CN109745564A - A kind of preparation method sucking dry powder composite - Google Patents
A kind of preparation method sucking dry powder composite Download PDFInfo
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- CN109745564A CN109745564A CN201910080246.7A CN201910080246A CN109745564A CN 109745564 A CN109745564 A CN 109745564A CN 201910080246 A CN201910080246 A CN 201910080246A CN 109745564 A CN109745564 A CN 109745564A
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Abstract
The present invention relates to a kind of preparation methods for sucking dry powder composite, method includes the following steps: lubricant and pharmaceutical carrier are obtained carrier complexes by the first shear-mixed by (1)；(2) by the carrier complexes of step (1) and long-acting cholinergic antagonist and long acting beta agonists carry out the second shear-mixed to get.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of preparation method for sucking dry powder composite, this is dry
Compound powder contains long-acting cholinergic antagonist and long acting beta agonists, can be by powder inhaler to pulmonary administration.
Background technique
Long-acting cholinergic antagonist and long acting beta agonists are to be commonly used in treatment Chronic Obstructive Pulmonary Disease
The drug of disease.Long-acting cholinergic antagonist can be in conjunction with acetylcholinergic receptor and beta receptor, to inhibit choline mediator institute
The bronchus tonicity of mediation, moreover it is possible to the bronchoconstriction reflection for blocking vagus nerve to be mediated.Long acting beta agonists can be with
In conjunction with beta receptor, adenosine cyclophosphate (cAMP) level is increased, makes tracheal smooth muscle diastole, it is also possible to reduce labrocyte medium
Release inhibits the response of neutrophil cell, eosinophil and lymphocyte, increases mucociliary conveying.The two combination
It can be relieved the dyspnea symptom of Patients with Chronic Obstructive Pulmonary Disease, drug effect, which is better than, to be administered alone.Foradil Aerolizer formoterol fumarate is made in the two
Drug can be deposited on pulmonary absorption after delivery device is atomized afterwards, and target-oriented drug further enhances, and toxic side effect is substantially reduced, and rise
Effect speed also obviously becomes faster, and has good safety and tolerance through clinical test verifying.
Since cholinergic recepter and beta receptor are widely distributed in vivo, long-acting cholinergic antagonist and long-acting beta receptor
Agonist is administered orally approach for needing higher dosage when Treatment of COPD, can cause biggish poison
Side effect.After dry powder inhaler formulations are made in the two, targeting is greatly enhanced, and toxic side effect is substantially reduced, and action speed is also obvious
It becomes faster, has good safety and tolerance through clinical test verifying.
Dry powder sucks product, and often there is higher technical difficulty, this is because active constituent is in pulmonary deposition and plays
Local action absorbs the aerodynamic diameter for usually requiring its active constituent less than 5 μm, and the binding force between particle is (such as at this time
Electrostatic force, Van der Waals force, capillary force) effect is complicated, the influence of formulation and technology parameter it is difficult to predict.
Active constituent accounts for that ratio in composition is very low, and cohesive force is strong in dry powder inhaler formulations, needs through technique and prescription
Active constituent is helped to be uniformly dispersed；On the other hand, strength or prolonged mixing are generally required in order to reach preferable dispersion degree,
This will lead to active constituent carrier surface combine it is too strong so that be not easy in use from carrier surface be detached from, thus with
Carrier deposit is absorbed in oral cavity and throat by gastrointestinal tract, is reduced the drug effect of drug and is increased unexpected effect.
Common solution includes adjusting the particle diameter distribution of carrier, such as CN1424909 is added through thickness lactose
Combine combination and the dispersing mode it is expected change active constituent and carrier；A large amount of lubricant (abilities are added in CN104146960A
Power controlling agent, Force control agents, FCAs are also referred to as in domain) reduce the combination between active constituent and carrier
Power；CN101484134A is micronized altogether using magnesium stearate and bulk pharmaceutical chemicals to reduce the binding force of bulk pharmaceutical chemicals；CN105982880A
Use the three-dimensional mixer slow-speed of revolution, for a long time mixing supplementary material.
