Summary of the invention
The inventor has invented a kind of fine budesonide formoterol aerosol astoundingly through a large amount of experiments, has successfully overcome some shortcomings of the prior art.
The purpose of this invention is to provide a kind of fine budesonide formoterol aerosol.
Another object of the present invention provides the method for preparing of above-mentioned budesonide and formoterol aerosol.
Specifically, the invention provides a kind of budesonide formoterol aerosol formulation, it comprises:
The granulated drug of budesonide and formoterol fumarate or its physiologically acceptable salt and solvate;
The hydrofluoroalkane propellant;
Basically do not contain polarity and be higher than the polar cosolvent of propellant;
And, randomly, contain surfactant.
In one embodiment of this invention, the invention provides a kind of budesonide formoterol aerosol formulation, it comprises:
The micronization granulated drug of budesonide and formoterol fumarate or its physiologically acceptable salt and solvate;
The hydrofluoroalkane propellant;
Basically do not contain polarity and be higher than the polar cosolvent of propellant;
And surfactant.
In one embodiment of this invention, the invention provides a kind of budesonide formoterol aerosol formulation, it comprises:
The micronization granulated drug of budesonide and formoterol fumarate or its physiologically acceptable salt and solvate;
The hydrofluoroalkane propellant;
Basically do not contain polarity and be higher than the polar cosolvent of propellant;
Do not contain surfactant.
In embodiments of the invention; The micronization granulated drug of budesonide and formoterol fumarate or its physiologically acceptable salt and solvate, wherein, the weight ratio of budesonide and formoterol fumarate is 50~300: 2~15; For example; 300: 8.3,160: 4.5, or 80: 4.5.
In embodiments of the invention, preferably, said granulated drug or micronization granulated drug account for the 0.01-5%W/W of said aerosol formulation, more preferably, are 0.01-3%W/W.
In embodiments of the invention, said granulated drug or micronization granulated drug, wherein, the diameter of the said granulated drug of 90%W/W is less than 5 μ m, and the diameter of the said granulated drug of 50%W/W is less than 3 μ m; Preferably, granulated drug is made by comminution by gas stream.
In embodiments of the invention, said hydrofluoroalkane propellant is preferably 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture.
In embodiments of the invention, the content of said hydrofluoroalkane propellant is the 93.5%-99.9%w/w of preparation.
In embodiments of the invention, said polarity is higher than the polar cosolvent of propellant, can be selected from propylene glycol or ethanol, more preferably is ethanol.
In embodiments of the invention; The said polarity that do not contain basically is higher than the polar cosolvent of propellant and is meant that not containing polarity is higher than the polar cosolvent of propellant, and the content that the polarity that perhaps contains is higher than the polar cosolvent of propellant is not more than 0.5%W/W (with respect to propellant).
In embodiments of the invention, said surfactant is Polyethylene Glycol or magnesium stearate or polyvinylpyrrolidone K25 (PVPK25).Here, described Polyethylene Glycol is PEG200~1800, can be PEG200, PEG300, PEG400, PEG1000; PEG1000 preferably.
In embodiments of the invention, the content of said surfactant is not more than the 1%W/W of preparation, more preferably, is not more than 0.5%W/W or is not more than 0.4%W/W, particularly preferably, is not more than 0.3%W/W.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate or its physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
And hydrofluoroalkane propellant.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate or its physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant;
And the surfactant that is not more than preparation 1%W/W.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate or its physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant;
And the polarity that is not more than propellant 0.5%W/W is higher than the polar cosolvent of propellant.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate or its physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant;
Be not more than the surfactant of preparation 1%W/W;
And the polarity that is not more than propellant 0.5%W/W is higher than the polar cosolvent of propellant.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate or its physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant, said hydrofluoroalkane propellant is preferably 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture;
And the surfactant that is not more than preparation 1%W/W, said surfactant is Polyethylene Glycol or magnesium stearate or PVPK25.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate and physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant, said hydrofluoroalkane propellant is preferably 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture;
And the polarity that is not more than propellant 0.5%W/W is higher than the polar cosolvent of propellant.
