Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1/1089 PCT - 1 - Boehringer Ingelheim Pharma KG
76623pct.205
Stainless steel canister for propellant-driven metering
aerosols
The present invention relates to corrosion-resistant
stainless steel canisters for propellant gas-containing
aerosol formulations for use in propellant gas-operated
inhalers. -
Background of the Invention
In propellant-driven inhalers, the active substances are
stored together with the propellant in cartridge-like
canisters. These canisters generally consist of an
aluminium container sealed with an aluminium valve cup in
which a valve is embedded. A canister of this kind can
then be placed in the inhaler in the manner of a cartridge
and is either left there permanently or replaced with a
new cartridge after use. Since chlorofluorocarbons (CFCs)
were proscribed on the grounds of their ozone-destroying
properties at the Rio de Janeiro Conference at the
beginning of the 90s, the use of fluorohydrocarbons (FHC)
is promoted as an alternative for use in propellant-driven
inhalers. The most promising example to date are TG 134a
(1,1,2,2-tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3-
heptafluoropropane). Accordingly, existing systems of
delivery for treatments by inhalation have had to be
converted to CFC-free propellants and new delivery systems
and active substance formulations have had to be
developed.
Surprisingly, it has been found that aluminium canisters
are not always resistant to drug formulations containing
fluorohydrocarbons as propellants but have a high risk of
corrosion depending on the composition of the
formulations. This is particularly true of formulations
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which contain electrolytes and/or free ions, particularly
free halides. In these cases, the aluminium is attacked,
which means that aluminium cannot be used as a casing
material for the canisters. Similar instabilities in the
aluminium canisters have been observed when
fluorohydrocarbons are used as propellants if the
formulations contain acid or basic components, e.g. in the
form of the active substances, the additives, in the form
of stabilisers, surfactants, flavour enhancers,
antioxidants, etc.
Description of the Invention
One of the tasks of the present invention is to provide a
canister for propellant-driven inhalers which is
corrosion-resistant in the presence of active substance
formulations for inhalation therapy containing a
fluorohydrocarbon as propellant, which has sufficient
compressive and breaking strength to withstand processing
and use, which ensures the quality of the formulations
stored therein and overcomes the other disadvantages known
from the prior art.
A further objective of the invention is to provide a
canister for propellant-driven inhalers, the container of
which consists of a single inherently homogeneous
material.
Surprisingly, it has been found that canisters consisting
of a container and a valve cup with valve wherein at least
the container consists of certain stainless steel alloys
solve the problem according to the invention. These
alloys contain as components chromium (Cr), nickel (Ni),
molybdenum (Mo), iron (Fe) and carbon (C). Such alloys
may additionally contain copper (Cu), manganese (Mn) and
silicon (Si). The container preferably consists of one of
the alloys described below.
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2a
According to an aspect of the invention, there is provided canister
containing an active substance formulation which contains salt, acid, base or
electrolyte with TG 134a and/or TG 227 as propellant gas for inhalation
therapy, the
canister consisting of a container and a valve cup with valve embedded
therein, and
the container being made of an alloy containing 40.0 - 53.0% iron, 24.0 -
26.0%
nickel, 19.0 - 21.0% chromium, 4.0 - 5.0% molybdenum, 0.0 - 2.0% manganese,
1.0 - 2.0% copper, 0.0 - 0.5% silicon, 0.0 - 0.045% phosphorus, 0.0 - 0.035%
sulphur
and 0.0 - 0.020% carbon.
A container for a canister of the invention is also provided.
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The invention further relates to the use of a container or
canister of this kind consisting of a container and a
valve cup with valve in propellant-operated metering
aerosols (inhalers) and a process for producing them.
The invention is hereinafter explained more fully with
reference to Figures 1 and 2.
Fig. 1 shows the canister consisting of container (2),
valve cup (8) and the valve (9) in cross-section.
Fig. 2 shows another embodiment of the valve cup (8) and
the valve (9) in cross-section.