But found in practical application, existing technical solution have the defects that it is certain, will lead to Product industrialization production
The validity period of higher cost or product is shorter.Such as it the mobility of composition after excessive thin carrier components is added can drop significantly
It is low, to influence subsequent filling and mixed uniformity coefficient, and increase product minuteness particle delivering score (FPF) effect not
It is good；Using a large amount of lubricant, and using the hybrid mode of high-energy (such as micronization and mechanical fusion altogether) by two kinds effectively at
Although dividing reduces interparticle active force with the method for mix lubricant, increase product minuteness particle delivering score (FPF),
But largely use may influence Drug safety to lubricant, and long-acting cholinergic antagonist belongs to tropane class drug,
Majority is the alkaloid that amino alcohol derived from tropane etc. is condensed into ester formation from different organic acids, and molecular structure is because containing
Ester bond is susceptible to hydrolysis more unstable, be micronized altogether with lubricant and mechanofusion process in formed localized hyperthermia can aggravate this change
Change, leads to the increase of the related substance of formulation products, shorten the validity period of product；And it is mixed using three-dimensional hybrid, V-type mixing etc.
When conjunction mode, since dispersion efficiency of the equipment to minuteness particle is low, one side product minuteness particle delivering score (FPF) is bad,
On the other hand longer incorporation time is needed, considerably increases artificial and other costs.
Summary of the invention
In order to overcome the drawbacks of the prior art, the preparation method that sucks dry powder composite new the present invention provides one kind,
The sucking dry powder composite includes long-acting cholinergic antagonist, long acting beta agonists, lubricant and pharmaceutical carrier, can
By powder inhaler to pulmonary administration.
The present invention adopts the following technical scheme that realize.
On the one hand, the present invention provides a kind of preparation method for sucking dry powder composite, method includes the following steps:
(1) lubricant and pharmaceutical carrier are obtained into carrier complexes by the first shear-mixed；
(2) carrier complexes of step (1) and long-acting cholinergic antagonist and long acting beta agonists are carried out the
Two shear-mixeds to get.The finely dispersed dry powder formulations that method of the invention obtains can be loaded on single dose by quantitative
Or multi-dose powder inhaler is to pulmonary administration.
Preferably, the lubricant is selected from stearate, amino acid and its one of derivative and polyethylene glycol or more
Kind, preferably magnesium stearate or leucine, reduce pharmaceutical carrier to activity by occupying the highenergy sites on pharmaceutical carrier surface
The affinity of component particle.
Preferably, the pharmaceutical carrier is selected from one of carbohydrate and glycitols or a variety of, preferably lactose monohydrate and nothing
One of water and milk sugar is a variety of.
Pharmaceutical carrier means that the ingredient for serving as filler in the formulation, lactose are the most common medicines in sucking dry powder composite
With carrier, safety has already passed through abundant verifying, also has been reported that use mannitol and amino acid as carrier in recent years.System
Active constituent or the compound containing active constituent can be incorporated into pharmaceutical carrier surface during agent, with meet dispersion, mix with
And the processing request of the processes such as Quantitative charging.In order to achieve the goal above, pharmaceutical carrier institute's accounting in sucking dry powder composite
Example usually requires the compound of significantly greater than active constituent or active constituent.
Preferably, it is pharmaceutically acceptable to be selected from tiotropium, glycopyrronium, aclidinium, Wumei ammonium for the long-acting cholinergic antagonist
Bromide, chloride, iodide and its monohydrate form, preferably Tiotropium Bromide or its monohydrate.
Preferably, the long acting beta agonists are selected from datro, Formoterol, Vilantro, salmeterol, Austria
The dihydrate of Da Teluo and its officinal salt, preferably Formoterol, its fumarate or its fumarate.
Preferably, the partial size D50 of the lubricant is less than 35 μm, and preferably less than 10 μm.Lubricant is using preceding appropriate
Processing is for the ease of dispersion, and the specific surface area and the stronger binding force between pharmaceutical carrier that acquisition is bigger, the processing side
Method is selected from comminution by gas stream, mechanical crushing method, spray drying process, recrystallization method, preferably comminution by gas stream.
Preferably, the D50 of the long-acting cholinergic recepter is less than 5 μm；Preferably, the D50 of the long acting beta agonists
Less than 5 μm.In this way, preferable Targeting Effect can be obtained.
