CN102366405A - Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant - Google Patents
Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant Download PDFInfo
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Abstract
The invention discloses a fluticasone propionate aerosol preparation with hydrofluoroalkane as a propellant. The preparation comprises a curatively or prophylactically effective amount of fluticasone propionate, or a pharmaceutically acceptable salt or solvate thereof, and a hydrofluoroalkane propellant. Fluticasone propionate or the pharmaceutically acceptable salt or solvate thereof is a granular medicine processed through spray drying. The aerosol preparation provided by the invention is a medical aerosol preparation with good stability. The aerosol preparation can be produced through a one-step or two-step canning method.
Description
Technical field
The invention belongs to technical field of medicine, more particularly, relating to a kind of is that hydrofluoroalkane is propellant, contains the aerosol of FLUTICASONE PROPIONATE with non-Freon.
Background technology
The aerosol medicine is a kind of preparation through the respiratory tract administration approach.
The basic order of respiratory tract administration technology is to make the medicine porous to pulmonary and be deposited on outer peripheral areas, has quick-acting, target spot administration and avoids advantages such as gastrointestinal tract first pass effect, side effect is little, dosage is little, has obtained internationally recognized.
The respiratory tract administration approach for treatment asthma and chronic obstructive pulmonary disease, reaches treatments such as those diseases that need the quick administration of general such as Cystic fibrosis, huge superiority is not only arranged, and be a kind of important therapeutic modality.But be different from general pharmaceutical preparation, the drug development that pulmonary absorbs has bigger technological challenge.Such as, the rational faculty of aerosol drug particles distributes, and the compatibility of drug particles and adjuvant and container all has high technical difficulty with the control of stability.The size that sucks microgranule is one of key issue that influences the aerosol preparations curative effect, and the suction granule of great majority above 5 microns will be trapped in the oral cavity or be stuck on the spout.Therefore, ideal inhalant particle size on average should reach the 2-3 micron, and 90% should be less than 5 microns.Yet; Even drug particles satisfies the particle diameter requirement of aerosol preparations, still exist because of under the effect of cohesiveness, sucking microgranule to trend towards caking, form big granule; With the absorption affinity owing to other adjuvants in the microgranule, microgranule is adsorbed on the first-class technical bottleneck of the packing of product easily.
Therefore, for overcoming above-mentioned difficult point, in aerosol preparations, add surfactant and cosolvent (for example U.S. Pat 5225183, and US5439670 is to albuterol, beclometasone equimolecular) usually.Surfactant can be stablized aerosol preparations drug particles or increase-volume medicine, also can play the function of lubricated aerosol can and valve.The cosolvent dispersion solvent of doing commonly used improves the dissolubility between surfactant and the propellant.Yet those skilled in the art is difficult to infer whether certain drug molecule can form stable aerosol molecule under the situation that does not contain or contain cosolvent and/or surfactant, the very difficult stable aerosol that obtains to meet clinical quality standard easily through the simple replacement of drug molecule.
About the disclosed patent of the aerosol preparations of FLUTICASONE PROPIONATE; For example RA Akehurst etc. discloses a kind of aerosol preparations that does not contain the FLUTICASONE PROPIONATE of surfactant in Chinese patent CN1075078, and active component wherein---FLUTICASONE PROPIONATE is micronized.
RA Akehurst etc. discloses a kind of aerosol preparations that does not contain the surfactant and the FLUTICASONE PROPIONATE of the polar co-solvent that is no more than propellant 5% in Chinese patent CN1075079, active component wherein---FLUTICASONE PROPIONATE also is micronized.
Johnson A.Keith etc. discloses a kind of aerosol preparations in U.S. Pat 5126123, it comprises the micronization FLUTICASONE PROPIONATE and dissolves in 1,1,1, the surfactant of 2-tetrafluoroethane etc.
K Bake Si Telan discloses a kind of medicinal aerosol formulations in Chinese patent CN1170356, it comprises HFA propellant, surfactant such as C8-C16 satisfied fatty acid or its salt etc.In this invention, active component still is micronized.
In sum, the disclosed FLUTICASONE PROPIONATE aerosol preparations of prior art instance all is to have adopted micronised active ingredient.
Spray drying method for preparation also has report potential being applied in of aerosol preparations in the document; For example; U.S. Pat 7090831; The spray drying of mentioning salmaterol prepares process and research, and U.S. Pat 7267813 and US7172752 have summarized the process that spray drying prepares beclometasone and formoterol.Yet the granule of spray drying preparation does not have report as yet in the concrete and optimized application of aerosol preparations in document.