Figure 1 shows the canister (1) according to the invention
in cross-section. The canister (1) consists of a
container (2) for holding the pharmaceutical formulation
and a valve cup (8) with valve (9). The shape and
dimensions of the canister correspond to those of the
aluminium canisters known from the prior art.
The container (2) according to the invention is made of an
alloy containing
40.0 - 53.0% iron,
23.0 - 28.0% nickel,
19.0 - 23.0% chromium,
4.0 - 5.0% molybdenum,
0.0 - 2.0% manganese,
1.0 - 2.0% copper,
0.0 - 1.0% silicon,
0.0 - 0.045% phosphorus,
0.0 - 0.035% sulphur and
0.0 - 0.020% carbon.
This alloy is an alloy according to material. number 1.4539
of the Iron and Steel List of the Society of German
Metallurgists.
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A preferred alloy of this kind has the following
composition:
19.0 - 21.0% chromium,
24.0 - 26.0% nickel,
4.0 - 5.0% molybdenum,
1.0 - 2.0% copper,
up to 2.0% manganese,
up to 0.5% silicon and
up to 0.02% carbon, the remainder being substantially
iron.
In an almost identical alternative alloy the molybdenum
content is restricted to 4.5 - 5.0%.
In an alternative embodiment the container (2) according
to the invention consists of an alloy according to
material number 1.4404 of the Iron and Steel List of the
Society of German Metallurgists.
The composition of the alloy is:
60.0 - 72.0% iron,
9.0 - 13.0% nickel,
17.0 - 21.0% chromium,
2.0 - 3.0% molybdenum,
0.0 - 1.5% manganese,
0.0 - 1.5% silicon,
0.0 - 0.04% phosphorus,
0.0 - 0.04% sulphur and
0.0 - 0.03% carbon.
Another embodiment of the container consists of an alloy
having the following composition:
16.5 - 18.5% chromium,
11.0 - 14.0% nickel,
2.0 - 2.5% molybdenum,
maximum 0.03% carbon, the remainder being iron.
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The alloys mentioned above are such that they are
corrosion-resistant to various liquefied fluorohydro-
carbons such as TG 134a (1,1,1,3-tetrafluorohydrocarbon)
and TG 227 (1,1,1,2,3,3,3-heptafluoropropane). These
include propellant gas formulations having active
substances suitable for inhalation therapy, surfactants,
cosolvents, stabilisers, complexing agents, flavour
correctors, antioxidants, salts, acids, bases or
electrolytes, such as hydroxide ions, cyanide ions and/or
halide anions such as fluoride, chloride, bromide or
iodide.
The container (2) is formed from a casing made of one of
the alloys described above. The container (2) has four
different zones: the flat or concave, inwardly domed base
(3), a cylindrical portion (4) which merges into the
tapering neck (5) in its upper third and finally ends in
the bead (6) which encircles the opening (7) of the
container.
The wall thickness of the container (2) is between 0.1 and
0.5 mm in a preferred embodiment, preferably between 0.15
and 0.35 mm, most preferably about 0.19 to 3.0 mm.
In a preferred embodiment the container (2) will withstand
a bursting pressure of more than 30,000 hPa, preferably
more than 100,000 hPa, most preferably more than
200,000 hPa. The weight of the container (2) is 5-15 g in
a preferred embodiment, 7-10 g in another and 7.9 - 8.7 g
in yet another. In an equally preferred embodiment the
container (2) has a volume of 5 to 50 ml. Other
containers have a volume of 10 to 20 ml whilst still
others have volumes of about 15 - 18 ml.
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In the sealed state the container (2) is tightly sealed by
means of the valve cup (8) after being filled with the
pharmaceutical formulation and the propellant.
In one embodiment the valve cup (8) also consists of
corrosion-resistant material. Preferably this is one of
the alloys described above for the containers and/or a
plastics material of suitable pharmaceutical quality.
In another embodiment the valve cup (8)-consists of
aluminium. In this case the seal (10) and/or the valve
(9) are constructed so that the valve cup (8) itself
cannot come into contact with the liquid inside the
container.