Preferably, the weight ratio of the long-acting cholinergic antagonist and the pharmaceutical carrier is 1:20~1:
2000。
Preferably, the weight ratio of the long acting beta agonists and the pharmaceutical carrier is 1:20~1:2000.
Preferably, the weight ratio of the lubricant and the pharmaceutical carrier is 1:20~1:2000.
The shear-mixed refers to since the particle in material group is by from external force such as cutter, agitating paddle or sieves
Effect forms sliding and the bump effect of shear surface each other, causes local mixing.The equipment of shear-mixed, which refers to, to be commonly used in
The equipment of material dispersion and crushing, including disc type beveller, blade beveller, high-speed mixer, high speed disintegrator, mixed at high speed
Machine etc., these equipment can be by the high speed rotations of cutter or agitating paddle by loose active constituent and lubricant composition group
Block is dispersed as elementary particle, and make its it is evenly dispersed be incorporated on carrier, but not to elementary particle generate crushing effect, preferably
High-speed mixer.It can be otherwise appropriately mixed in technical process to promote lubricant and active constituent and divide in the carrier
Scattered uniformity coefficient, the mixing apparatus include V-Mixer, three-dimensional mixer, wet mixing pelletizer, Universal mixing machine
Deng.
Preferably, the equipment of first shearing and second shearing is selected from disc type beveller, blade beveller, high speed
Blender, high speed disintegrator and high-speed mixer.
Preferably, the linear velocity of the cutter or agitating paddle of first shearing and second shearing is 1-100m/s, excellent
It is selected as 10-60m/s.
Preferably, the first shear-mixed time is 1-10min.
Preferably, the second shear-mixed time is 0.3-10min.
On the other hand, the present invention also provides a kind of sucking dry powder composite that the above method is prepared, the composition packets
Containing long-acting cholinergic antagonist, long acting beta agonists, lubricant and pharmaceutical carrier, list can be loaded on by quantitative
Dosage or multi-dose powder inhaler are to pulmonary administration.
Manufactured composition powder can be quantitative in advance be loaded in single dose or multi-dose container, can be by appropriate
Packaging chemically and physically protected with providing, by actively or passively formula suction apparatus be administered, the container can be capsule or bubble-cap,
It is preferred that capsule.
The invention has the benefit that
The present invention further studies convenient mixing device and hybrid parameter on the basis of early-stage study, utilizes shear-mixed
Technique provides a kind of preparation method of dry powder composite for sucking by being prepared into carrier complexes.The composition can
By powder inhaler to pulmonary administration, aerodynamics minuteness particle score (FPF) with higher has suction characteristics
It is excellent, formulation properties stability is stronger, the higher feature of safety.
Specific embodiment
Embodiment 1: the preparation of micronised Tiotropium bromide
Tiotropium bromide monohydrate, thiatro bromoaminium anhydrous compound are micronized in airslide disintegrating mill respectively, crush pressure
Power is 0.6Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 2: the preparation of micronized formoterol
Formoterol fumarate dihydrate, formoterol fumarate are micronized respectively in airslide disintegrating mill,
Crushing pressure is 0.6Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 3: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, and the Tiotropium Bromide good fortune for sucking is not
Special Luo Gan's powder preparation
According to the form below weighs lactose monohydrate and magnesium stearate (D50=3.01 μm) 10min is mixed in three-dimensional mixer, it shifts
It is appropriate to stand with the linear velocity of the cutter mixing 10min of 10m/s into high-speed mixer, carrier complexes are prepared, are then added
The formoterol fumarate dihydrate prepared in the micronised Tiotropium bromide monohydrate and embodiment 2 prepared in embodiment 1,
With the linear velocity of the cutter mixing 10min of 10m/s in high-speed mixer, 20min is finally mixed in three-dimensional mixer.
Embodiment 4: using mannitol as pharmaceutical carrier, leucine is lubricant, the Tiotropium Bromide Formoterol for sucking
Dry powder preparation
According to the form below weighs mannitol and leucine (D50=9.50 μm) 5-10min is mixed in three-dimensional mixer, it is transferred to
It is appropriate to stand with the linear velocity of the cutter mixing 2min of 30m/s in high-speed mixer, carrier complexes are prepared, is then added and implements
The Formoterol prepared in the micronised Tiotropium bromide and embodiment 2 prepared in example 1 is in high-speed mixer with the cutter of 30m/s
Linear velocity mixes 1min, and 20min is finally mixed in three-dimensional mixer.