In a word; To the specific medication molecule; Through not adding or add specific surfactant and cosolvent, can improve concrete composition contained in the aerosol preparations (comprising medicine, propellant, surfactant and cosolvent etc.) its suitability each other and the quality and the stability of whole aerosol preparations.
Summary of the invention
The inventor has invented a kind of stable FLUTICASONE PROPIONATE 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 stable FLUTICASONE PROPIONATE aerosol.
Another object of the present invention provides the method for preparing of the aerosol of aforementioned stable.
Specifically, the invention provides a kind of aerosol of FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate and hydrofluoroalkane propellant that it comprises treatment or prevents to go up effective dose; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug of handling through spray drying method.
In embodiments of the invention, the propellant that said aerosol is selected for use can be hydrofluoroalkane or its mixture, and they should have enough vapour pressures so that as effective propellant, preferably; Described hydrofluoroalkane propellant is 1,1,1,2-tetrafluoroethane or 1; 1,1,2; 3,3,3-seven fluorine n-propanes or its mixture.The content of propellant is the 89%-99.9%w/w of preparation.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate, hydrofluoroalkane propellant and surfactant that it comprises treatment or prevents to go up effective dose; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate, hydrofluoroalkane propellant and surfactant that it comprises treatment or prevents to go up effective dose; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes; Described surfactant is not more than the 1.0%w/w (preferably be not more than 0.5%w/w, more preferably be not more than 0.2%w/w) of preparation.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, it comprises treatment or prevention and goes up FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt of effective dose or the cosolvent that solvate, hydrofluoroalkane propellant and polarity are higher than propellant; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, it comprises treatment or prevention and goes up FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt of effective dose or the cosolvent that solvate, hydrofluoroalkane propellant and polarity are higher than propellant; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes; The cosolvent that described polarity is higher than propellant is not more than the 5.0%w/w of propellant, is preferably the 2.5%w/w that is not more than propellant.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, it comprises treatment or prevention and goes up FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt of effective dose or the cosolvent that solvate, hydrofluoroalkane propellant, surfactant and polarity are higher than propellant; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, it comprises treatment or prevention and goes up FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt of effective dose or the cosolvent that solvate, hydrofluoroalkane propellant, surfactant and polarity are higher than propellant; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes; Described surfactant is not more than the 1.0%w/w (preferably be not more than 0.5%w/w, more preferably be not more than 0.2%w/w) of preparation; The cosolvent that described polarity is higher than propellant is not more than the 5.0%w/w of propellant, is preferably the 2.5%w/w that is not more than propellant.
In a kind of preferred embodiment provided by the invention; The invention provides a kind of aerosol of FLUTICASONE PROPIONATE, it comprises treatment or prevention and goes up FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt of effective dose or the cosolvent that solvate, hydrofluoroalkane propellant, surfactant and polarity are higher than propellant; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug that spray drying method makes; Described hydrofluoroalkane propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture; Described surfactant is not more than the 1.0%w/w (preferably be not more than 0.5%w/w, more preferably be not more than 0.2%w/w) of preparation; The cosolvent that described polarity is higher than propellant is not more than the 5.0%w/w (preferably being not more than 2.5%w/w) of propellant.
In embodiments of the invention, said surfactant is selected from oleic acid (OA) or Polyethylene Glycol (PEG) or sorbester p37 (Span-85) or glycerol (Glycerol) or lecithin (Lecithin) or magnesium stearate; Here, described Polyethylene Glycol is PEG200～1800, can be PEG200, PEG300, PEG400, PEG1000; PEG1000 preferably.
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, said granulated drug is spray-dried, and its granular size is between 1-10um, preferably between 1-5um; What optimize is 50% less than 3um, and 90% less than 5um.
In embodiments of the invention, FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate account for the 0.01-5%w/w of preparation total amount in the said preparation, are preferably 0.01%-3%w/w, more preferably are 0.01%-1%w/w.
Be applicable to the device of aerosol preparations of the present invention, comprise a container that can bear used propellant vapour pressure, this container seals with a metering valve, and its nozzle diameter is in (optimization between 0.3-0.5mm) between the 0.2-0.6mm; Wherein said container is that a kind of inner surface does not have coating or cated jar, optimization be a kind of fluorine coating; Said jar is a canister, is aluminum or aluminium alloy can.