In a kind of preferred embodiment of the present invention, the invention provides a kind of budesonide and formoterol aerosol, be to be prepared from following component:
Account for budesonide and the micronization granulated drug of formoterol fumarate and physiologically acceptable salt and solvate of the 0.01-5%W/W of said aerosol formulation; 0.01-3%w/w preferably.
The hydrofluoroalkane propellant, said hydrofluoroalkane propellant is preferably 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture;
Be not more than the surfactant of preparation 1%W/W, said surfactant is Polyethylene Glycol or magnesium stearate or PVPK25.
And the polarity that is not more than propellant 0.5%W/W is higher than the polar cosolvent of propellant.
On the other hand, the invention provides the method for preparing of above-mentioned budesonide and formoterol aerosol.If aerosol formulation does not contain (or few) surfactant and cosolvent, medicine and propellant can first mix homogeneously, and be directly canned, promptly one goes on foot canned method.
The medicine that is used for aerosol formulation can be to be used to treat respiratory disorder (for example asthma and/or chronic obstructive pulmonary disease etc.) etc.; The short acting beta agonists trachea expanding agent is arranged; Like albuterol, terbutaline, isoproterenol etc.; It also can be the long acting beta agonists trachea expanding agent; For example salmaterol, formoterol also have steroid hormone such as beclometasone, budesonide, fluticasone and non-steroidal hormone cromoglicic acid etc., also comprise cholinolytic trachea expanding agent ipratropium bromide etc. simultaneously.
Though the said medicine molecule all can be used for treating respiratory disorder, no matter on structure, on physiologically acceptable salt or acid group or the base, these medicines are all inequality, and therefore, it reaches the aerosol formulation that meets clinical quality standard and forms also just obviously different.
On the basis of limited experiment, those skilled in the art is difficult to infer with the prescription of known aerosol system the aerosol formulation constituent of another kind of medicine.For example the beclometasone aerosol formulation generally need contain cosolvent such as ethanol.But the cosolvent composition of same ratio and inapplicable other medicines molecule such as salmaterol, FLUTICASONE PROPIONATE, the latter can not have under the situation of cosolvent usually, forms stable aerosol formulation.Even in similar molecule; Those skilled in the art also is difficult to infer whether certain drug molecule can form stable aerosol molecule under the situation that does not contain cosolvent and/or surfactant, the very difficult stable aerosol formulation that obtains to meet clinical quality standard easily through the simple replacement of drug molecule.
The characteristics of budesonide of the present invention and formoterol fumarate aerosol formulation are not contain basically under the situation of surfactant and cosolvent, and the granulated drug of budesonide and physiologically acceptable salt and solvate can form than contain cosolvent aerosol formulation more stable and that more optimize.
" be substantially devoid of surfactant " and be meant that preparation does not contain the surfactant of obvious amount, preferred, the content of its surfactant is not more than the 1.0%W/W of preparation.
" be substantially devoid of cosolvent " and be meant that preparation does not contain polarity and is higher than the polar liquid component of propellant, ethanol for example preferably is not more than the 0.5%W/W of propellant.
The particle diameter of said budesonide medicine and formoterol fumarate molecule requires all medicines should suck in the lung when taking this aerosol formulation basically, therefore, with less than 10 microns for well, 1-5 micron preferably.According to the characteristics of aerosol formulation self, the size that sucks microgranule is the key factor that influences the aerosol curative effect, and it will directly influence the aerosol formulation medicine maybe can breathe part at the deposition of pulmonary.Aerosol formulation can be breathed the ratio that part accounts for the medicine total amount; Being often referred to droplet distribution tests index---fine granular distributes; Be Fine Particle Fraction (write a Chinese character in simplified form FPF%, below herewith), generally require between 20-70%; Desirable between 30-60%, be the important indicator of investigating aerosol preparations.And the technological means of measuring FPF can be the binary collision technology, collides (ACI) and impinger of future generation (NGI) technology step by step, in conjunction with high performance liquid chromatograph (HPLC) analytical method.Budesonide formoterol aerosol formulation provided by the invention, through after collision is measured with HPLC step by step, it optimizes the FPF% value of writing out a prescription all more than 30%-40%, can stablize repetition.
The specific embodiment
By way of example and unrestricted following embodiment is used for explaining the present invention.