Embodiment 5: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, and the Tiotropium Bromide good fortune for sucking is not
Special Luo Gan's powder preparation
According to the form below weighs lactose monohydrate and magnesium stearate (D50=3.01 μm) 5-10min is mixed in three-dimensional mixer, turn
It moves in disc type beveller, sand disc gap 5mm, 1min is mixed with 60m/s abrasive disk linear velocity, appropriate to stand, preparation carries
Nanocrystal composition, the fumaric acid that the micronised Tiotropium bromide monohydrate prepared in embodiment 1 then is added and is prepared in embodiment 2
Formoterol dihydrate mixes 0.3min in high-speed mixer with 60m/s speed, finally mixes in three-dimensional mixer
10min。
Embodiment 6: using Lactis Anhydrous as pharmaceutical carrier, magnesium stearate is lubricant, and the Tiotropium Bromide good fortune for sucking is not
Special Luo Gan's powder preparation
According to the form below weighs Lactis Anhydrous and magnesium stearate (D50=3.01 μm) it is transferred in high-speed mixer, with 100m/s's
Linear velocity mixes 1min, is then added the micronised Tiotropium bromide monohydrate prepared in embodiment 1, prepares in embodiment 2
Formoterol fumarate dihydrate, it is finally mixed then at three-dimensional in high-speed mixer with agitating paddle linear velocity 10m/s mixing 2min
20min is mixed in conjunction machine.
Embodiment 7: using lactose monohydrate as pharmaceutical carrier, polyethylene glycol is lubricant, and the Tiotropium Bromide good fortune for sucking is not
Special Luo Gan's powder preparation
According to the form below weighs lactose monohydrate and polyethylene glycol, mixes 2min, system in a high speed mixer with the linear velocity of 60m/s
Standby powdered compound, is then added the micronised Tiotropium bromide monohydrate (D prepared in embodiment 150=2.65 μm) and implement
The formoterol fumarate dihydrate prepared in example 2 mixes 2min in high-speed mixer with 60m/s linear velocity, finally again
10min is mixed in three-dimensional mixer.
Embodiment 8: the preparation of micronization Wumei bromine ammonium, aclidinium bromide, glycopyrronium bromide
It by Wumei bromine ammonium, aclidinium bromide, glycopyrronium bromide, is micronized in airslide disintegrating mill respectively, crushing pressure is
1.2Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 9: the preparation of micronization Vilantro, Ao Dateluo, datro, salmeterol
By trifluoromethanesulfonic acid Vilantro, hydrochloric acid Ao Dateluo, maleic acid datro, SALMETEROL XINAFOATE in air-flow
It is micronized in pulverizer, crushing pressure is 1.2Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 10: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, Wumei bromine ammonium, dimension for sucking
The preparation of Lactel Luo Gan's powder
According to the form below weighs magnesium stearate and lactose monohydrate, mixes 10min, preparation in high-speed mixer with 20m/s linear velocity
Compound.The 1/4 of compound is taken, trifluoromethanesulfonic acid Vilantro prepared by embodiment 9 and Wumei bromine prepared by embodiment 8 is added
Ammonium mixes 2min in high-speed mixer with 10m/s linear velocity, is eventually adding remaining compound, mixes in three-dimensional mixer
Close 5min.
Embodiment 11: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, and aclidinium bromide Austria for sucking reaches
Special Luo Gan's powder preparation
According to the form below weighs magnesium stearate and lactose monohydrate, mixes 10min, preparation in high-speed mixer with 20m/s linear velocity
Compound.Be added embodiment 9 prepare hydrochloric acid Ao Dateluo and embodiment 8 prepare aclidinium bromide, in high-speed mixer with
10m/s linear velocity mixes 2min, and 10min is mixed in three-dimensional mixer.