A preferred embodiment of the valve cup (8) is as
described in GB 2324121, to which reference is hereby made
in its entirety.
In the closed state of the canister, the valve cup (8) is
crimped around the container (2) at its bead (6). In
preferred embodiments a seal or gasket (10) seals the
valve cup (8) relative to the bead (6). The seal may be
annular or disc shaped. It is preferably disc shaped. It
may consist of materials known from the prior art which
are suitable for use with pharmaceutical formulations with
fluorohydrocarbons as the propellants. Examples of
suitable materials include thermoplasts, elastomers,
materials such as neoprene, isobutylene, isoprene, butyl
rubber, buna rubber, nitrile rubber, copolymers of
ethylene and propylene, terpolymers of ethylene, propylene
and a diene, e.g. butadiene, or fluorinated polymers. The
preferred materials are ethylene/propylene/diene
terpolymers (EPDM).
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On the side of the valve cup (8) facing the inside of the
container, a valve (9) is constructed so that the valve
stem (12) passes through the valve cup (8) to the other
side. The valve (9) sits in the central opening of the
gasket (10) to form a seal. The gasket (10) and valve (9)
together seal the valve cup (8) from the inside of the
container, so that it cannot come into contact with the
liquid in the container (2).
The valve (9) is constructed so that every element which
is capable of coming into contact with the liquid inside
the container (2) consists of a material which is
corrosion-resistant with respect to this liquid. Such
elements include for example the spring or springs (11),
the valve stem (12), which projects from the inside to the
outside through the opening (17) in the valve cup (8), the
metering chamber (13) and the valve body (14). The spring
(11) consists of steel, preferably a stainless steel. The
other elements of the valve (9) may consist, for example,
of steel, the alloy described above and/or a plastic. The
elements (12), (13) and (14) preferably consist of a
plastic, particularly a polyester, most preferably
polybutylene terephthalate.
As shown in Figure (1), one or more other gaskets or
seals, e.g. the gaskets (15) and/or (16), may be provided
to prevent liquid or gas from escaping outwards from the
inside of the container. The gasket or gaskets may be
arranged so that the liquid inside the container comes
into contact only with the container jacket and the valve,
apart from the actual gasket or gaskets.
The gasket (15) seals off the valve stem, which is
optionally vertically movable, at the point where it
penetrates the valve cup (8). The gasket (16) seals the
valve stem (12) inside the valve relative to the valve
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body (14) and/or the metering chamber (13). In this way,
the gaskets (15) and (16) prevent any liquid or gas from
escaping from the interior of the container along the
outer casing of the valve stem and out of the canister or
from coming into contact with the valve cup :by this route.
The gaskets (15) and (16) may be made of the same material
as the gasket (10), preferably an ethylene/propylene/diene
terpolymer.
In one embodiment in which the valve cup (8) is not made
of aluminium but of one of the corrosion-resistant
materials described above, it is not necessary for the
gasket (10) together with the valve (9) to isolate the
valve cup completely from the inside of the container.
Therefore, it is not necessary in this case for the gasket
(10) and valve (9) to be in sealing contact with one
another. There may be a gap between the gasket (10) and
the valve (9). In such a case the gasket (10) sits
directly on the underside of the valve cup (8), for
example, and seals the edge of the valve cup (8) relative
to the bead (6) on the container. The gasket (15) then
seals the opening (17) in the valve cup (8) from the
interior of the container.
Figure 2 shows another embodiment of the valve cup (8)
with embedded valve (9). This embodiment is largely
identical to that in Figure 1. The major difference is
that the gasket (10) and the gasket (16) in the embodiment
in Figure 2 are combined to form one gasket (18). The
gasket (18) encloses the underside of the valve plate
(18). It is arranged so that the valve body (14) is
embedded in the gasket. The valve stem (12) passes
through the gasket via the opening (19) which is located
directly below the opening (17) in the valve cup (8). The
opening (19) is of such dimensions as to seal the valve
stem (12) relative to the valve cup (8). The sealing
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material for the gasket (18) is identical to that
described for the gasket (10).
