Medical aerosol formulations

Details Medical aerosol formulations Medical aerosol formulations

1999-08-04

2002-10-08

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C514S177000, C514S263340, C514S374000, C514S471000, C514S490000, C514S506000, C514S646000, C514S693000, C514S699000, C514S721000, C514S728000, C514S730000, C514S731000, C514S736000, C514S738000, C514S772000, C514S957000, C514S958000

Reexamination Certificate

active

06461591

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a pressure-liquefied propellant mixture based on hydrofluoroalkanes, to a medicinal aerosol formulation which contains such a propellant mixture, and to a process for the preparation of the aerosol formulation.
BACKGROUND OF THE INVENTION
Many gases, such as, for example, carbon dioxide and nitrogen, can admittedly be liquefied under pressure, but are not suitable as propellants for metered aerosols because the internal pressure in the container decreases very considerably with increasing emptying. For these reasons, only those propellant gases which can be liquefied at room temperature and only lead to a slight decrease in the internal pressure when the contents are successively sprayed are suitable for medicinal metered aerosols. These include the propellant-type alkanes, such as, for example, propane, butane and isobutane, and also the chlorofluorocarbons (CFCs), such as, for example, trichlorofluoromethane (F11), dichlorodifluoromethane (F12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114).
For aerosol applications such as hairsprays, deodorant sprays and the like, occasionally combinations of propellants have also been proposed.
For example, WO-A-94/01511 discloses aerosol formulations formed from a compressed gas (nitrogen, carbon dioxide, compressed air, oxygen, xenon and/or argon), a liquefied hydrocarbon propellant, active compound and carrier, where the formulations can typically contain 0.05-2.5% by weight of nitrogen and 1.0-12.0% by weight of liquefied hydrocarbon propellant and preferably have a content of 80-95% by weight of volatile carrier compounds, such as ethanol, propanol, pentane, water, acetone and the like. In the Derwent Abstract AN 86-228980, a dermatophytic agent is furthermore described, which contains 0.1-2% by weight of tolunaphthate, 0.5-70% by weight of propellant and 30-80% by weight of fluorinated alkyl halide (trichloromonofluoromethane, tetrachlorodifluoroethane, trichlorotrifluoroethane and/or dibromotetrafluoroethane) having a boiling point of at least 20° C. as a solvent; as a propellant, petroleum gas, dimethyl ether, dichlordifluoromethane, dichlorotetrafluoroethane, carbon dioxide etc. should be suitable. On the other hand, WO-A-93/17665 discloses a method for the administration of physiologically active compounds, in which a supercritical liquid solution is formed from a supercritical liquid solvent and the active compound and this is then moved into the subcritical range. As supercritical solvents, carbon dioxide, dinitrogen monoxide, chlorofluorocarbons, xenon, sulphur hexafluoride, ethanol, acetone, propane and/or water should be suitable.
On account of the ozone problem, caused by the removal of free-radical chlorine atoms from the CFCs, many countries came to an understanding in the Montreal Agreement no longer to use the CFCs as propellants in future. Suitable CFC substitutes for the medicinal area are fluorinated alkanes, especially 1,1,1,2-tetrafluoroethane (HFA 134a) and l,1,1,2,3,3,3-heptafluoropropane (HFA 227), since these are inert and have a very low toxicity. On account of their physical properties, such as pressure, density, etc., they are particularly suitable to replace the CFCs such as F11, F12 and F114 as propellants in metered aerosols.
