Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1996-12-12
2003-06-24
Bawa, Raj (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S489000
Reexamination Certificate
active
06582677
ABSTRACT:
This invention relates to pressurised aerosol compositions, in particular compositions of inhalation medicaments.
Pressurised aerosols for the administration of medicaments, and indeed for other applications, conventionally contain one or more liquified chlorofluorocarbons (CFC's) as propellant. Such materials are suitable for use in such applications since they have the right vapor pressures (or can be mixed in the right proportions to achieve a vapor pressure in the right range) and are essentially taste- and odor-free.
In recent years there has been increasing concern about the depletion of the ozone layer in the upper atmosphere. This is believed to be due to the release into the atmosphere of CFC's and has led to a search for alternative agents for use in all applications of CFC's. To this end, aerosols for many applications are now pressurized using pressurised gases such as nitrogen or hydrocarbons. However, such propellants are generally not suitable for use in the administration of inhalation medicaments since they are toxic and/or the pressure within the canister falls each time the device is used which leads to unreproducible dosing.
The use of hydrofluorocarbons as aerosol propellants as also been suggested. European Patent Application 0 372 777, published after the earliest priority date of this application, states that the use of the hydrofluorocarbon propellant 134a and drug as a binary mixture or in combination with a conventional surfactant such as sorbitan trioleate does not provide formulations having suitable properties for use with pressurized inhalers and suggests that satisfactory formulations may be made by adding a compound having a higher polarity than propellant 134a, such as pentane or ethanol. It is stated that the addition of a compound of higher polarity than propellant 134a to propellant 134a provides a mixture in which increased amounts of surfactant may be dissolved compared to their solubility in propellant 134a alone. It is further stated that the presence of increased amounts of solubilized surfactant allows the preparation of stable, homogenous suspensions of drug particles. The use of such co-solvents is undesirable since they may have unsuitable properties, for example, they may be flammable and/or toxic.
U.S. Pat. No. 4,352,789 suggests the use of perfluorinated surfactants which are insoluble in CFC or perfluorinated propellants as a coating for finely divided medicament to be formulated in CFC or perfluorinated propellants.
Surprisingly, we have now found that mixtures of hydrofluorocarbons and fluorinated surfactants have properties which render them suitable for use as propellant systems for aerosol compositions.
Thus, according to the invention there is provided a pressurized aerosol composition comprising a liquefied hydrofluorocarbon propellant containing substantially no non-hydrofluorocarbon solvent, having dispersed therein a medicament and a fluorinated surfactant.
The compositions according to the invention are advantageous in that the solubility of the surfactant is such as to ensure good dispersion of the medicament and smooth operation of the aerosol valve. In particular, and in contrast to EP-A-0 372 777, the surfactants which characterize the present invention are sufficiently soluble in hydrofluorocarbons to enable them to be used without the presence of an additional substance as co-solvent.
The propellant mixtures of the present invention may also be advantageous in that they are substantially taste- and odor free and have suitable vapor pressures for the administration of medicaments by inhalation, yet are environmentally safe and acceptable, especially when compared with compositions including chlorofluorocarbons. In addition, they may be less irritant than corresponding compositions including conventional surfactants such as oleic acid and sorbitan trioleate.
A wide range of fluorinated surfactants may be used in the compositions of the present invention. The surfactant may be perfluorinated or otherwise.
Perfluorinated surfactants which may be used include ionic surfactants, both anionic and cationic, eg perfluorinated alcohol phosphate esters and their salts, perfluorinated sulphonamide alcohol phosphate esters and their salts, and perfluorinated alkyl sulphonamide alkylene quaternary ammonium salts. However, we prefer surfactants which are non-ionic.
Other surfactants may be used which, while not perfluorinated as such, contain at least one perfluorinated alkyl group.
We prefer surfactants which contain at least one (CF
2
) group, more preferably from 2 to 60, eg 5 to 20 such groups.
We prefer surfactants which contain one or more ether or carboxylic ester linkages, more preferably from 2 to 60, eg 4 to 10 such linkages. We particularly prefer compounds which contain both ether and ester linkages.
We prefer surfactants which contain at least one (CH
2
) group, more preferably from 2 to 60, eg 5 to 20 such groups. We further prefer surfactants which contain at least one (OCH
2
CH
2
) group, more preferably from 2 to 30, eg 3 to 10 such groups.
Preferred non-ionic surfactants include, for example fluorinated alcohols, esters, amides, N-oxides or sulphonamides. We particularly prefer polyfluoroalkyloxyethylenes of the general formula C
m
F
2m+1
CH
2
(OC
2
H
4
)
n
OH in which m is an integer from 7 to 18 and n is an integer from 2 to 6. Other preferred surfactants include:
(CF
3
)
2
CFO(CF
2
)
z
CONH(CH
2
)
3
N(O)(CH
3
)
2
,
(CF
3
)
2
CFOCF
2
CF
2
CH
2
CH
2
(OCH
2
CH
2
)
z
OH,
in which z is an integer from about 2-20,
CF
3
CF
2
CF
2
O(CF(CF
3
)CF
2
CF
2
O)
n
CF
2
CF
2
CF
3
,
in which n is an integer from about 10-60.
Further examples of preferred surfactants are the following:
The fluoroaliphatic polymeric esters known as FC 430 and FC 431, available from 3M. These are believed to be acrylic polymers having a fluorinated portion based on
and a portion including an ethylene/propylene oxide block copolymer. These surfactants may be supplied as a 50:50 mixture with ethyl acetate, the latter compound being preferably removed before the surfactant is used in accordance with the present invention.
Other fluorinated surfactants produced by 3M that may be mentioned include FC 170c, FC 171 and FC 807. We particularly prefer surfactants which have both a fluorinated portion, especially a perfluorinated portion, and a hydrophilic portion, eg a portion based on an ethylene and/or propylene oxide.
Other fluorinated surfactants which may be mentioned are ethyl perfluorooctylsulphonamide, the linear perfluoropolyether known as Fomblin-M, perfluorodecalin and tris(1H, 1H, 5H-octafluoropentyl)phosphate. All of these are available from Fluorochem Ltd.
Mixtures of fluorinated surfactants may also be used, eg mixtures of two or more of the fluorinated surfactants listed above. Alternatively, mixtures may be used of one or more fluorinated surfactants with one or more of the surfactants conventionally used in aerosol compositions, eg CFC-pressurized compositions. Examples of such conventional surfactants are: natural oils, sorbitan oleates, eg monooleate and trioleate, sorbitan monolaurate, monoglycerides, eg glyceryl monooleate, monostearate and monolaurate, lecithins, oleic acid, etc.
Other surfactants and adjuvants that may be added include poloxamers and/or polyethylene glycols, eg PEG 1000 and PEG 1500.
In the present context, the term ‘hydrofluorocarbon’ is to be taken to mean a compound of general formula
C
x
H
y
F
z
in which x is an integer from 1 to 3, y+z=2x+2 and y and z are both at least 1.
Particular hydrofluorocarbons of interest are CF
3
CFH
2
(Propellant
134
a
), CH
3
CHF
2
(Propellant
152
a
) and CF
3
CHFCF
3
(Propellant 227). We particularly prefer compositions including propellant 227.
In general the vapor pressure of the mixture should be in the range suitable and permitted for aerosol propellants. The, vapor pressure may be varied by mixing one or more hydrofluorocarbons and/or some other suitable vapor pressure modifying agent in appropriate proportions.
We prefer
Lim Joseph Geok Paan
Somani Asit
Steele Gerald
Aventis Pharmaceuticals Inc.
Bawa Raj
Nixon & Vanderhye P.C.
Wang George C.
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