The container (2) according to the invention is produced
analogously to the processes known from the prior art for
producing aluminium canisters and the like, in which the
container is stamped out of a sheet of the material in
question, or the corresponding alloy. In the present
invention, the container (2) is stamped out of a sheet of
the above-mentioned alloys of chromium ..(Cr), nickel (Ni),
molybdenum (Mo), iron (Fe) and carbon (C) or from an alloy
which additionally contains copper (Cu), manganese (Mn)
and silicon (Si).
The container (2) or canister consisting of container (2)
and valve cup (8) with valve (9) according to the
invention is particularly suitable for use with propellant
gas formulations containing fluorohydrocarbons.
Propellant gas formulations which can preferably be used
in conjunction with the invention are disclosed in
WO 94/13262, to which reference is hereby made.
Particularly preferred formulations disclosed therein are
acid-stabilised and/or ethanolic propellant gas
formulations containing 1,1,2,2-tetrafluoroethane
(TG 134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (TG 227)
as the propellant gas, particularly those which contain
ipatropium bromide, oxitropium bromide, albuterol,
tiotropium bromide or fenoterol as active substance.
Depending on the active substance, inorganic or organic
acids may be used as stabilisers. Examples of inorganic
acids include, in addition to halic acids and other
mineral acids: sulphuric acid, hydrochloric acid, nitric
acid or phosphoric acid, whilst examples of organic acids
include ascorbic acid or citric acid. In the case of the
salts of the active substances, the preferred acids are
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those wherein the anion is identical to that of the salt
of the active substance. Citric acid is generally
suitable for all active substances and their salts and is
also most preferred.
The acid content is such that the pH of the formulation is
between 1.0 and 7.0, preferably between 2.0 and 5.0 and
most preferably about 3.5. In the case of inorganic acids
the preferred acid content is in the range from about
0.00002 to 0.01 N. In the case of ascorbic acid the
preferred content is roughly in the range from 0.0045 to
5.0 mg/ml and in the case of citric acid it is within the
range from 0.0039 to 27.7 mg/ml.
The formulations may additionally contain ethanol as
cosolvent. The preferred amount is 1.0 to 50.0% by weight
of the formulation.
The following are some preferred formulations by way of
example which can be stored in a canister or a container
of the type described above:
Exami 1
Ipatropium bromide monohydrate 0.001 - 2.5% by weight
Absolute ethanol 0.001 - 50% by weight
TG 134a 50.0 - 99.0% by weight
Inorganic acid 0.01 - 0.00002 normal
Water 0.0 - 5.0% by weight
Example
Ipatropium bromide monohydrate 0.001 - 2.5% by weight
Absolute ethanol 0.001 - 50% by weight
TG 134a 50.0 - 99.0% by weight
Ascorbic acid 0.00015 - 5.0 mg/ml
Purified water 0.0 - 5.0% by weight
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Example 3
Ipatropium bromide monohydrate 0.0187% by weight
Absolute ethanol 15.0000% by weight
TG 134a 84.47730% by weight
Citric acid 0.0040% by weight
Purified water 0.5000% by weight
Total 100.0000% by weight
Example 4
Ipatropium bromide monohydrate 0.03.74% by weight
Absolute ethanol 15.0000% by weight
TG 134a 84.4586% by weight
Citric acid 0.0040% by weight
Purified water 0.5000% by weight
Total 100.0000% by weight
Example 5
Ipatropium bromide monohydrate 0.0748% by weight
Absolute ethanol 15.0000% by weight
TG 134a 84.4212% by weight
Citric acid 0.0040% by weight
Purified water 0.5000% by weight
Total 100.0000% by weight
Exam lp e 6
Fenoterol hydrobromide 0.192% by weight
Absolute ethanol 30.000% by weight
TG 134a 67.806% by weight
Citric acid 0.002% by weight
Purified water 2.000% by weight
Total 100.000095 by weight
A method of filling the canisters with the corresponding
formulation might be, for example, the dual stage pressure
fill method, the single stage cold fill method or the
single stage pressure fill method.