U.S. Pat. No. 4,139,607 furthermore proposed a propellant system formed from liquefied bis(difluoromethyl) ether and gaseous carbon dioxide, which unlike combinations of carbon dioxide with other known propellants such as trichlorofluoromethane or methylene chloride should produce satisfactory aerosol patterns, but which has not been successful. According to the disclosure of U.S. Pat. No. 4,139,607, other, conventional propellants such as dinitrogen monoxide, hydrocarbons and fluorocarbons or liquid carriers, such as ethanol, perchloroethylene, trichloroethylene, acetone, amyl acetate, water and the like, can be added to the propellant system, ethanol and bis(difluoromethyl) ether in the weight ratio of approximately 1:1 usually being used in the examples disclosed. On the other hand, it is stated in the Derwent Abstract AN 89-184245 that hydrocarbons, such as butanes and pentanes, other compressed gases, such as carbon dioxide, dimethyl ether, nitrogen and dinitrogen oxide, or fluorocarbons could also be used instead of CFCs in aerosol pressure packs for the administration of medicaments.
CFC-free medicinal aerosol preparations containing HFA 134a are already encompassed by the general teaching of U.S. Pat. No. 2,868,691 and U.S. Pat. No. 3,014,844 and disclosed in DE-A-2 736 500 and EP-A-0 372 777. Examples containing HFA 227 are found in WO-A-91/11495, EP-A-0 504 112 and EP-B-0 550 031. It is known from various publications that the customary auxiliaries used in CFC-containing metered aerosols, such as, for example, lecithin, sorbitan trioleate and oleic acid, only dissolve inadequately in hydrofluoro-alkanes (in the context of the present invention designated by “HFA”), such as, for example HFA 134a and HFA 227, because chain lengthening and the substitution of the chlorine atoms by fluorine atoms leads to a worsening of the solubility properties for polar substances. Even in the case of the CFCs, which in comparison to the HFAs are considerably better solvents, ethanol or other cosolvents were often added to improve the solubility in order to be able to administer pharmaceuticals such as, for example, isoprenaline and epinephrine (cf. U.S. Pat. No. 2,868,691) as an aerosol. It was therefore obvious to improve not only the solubility of the CFCs, but also that of the HFAs, by addition of ethanol. Examples of this are found in the specialized literature and in various patent applications. Alternatively to this, there are a number of developments of aerosol preparations containing HFA 134a and/or HFA 227 liquefied under pressure, which use propellant-soluble auxiliaries, such as, for example, fluorinated surface-active substances (WO-A-91/04 011), mono- or diacetylated glycerides (EP-A-0 504 112) or polyethoxylated compounds (WO-A-92/00 061), which can dissolve in the two propellants in the necessary amount without addition of ethanol. Hitherto, however, only one product based on HFAs has been permitted as a bioequivalent substitute, namely a suspension aerosol formulation of salbutamol sulphate in HFA 134a, ethanol and oleic acid (Airomir®, 3M Health Care Ltd., England).
OBJECTS OF THE INVENTION
For new developments of medicinal, CFC-free aerosol preparations, hydrofluoroalkanes such as HFA 134a (vapour pressure about 6 bar at 20° C.) and HFA 227 (vapour pressure about 4.2 bar at 20° C.) are preferably used today as propellants. Both propellants differ with respect to their density (about 1.4 mg/ml for HFA 227 and 1.2 mg/ml for HFA 134a at 20° C.), which is important, in particular for suspensions. If the active compound has a higher density than the propellant, sedimentation occurs, if its density is lower, flotation occurs. It therefore suggests itself under certain circumstances to use propellant mixtures to solve the problem and/or to add cosolvents such as ethanol, diethyl ether or other low-boiling solvents or propellants such as n-butane to lower the density. An important disadvantage of the HFAs is their low dissolving power in comparison to the CFCs, in particular in comparison to F11. The solvent properties decrease with increasing chain length in the sequence F11>HFA 134a>HFA 227. For this reason, without increasing the hydrophilicity by addition of polar solvents, such as, for example, ethanol, the suspending auxiliaries customarily used in CFCs, such as sorbitan trioleate, lecithin and oleic acid, can no longer be dissolved and thus used in the customary concentrations (about 1:2 to 1:20, based on the active compound).
It is generally known that in the case of suspension formulations only active compound particles which are smaller than 6 &mgr;m are respirable. For the desired deposition thereof in the lungs, these must therefore be comminuted before processing by means of special procedures, such as,

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