Embodiment 12: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, and the glycopyrronium bromide indenes for sucking reaches
Special Luo Gan's powder preparation
According to the form below weighs magnesium stearate and lactose monohydrate, mixes 10min, preparation in high-speed mixer with 20m/s linear velocity
Compound.Maleic acid datro prepared by embodiment 9 and glycopyrronium bromide prepared by embodiment 8 is added, in high-speed mixer
2min is mixed with 10m/s linear velocity, 10min is mixed in three-dimensional mixer.
Embodiment 13: using lactose monohydrate as pharmaceutical carrier, magnesium stearate is lubricant, the husky beauty of the Tiotropium Bromide for sucking
Special Luo Gan's powder preparation
According to the form below weighs magnesium stearate and lactose monohydrate, mixes 10min, preparation in high-speed mixer with 20m/s linear velocity
Compound.SALMETEROL XINAFOATE prepared by embodiment 9 and Tiotropium Bromide prepared by embodiment 1 is added, in high-speed mixer
2min is mixed with 10m/s linear velocity, 10min is mixed in three-dimensional mixer.
Embodiment 14: using lactose monohydrate as pharmaceutical carrier, acetylcysteine is lubricant, the Tiotropium Bromide for sucking
The preparation of salmeterol dry powder
According to the form below weighs acetylcysteine and lactose monohydrate, mixes 10min in high-speed mixer with 20m/s linear velocity,
Prepare compound.SALMETEROL XINAFOATE prepared by embodiment 9 and Tiotropium Bromide prepared by embodiment 1 is added, in high-speed stirred
2min is mixed with 10m/s linear velocity in machine, 10min is mixed in three-dimensional mixer.
Comparative example 1
The micronization richness horse that according to the form below weighs the micronised Tiotropium bromide monohydrate of the preparation of embodiment 1, prepared by embodiment 2
Sour Formoterol dihydrate, lactose monohydrate, 60rpm revolving speed grinds 30min in three-dimensional mixer.
Comparative example 2
The micronization richness horse that according to the form below weighs the micronised Tiotropium bromide monohydrate of the preparation of embodiment 1, prepared by embodiment 2
Sour Formoterol dihydrate, magnesium stearate, lactose monohydrate, carry out mechanical fusion, in vibrating-disk beveller with 700r/
Min revolving speed grinds 10min.
Comparative example 3
The micronization richness horse that according to the form below weighs the micronised Tiotropium bromide monohydrate of the preparation of embodiment 1, prepared by embodiment 2
Sour Formoterol dihydrate, magnesium stearate, are stirred 2min, are then transferred in airslide disintegrating mill, with 1.2MPa pressure
Air-flow crushing is carried out, it is appropriate to stand, prepare mixture of powders.Then lactose monohydrate is added, 3min is mixed in high-speed mixer,
Agitating paddle linear velocity 10m/s, is finally transferred in three-dimensional mixer and mixes 5-10min.
Embodiment 15: the glycopyrronium bromide dry powder nature for sucking is studied
The purpose of the research is to simulate the performance of obtained composition during the administration.
In general, inhalation powder spray can be used twin-stage ram (TI) in the deposition process of respiratory tract and be simulated,
The fine grained total amount (FPD) measured is drug deposition in the analog result of drug in bronchiole and alveolar.
The powder of Example 3-7,10-14 and comparative example 1-3, by 25mg/ filling capsules, preparation can be by dry
Glycopyrronium salt dry powder inhaler formulations from powder suction apparatus to pulmonary administration, by drug delivery device twin-stage ram TI, with 60L/min
Each capsule of measurement of rate of flow in dry powder fine grained total amount (FPD) and transmitting dosage (ED), and computational aerodynamics microfine
Subfraction (FPF=FPD/ED).
The powder of Example 3 loads bubble-cap by 13mg loading amount, and preparation can be by powder inhaler to pulmonary administration
Glycopyrronium bromide dry powder inhaler formulations, by drug delivery device twin-stage ram TI, with dry powder in each capsule of the measurement of rate of flow of 60L/min
Fine grained total amount (FPD) and transmitting dosage (ED), calculate separately the aerodynamics minuteness particle score of two kinds of effective components
(FPF=FPD/ED).
As a result as follows:
These data show, the present invention use by being prepared into carrier complexes, utilizing the preparation of shear-mixed technique
Prescription and the prescription (comparative example 1-3) for not preparing carrier complexes in the prior art, not prepared using shear-mixed technique
It compares, the minuteness particle score of each active component significantly improves, that is, improves the effective dose for being delivered to lung, greatly shorten simultaneously
Incorporation time.