On the other hand, the invention provides the method for preparing of the aerosol of above-mentioned FLUTICASONE PROPIONATE, prepare process comprising microgranule:
An amount of fluticasone of weighing is placed in the clean container (like the 1000ml beaker), adds an amount of solvent (like ethanol), stirs or ultrasonicly dissolves the about 2～4mg/ml of concentration fully to drug molecule.In the flow velocity suction spray dried device of peristaltic pump through spray dryer, select No. 1 nozzle with 1.5-3.0ml/min, the spraying about 1.4mm in aperture, it is 80-120 ℃ that the sample introduction temperature is set, and going out kind temperature is 45-65 ℃, and air-breathing is 50%.Regulating the aerosol apparatus overall flow rate at last is 800 liters/hour.Whole process adopts nitrogen protection, collects and adopts the vial material.With in drug particles and/or surfactant and/or the cosolvent adding aerosol container, roll the cap seal mouth then, add an amount of propellant through valve rod.Ultrasonic, the shaking table jolting, preparation finishes.
Usually aerosol drug molecule microgranule is to adopt the air-flow micronization.But the air-flow micronization to the drug particles micronization before the having relatively high expectations of physical property of crystal form and medicine; Only be used in some specific crystal form and material; Scope is selected little, and the drug particles crystal form behind the micronization is chaotic, the particle size distribution range broad; Aerosol preparations stable difficult with control, the selectivity of aerosol preparations adjuvant is also smaller.
And spray-dired microgranule, the more even unanimity of its granule reaches the same granularity scope more than 90% easily; Influences such as drawing of avoiding possibly causing behind the general micronization is wet, high temperature degradation have improved the inner Stability Control and adjuvant alternative of aerosol preparations greatly.In addition; Spray drying is except that being applicable to general common drug molecule; Also be applicable to microgranule preparation to the heat sensitivity thing; Because of the material that sprayed just just receives high temperature when the atomisation size particles,, can keep these active materials after drying, still to keep its active ingredient and not be damaged so be to be heated moment.Simultaneously, through being equipped with freeze drying plant, spray drying can be handled any drug molecule; The molecule bad like pure soluble substance or water solublity (for example fluticasone propionate, salmaterol equimolecular) can prepare the microgranule (for example two kinds of active component of fluticasone propionate and salmaterol carry out the spray drying micronization synchronously) of compound recipe aerosol preparations drug molecule synchronously according to ratio; Thereby reduce the granulating process step; Make technology oversimplify and be easy to and control, save time, reduce cost.
Aerosol preparations of the present invention has the particle size distribution and simple technical process of good stable property and aerosol preparations not or have under the situation of small amounts of co-solvents and surfactant.
The medicine that is used for aerosol preparations can be to be used to treat respiratory disorder (for example asthma and/or chronic obstructive pulmonary disease etc.) isoreactivity molecule; 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, 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 its structure, on physiologically acceptable salt or acid group or the base, still in route of administration and pharmaceutical preparation, multiple variation can be arranged.
Under the situation of omitting surfactant and cosolvent composition, micronized FLUTICASONE PROPIONATE, salmaterol can form stable aerosol preparations (Chinese patent CN 1075078), and its technical process can be used canned method of a step, and process equipment requires height relatively.Through technical research of the present invention; Under the situation that does not contain or contain small amounts of co-solvents and surfactant; The FLUTICASONE PROPIONATE of spray drying preparation or the granulated drug of its physiologically acceptable salt and solvate can form the same stable aerosol preparations of optimizing that reaches, and its technical process can be used a step or canned method of two steps.According to the characteristics of aerosol preparations self, the size that sucks microgranule is the key factor that influences the aerosol curative effect, and it will directly influence the aerosol preparations medicine maybe can breathe part at the deposition of pulmonary.Aerosol preparations 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.
Spray drying provided by the invention prepares aerosol preparations, and through after collision step by step and the HPLC mensuration, the FPF% value of its prescription all more than 30%-40%, can be stablized repetition.
The specific embodiment
By way of example and unrestricted following embodiment is used for explaining the present invention.Alcoholic acid weight percent is the percentage ratio with respect to propellant in the following example.
Embodiment 1 propellant+FLUTICASONE PROPIONATE
An amount of FLUTICASONE PROPIONATE 3g that weighs is placed in the clean 1000ml beaker, adds an amount of 800ml ethanol, stirs or ultrasonicly dissolves the about 3.75mg/ml of concentration fully to drug molecule.In the flow velocity suction spray dried device of peristaltic pump through spray dryer, select No. 1 nozzle with 1.5ml/min, the spraying about 1.4mm in aperture, it is 90 ℃ that the sample introduction temperature is set, and going out kind temperature is 55 ℃, and air-breathing is 50%.Regulating the aerosol apparatus overall flow rate at last is 800 liters/hour.Whole process adopts nitrogen protection, collects and adopts the vial material.(annotate: the spray drying among other embodiment of the present invention is with reference to this method)
The FLUTICASONE PROPIONATE (0.015g) of above spray drying preparation is directly weighed in the aluminium pot of clean dried, seal bottle rapidly, add 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g) with metering valve.Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is between 30-40% in this aerosol preparations.
