Medicinal aerosol formulations

Details Medicinal aerosol formulations Medicinal aerosol formulations

2001-04-13

2003-07-01

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C128S200140, C128S200210

Reexamination Certificate

active

06585958

ABSTRACT:

This application is a 371 of PCT/CH/99/00337, filed Jul. 22, 1999.
FIELD OF THE INVENTION
The present invention relates to a pressure-liquefied propellant mixture based on hydrofluoro-alkanes, the use of this propellant mixture in aerosol formulations, and a process for the preparation of the aerosol formulations.
BACKGROUND OF THE INVENTION
Many gases, such as carbon dioxide and nitrogen, can indeed be liquefied under pressure, but are not suitable as propellants for metered-dose aerosols, because the internal pressure in the container decreases very greatly as it becomes more empty. For this reason, only those propellants are used for medicinal metered-dose aerosols, which propellants can be liquefied at room temperature and in any case only lead to a slight decrease in the internal pressure in the container when the contents are successively removed by spraying. These include the short-chain alkanes, such as propane, butane and isobutane, and the chlorofluorocarbons (CFCs), such as trichlorofluoromethane (F11), dichlorodifluoromethane (F12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114).
WO-A-93/17665 in fact 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 converted into the subcritical range. The supercritical solvent used was carbon dioxide, it being stated that, in addition to carbon dioxide, dinitrogen oxide, chlorofluorocarbons such as dichlorodifluoromethane and trichlorofluoromethane, xenon, sulfur hexafluoride, ethanol, acetone, propane, water and mixtures thereof are suitable.
In Research Disclosure (1978), 170, 58, XP-002090730, it was further mentioned that some fluorocarbon and chlorofluorocarbon propellants can be used in aerosol products such as hairsprays, deodorants and antiperspirants as co-propellants together with carbon dioxide or dinitrogen monoxide. The 2,2-dichloro-1,1,1-trifluoroethane (F123), 1,2-dichloro-1,1-difluoroethane (F132b), 2-chloro-1,1,1-trifluoroethane (F133a), 1,1-dichloro-1-fluoroethane (F114b) and 1-chloro-1,1-difluoroethane (F142b) mentioned as examples are chlorinated and, moreover, not very customary propellants. A hairspray in which trifluoromonochloroethane (F133a) together with carbon dioxide and/or dinitrogen monoxide is used as a propellant mixture is also disclosed in U.S. Pat. No. 4,397,836.
On account of the ozone problem caused by the elimination of free-radical chlorine atoms from CFCs, in the Montreal Agreement many countries came to an understanding that they would no longer use CFCs as propellants in future. Suitable CFC substitutes for the medicinal field are fluorinated alkanes (in the context of the present invention also designated as HFA), especially 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), as these are inert and have a very low toxicity. On account of their physical properties, such as pressure, density, etc., they are particularly suitable for replacing CFCs such as F11, F12 and F114 as propellants in metered-dose aerosols.
U.S. Pat. No. 4 139 607, on the other hand, proposed a propellant system formed from liquefied bis(difluoromethyl) ether and gaseous carbon dioxide, which in contrast to combinations of carbon dioxide with other known propellants such as trichloro-fluoromethane or methylene chloride should afford satisfactory aerosol samples, but, however, has not been accomplished. The document in fact mentions that other propellants such as dinitrogen monoxide, hydrocarbons and fluorohydrocarbons or liquid carriers, such as ethanol, perchloroethylene, trichloroethylene, acetone, amyl acetate, water and the like, can be added to the propellant system; the disclosed formulations, however, mostly contain about 50% of ethanol. In Derwent Abstract AN 89-184245, it is only stated that in aerosol pressure packs for the administration of medicaments instead of CFCs, hydrocarbons, such as butane and pentane, other compressed gases, such as carbon dioxide, dimethyl ether, nitrogen and dinitrogen oxide, or fluorohydrocarbons could also be used.
Medicinal aerosol preparations containing hydrofluoroalkanes such as HFA 134a are already embraced by the 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 of formulations containing HFA 227 are found, for example, 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 excipients used in CFC-containing metered-dose aerosols, such as lecithin, sorbitan trioleate and oleic acid, only dissolve inadequately in hydrofluoroalkanes such as HFA 134a and HFA 227, because a chain extension and the substitution of the chlorine atoms by fluorine atoms leads to a worsening of the solubility properties of the permitted excipients mentioned. Even in the case of CFCs, which are considerably better solvents than HFAs, ethanol or other cosolvents were often added to improve the solubility in order to be able to administer pharmaceutical substances such as 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 CFCs, but also that of HFAs, by addition of ethanol. Examples of this are found in the technical literature and in various patent applications. Alternatively to this, there are a number of developments of pressure-liquefied aerosol preparations containing HFA 134a and/or HFA 227 which use propellant-soluble excipients, such as fluorinated surface-active substances (WO-A-91/04011), mono- or diacetylated glycerides (EP-A-0 504 112) or polyethoxylated compounds (WO-A-92/00061), which can be dissolved in the necessary amount in the two propellants even without addition of ethanol.
For CFC-free medicinal aerosol preparations having a high vapor pressure, the propellant preferably used today is usually HFA 134a (vapor pressure about 6 bar at 20° C.) and for those with a lower vapor pressure it is HFA 227 (vapor pressure about 4.2 bar at 20° C.). Both propellants differ with respect to their density (about 1.4 mg/ml for HFA 227 and about 1.2 mg/ml for HFA 134a at 20° C.), which is particularly of importance for suspensions. If the active compound has a higher density than the propellant, sedimentation occurs; if its density is lower, flotation occurs. To solve the problem, it is therefore suggested under certain circumstances to use propellant mixtures and/or, to lower the density, to add cosolvents such as ethanol, diethyl ether or other low-boiling solvents or propellants such as n-butane. A significant disadvantage of the hydrofluoroalkanes is their relatively low dissolving power in comparison with CFCs, in particular in comparison with F11. The solvent properties decrease with increasing chain length in the sequence F11>HFA 134a >HFA 227. For this reason, the suspending aids customarily used in CFCs, such as sorbitan trioleate, lecithin and oleic acid, can no longer be dissolved in the customary concentrations (weight ratios of typically approximately 1:2 to 1:20, based on the active compound) by addition of polar solvents without increasing the hydrophilicity.
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 or micronized before processing by means of special procedures, such as using pinned-disk, ball or air-jet mills. A grinding process as a rule leads to an increase in surface area, which is accompanied by an increase in the electrostatic charge of the micronized active compound, on account of which the flow behaviour and the active compound dispersion is usually impaired. As a result of the interfacial and charge activities, there is often an agglomeration of active compound particles or alternatively adsorption of active compound at interfaces, which becomes conspicuous, for example, in the acc

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