In description of the present invention, if no special instructions, described " % " is " % " of weight ratio.
Embodiment 1
Micronized budesonide and formoterol fumarate are weighed; Insert in the plastic coat vial or aluminium pot of clean dried; Seal bottle rapidly with metering valve, add hydrofluoroalkane propellant HFA 134a, then with ultrasonic 30 seconds of populated aerosol jar through metering valve.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W.The FPF% of this aerosol formulation budesonide reaches 44%, and the FPF% of formoterol fumarate is 38%.
By contrast, contain the aerosol of surfactant and cosolvent, the budesonide of 0.073%W/W adds 2.5% ethanol, and the FPF% of budesonide can only reach about 15%.
Embodiment 2
With micronized budesonide, formoterol fumarate and cetomacrogol 1000 are directly weighed in aluminium pot, seal bottle rapidly with metering valve, add hydrofluoroalkane propellant HFA134a through metering valve, then with ultrasonic 30 seconds of populated aerosol jar.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and 0.3%PEG1000.The FPF% of this aerosol formulation budesonide reaches 47%, and the FPF% of formoterol fumarate reaches 55%.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W, 0.0224%PEG1000.The FPF% of this aerosol formulation budesonide reaches 44%, and the FPF% of formoterol fumarate reaches 59%.
Embodiment 3
With micronized budesonide, formoterol fumarate and magnesium stearate are directly weighed in aluminium pot, seal bottle rapidly with metering valve, add hydrofluoroalkane propellant HFA 134a through metering valve, then with ultrasonic 30 seconds of populated aerosol jar.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and 0.1% magnesium stearate.The FPF% of this aerosol formulation budesonide reaches 35%, and the FPF% of formoterol fumarate reaches 38%.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and 0.0028% magnesium stearate.The FPF% of this aerosol formulation budesonide reaches 39%, and the FPF% of formoterol fumarate reaches 38%.
Embodiment 1-3 proves, budesonide and formoterol fumarate aerosol preparations, and when not containing surfactant or containing low quantity of surfactant, its FPF% value all can reach more than 30%.
Embodiment 4
With micronized budesonide, formoterol fumarate and ethanol are directly weighed in aluminium pot, seal bottle rapidly with metering valve, add hydrofluoroalkane propellant HFA 134a through metering valve, then with ultrasonic 30 seconds of populated aerosol jar.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and the ethanol of 0.25%W/W.The FPF% of this aerosol formulation budesonide reaches 32%, and the FPF% of formoterol fumarate reaches 35%.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and the ethanol of 0.5%W/W.The FPF% of this aerosol formulation budesonide reaches 27%, and the FPF% of formoterol fumarate reaches 29%.
Embodiment 4 explanation: only containing under the situation that small amounts of co-solvents is not more than propellant 0.5%, its FPF% value is between 20-30%.
Embodiment 5
With micronized budesonide, formoterol fumarate and PEG1000, ethanol is directly weighed in aluminium pot, seals bottle rapidly with metering valve, adds hydrofluoroalkane propellant HFA134a through metering valve, then with ultrasonic 30 seconds of populated aerosol jar.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and the PEG1000 of 0.0224%W/W, the ethanol of 0.5%W/W.The FPF% of this aerosol formulation budesonide reaches 26%, and the FPF% of formoterol fumarate reaches 52%.
Wherein, the gained aerosol contains the budesonide of 0.3%W/W, the formoterol fumarate of 0.025%W/W and the PEG1000 of 0.3%W/W, the ethanol of 0.5%W/W.The FPF% of this aerosol formulation budesonide reaches 27%, and the FPF% of formoterol fumarate reaches 48%.
Embodiment 5 explanations: when containing small amounts of co-solvents and low quantity of surfactant, its FPF% value of budesonide is between 20-30%, and the FPF% of formoterol fumarate is more than 40%.
Above-described, be according to preferred embodiment of the present invention, be not in order to limiting scope of the present invention, the above embodiment of the present invention can also be made various variations.Be that every simple, equivalence of doing according to the claims and the description of application of the present invention changes and modification, all fall into claim protection domain of the present invention.The present invention not technology contents of detailed description is those skilled in the art's a common practise.