Embodiment 2 2.5% ethanol+FLUTICASONE PROPIONATE
(0.015g) directly weighs in the aluminium pot of clean dried with spray-dired FLUTICASONE PROPIONATE, adds cosolvent ethanol then, seals bottle rapidly with metering valve, adds 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g).Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 2.5%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is about 50% in this aerosol preparations.
Embodiment 3 0.1% oleic acid+2.5% ethanol+FLUTICASONE PROPIONATEs
(0.015g) directly weighs in the aluminium pot of clean dried with spray-dired FLUTICASONE PROPIONATE, adds surfactant oleic acid and cosolvent ethanol then, seals bottle rapidly with metering valve, adds 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g).Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%w/w oleic acid and 2.5%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is about 50% in this aerosol preparations.
Embodiment 4 0.1% oleic acid+5.0% ethanol+FLUTICASONE PROPIONATEs
(0.015g) directly weighs in the aluminium pot of clean dried with spray-dired FLUTICASONE PROPIONATE, adds surfactant oleic acid and cosolvent ethanol then, seals bottle rapidly with metering valve, adds 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g).Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%w/w oleic acid and 5.0%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is about 50% in this aerosol preparations.
Embodiment 5 0.1% Polyethylene Glycol+2.5% ethanol+FLUTICASONE PROPIONATEs
(0.015g) directly weighs in the aluminium pot of clean dried with spray-dired FLUTICASONE PROPIONATE, adds Surfactant PEG 1000 and cosolvent ethanol then, seals bottle rapidly with metering valve, adds 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g).Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%w/w PEG1000 and 2.5%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is about 60% in this aerosol preparations.
Embodiment 6 0.1% Polyethylene Glycol+5.0% ethanol+FLUTICASONE PROPIONATEs
(0.015g) directly weighs in the aluminium pot of clean dried with spray-dired FLUTICASONE PROPIONATE, adds Surfactant PEG 1000 and cosolvent ethanol then, seals bottle rapidly with metering valve, adds 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g).Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%w/wPEG1000 and 5.0%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of this aerosol preparations F is about 45%.
Embodiment 2-6 compares with embodiment 1, spray-dired FLUTICASONE PROPIONATE contain 2.5% or even the alcoholic acid aerosol preparations of 5.0% cosolvent, its FPF% is higher than or is equal to the aerosol preparations that only contains propellant all more than 40%.
Embodiment 7 propellants+FLUTICASONE PROPIONATE
The FLUTICASONE PROPIONATE (0.015g) of comminution by gas stream is directly weighed in the aluminium pot of clean dried, seal bottle rapidly, add 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g) with metering valve.Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, and each the unlatching provides～the 100ug FLUTICASONE PROPIONATE.The FPF% of this aerosol preparations is basically between 20-40%.
Embodiment 7 compares with embodiment 1; Under the situation that does not contain surfactant and cosolvent; The aerosol preparations FPF% value of comminution by gas stream preparation is between 20-40%, and FPF% value repeatability is not as the aerosol preparations of spray drying preparation, because of drug particles particle size distribution behind the comminution by gas stream receives the crude drug surface properties affect; Particle size distribution repeatability is bad, and granule is inhomogeneous.By contrast, spray-dired drug particles particle diameter, meansigma methods reaches 2-3um easily, the aerosol preparations FPF% good reproducibility of preparation.
Under the situation that contains small amounts of co-solvents and surfactant, the aerosol preparations FPF% repeatability of the spray drying preparation also aerosol preparations than the comminution by gas stream preparation is good.
Embodiment 8 2.5% ethanol+FLUTICASONE PROPIONATE
The micronized FLUTICASONE PROPIONATE of air-flow (0.015g) is directly weighed in the aluminium pot of clean dried, add cosolvent ethanol then, seal bottle rapidly, add 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g) with metering valve.Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 2.5%w/w ethanol, and each the unlatching provides～the 100ug FLUTICASONE PROPIONATE.The FPF% of this aerosol preparations is about 30%.
Embodiment 9 0.1% oleic acid+2.5% ethanol+FLUTICASONE PROPIONATEs
The micronized FLUTICASONE PROPIONATE of air-flow (0.015g) is directly weighed in the aluminium pot of clean dried, add surfactant oleic acid and cosolvent ethanol then, seal bottle rapidly, add 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g) with metering valve.Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%w/wOA and 2.5%w/w ethanol, and each the unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of FLUTICASONE PROPIONATE is between the 20-30% in this aerosol preparations.