Embodiment 16: the stability study of composition
The purpose of the research is to investigate the stability of composition at different conditions.
The powder of Example 3,5 and comparative example 1-3 is placed under acceleration environment by 25mg/ filling capsules
It is placed under conditions of (40 DEG C of 75%RH), related substance is measured by sampling after January, March, impurity content is counted, with implementation
Example 3,5 is compared, and judges the variation tendency of impurity, as a result as follows:
Statistics indicate that the prescription for the shear-mixed technique preparation that the present invention uses and the prescription, the Qi Tagong that do not add lubricant
The prescription of skill preparation is compared, and chemical stability substantially quite (comparative example 1), but is substantially better than and is mixed using high-energy
The prescription (comparative example 2,3) of (micronization or mechanical fusion altogether).
Claims (10)
1. a kind of preparation method for sucking dry powder composite, method includes the following steps:
(1) lubricant and pharmaceutical carrier are obtained into carrier complexes by the first shear-mixed；
(2) carrier complexes of step (1) second is carried out with long-acting cholinergic antagonist and long acting beta agonists to cut
Cut mixing to get.
2. preparation method according to claim 1, which is characterized in that the lubricant be selected from stearate, amino acid and
One of its derivative and polyethylene glycol are a variety of, preferably magnesium stearate or leucine.
3. preparation method according to claim 1 or 2, which is characterized in that the pharmaceutical carrier is selected from carbohydrate and glycitols
One of or a variety of, preferably one of lactose monohydrate and Lactis Anhydrous or a variety of.
4. preparation method according to any one of claim 1 to 3, which is characterized in that the long-acting cholinergic recepter resistance
Disconnected agent is selected from tiotropium, glycopyrronium, aclidinium, the pharmaceutical bromide of Wumei ammonium, chloride, iodide and its monohydrate shape
Formula, preferably Tiotropium Bromide or its monohydrate.
5. preparation method according to any one of claim 1 to 4, which is characterized in that the long acting beta agonists choosing
From datro, Formoterol, Vilantro, salmeterol, Ao Dateluo and its officinal salt, preferably Formoterol, its
The dihydrate of fumarate or its fumarate.
6. preparation method according to any one of claim 1 to 5, which is characterized in that the partial size D50 of the lubricant is small
In 35 μm, preferably less than 10 μm；
Preferably, the D50 of the long-acting cholinergic recepter is less than 5 μm；
Preferably, the D50 of the long acting beta agonists is less than 5 μm.
7. preparation method according to any one of claim 1 to 6, which is characterized in that the long-acting cholinergic recepter
The weight ratio of blocking agent and the pharmaceutical carrier is 1:20~1:2000；
Preferably, the weight ratio of the long acting beta agonists and the pharmaceutical carrier is 1:20~1:2000；
Preferably, the weight ratio of the lubricant and the pharmaceutical carrier is 1:20~1:2000.
8. preparation method according to any one of claim 1 to 7, which is characterized in that first shearing and described the
The equipment of two shearings is selected from disc type beveller, blade beveller, high-speed mixer, high speed disintegrator and high-speed mixer.
9. preparation method according to any one of claim 1 to 8, which is characterized in that first shearing and described the
The cutter of two shearings or the linear velocity of agitating paddle are 1-100m/s, preferably 10-60m/s；
Preferably, the first shear-mixed time is 1-10min；
Preferably, the second shear-mixed time is 0.3-10min.
10. a kind of sucking dry powder composite that the preparation method as described in any one of claims 1 to 9 obtains, the composition
Comprising long-acting cholinergic antagonist, long acting beta agonists, lubricant and pharmaceutical carrier, can be loaded on by quantitative
Single dose or multi-dose powder inhaler are to pulmonary administration.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111297837A (en) * | 2020-03-26 | 2020-06-19 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
| WO2021143785A1 (en) * | 2020-01-15 | 2021-07-22 | 四川海思科制药有限公司 | Pharmaceutical composition of aerosol inhalant containing indacaterol and preparation method thereof |
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Application publication date: 20190514 |