-23 | 2012-09-12 | 奇斯药制品公司 | Combination therapy for copd |
| CN105848641A (en) * | 2013-12-30 | 2016-08-10 | 奇斯药制品公司 | Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination |
| WO2016170518A1 (en) * | 2015-04-24 | 2016-10-27 | Glenmark Specialty S.A. | Pharmaceutical compositions comprising arformoterol and glycopyrronium |
-
2017
- 2017-06-27 CN CN201710504025.9A patent/CN107233311B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101394835A (en) * | 2006-03-01 | 2009-03-25 | 呼吸有限公司 | Nebulizer formulation and production method thereof |
| CN101657191A (en) * | 2007-04-19 | 2010-02-24 | 奇斯药制品公司 | Use of a composition comprising formoterol and beclomethasone dipropionate for the prevention or treatment of an acute condition of asthma |
| CN102665678A (en) * | 2009-12-23 | 2012-09-12 | 奇斯药制品公司 | Combination therapy for copd |
| CN105848641A (en) * | 2013-12-30 | 2016-08-10 | 奇斯药制品公司 | Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination |
| WO2016170518A1 (en) * | 2015-04-24 | 2016-10-27 | Glenmark Specialty S.A. | Pharmaceutical compositions comprising arformoterol and glycopyrronium |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112804991A (en) * | 2019-06-27 | 2021-05-14 | 上海谷森医药有限公司 | Inhalable solution formulations containing formoterol fumarate and aclidinium bromide |
| CN112972384A (en) * | 2019-12-02 | 2021-06-18 | 长风药业股份有限公司 | Preparation method of glycopyrronium bromide and indacaterol bulk drug micro-powder mixture |
| CN112972384B (en) * | 2019-12-02 | 2022-03-18 | 长风药业股份有限公司 | Preparation method of glycopyrronium bromide and indacaterol bulk drug micro-powder mixture |
| CN114924020A (en) * | 2022-05-30 | 2022-08-19 | 上海奥科达生物医药科技有限公司 | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution |
| CN116165319A (en) * | 2022-05-30 | 2023-05-26 | 上海奥科达医药科技股份有限公司 | Method for detecting diastereoisomers in formoterol fumarate inhalation solution |
| CN116165319B (en) * | 2022-05-30 | 2023-11-17 | 上海奥科达医药科技股份有限公司 | Method for detecting diastereoisomers in formoterol fumarate inhalation solution |
| CN115267024A (en) * | 2022-07-31 | 2022-11-01 | 浙江知一药业有限责任公司 | Pharmaceutical composition for treating respiratory system diseases and detection method thereof |
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