Embodiment 10 0.1% oleic acid+5.0% ethanol+FLUTICASONE PROPIONATEs
The micronized FLUTICASONE PROPIONATE of air-flow (0.015g) is directly weighed in the aluminium pot of clean dried, add cosolvent ethanol and surfactant oleic acid then, seal bottle rapidly, add 1,1,1 through metering valve, 2-tetrafluoroethane (9.3g) with metering valve.Then with ultrasonic 30 seconds of populated aerosol jar.
The gained aerosol contains the FLUTICASONE PROPIONATE of 0.16%w/w, 0.1%OA, and 5.0%w/w ethanol, the each unlatching provides～the 125ug FLUTICASONE PROPIONATE.The FPF% of this aerosol preparations is about 20-30%.
Embodiment 8-10 compares with embodiment 7, the aerosol of air-flow micronization preparation contain 2.5% or even during 5.0% cosolvent ethanol, only about 20-30%, its quality is no more than the aerosol preparations that does not contain cosolvent to its FPF%.
By on can know; The aerosol of spray drying preparation provided by the invention; Under the situation that does not contain or contain small amounts of co-solvents, (be not more than 5.0% ethanol); The granulated drug of FLUTICASONE PROPIONATE and physiologically acceptable salt and solvate can form aerosol preparations stable and that optimize, is superior to the aerosol of air-flow micronization preparation on the whole.
Above-described is according to preferred embodiment of the present invention, is not in order to limiting scope of the present invention, and 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.
Claims (10)
1. the aerosol of a FLUTICASONE PROPIONATE, it comprises FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate and hydrofluoroalkane propellant that effective dose is gone up in treatment or prevention; Here, described FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate are the granulated drug of handling through spray drying method.
2. aerosol as claimed in claim 1, wherein, said granulated drug is spray-dried, and its granular size is between 1-10um, preferably between 1-5um; More preferably be 50% less than 3um, 90% less than 5um.
3. aerosol as claimed in claim 1, wherein, FLUTICASONE PROPIONATE or its pharmaceutically acceptable salt or solvate account for the 0.01-5%w/w of preparation total amount in the said preparation, are preferably 0.01%-3%w/w, more preferably are 0.01%-1%w/w.
4. aerosol as claimed in claim 1, it comprises the cosolvent that surfactant and/or polarity are higher than propellant further.
5. according to the described aerosol of arbitrary claim in the claim 1 to 4, wherein, said hydrofluoroalkane propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes or its mixture.
6. aerosol according to claim 4, wherein, said surfactant is selected from oleic acid or Polyethylene Glycol or sorbester p37 or glycerol or lecithin or magnesium stearate.
7. aerosol according to claim 4, wherein, the cosolvent that said polarity is higher than propellant is propylene glycol or ethanol, is preferably ethanol.
8. aerosol according to claim 4, wherein, said surface-active contents is not more than the 1.0%w/w of preparation, preferably is not more than 0.5%w/w, more preferably for being not more than 0.2%w/w.
9. aerosol according to claim 4, wherein, the cosolvent content that said polarity is higher than propellant is not more than the 5.0%w/w of propellant, preferably is not more than 2.5%w/w.
10. device that is used for the said aerosol of the arbitrary claim of claim 1-9, it comprises a container that can bear used propellant vapour pressure, wherein said container is a kind of do not have coating or cated jar of inner surface; This container seals with a metering valve, its nozzle diameter between 0.2-0.6mm, optimization be 0.3-0.5mm.
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Cited By (1)
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| CN102626386A (en) * | 2012-04-28 | 2012-08-08 | 山东大学 | Bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and preparation method and application thereof |
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| CN1305369A (en) * | 1998-04-18 | 2001-07-25 | 葛兰素集团有限公司 | Pharmaceutical aerosol formulation |
| CN1409627A (en) * | 1999-11-03 | 2003-04-09 | 葛兰素集团有限公司 | Novel apparatus and process for preparing crystalline particles |
| US20050152845A1 (en) * | 2002-02-04 | 2005-07-14 | Keith Biggadike | Amorphous fluticasone 2-furoate, pharmaceutical compositions thereof and its conversion to the crystalline unsolvated form |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626386A (en) * | 2012-04-28 | 2012-08-08 | 山东大学 | Bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and preparation method and application thereof |
| CN102626386B (en) * | 2012-04-28 | 2014-10-29 | 山东大学 | Bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and preparation method and application thereof |
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