AU772768B2

AU772768B2 - Special steel canister for propellant-operated dosing aerosols

Info

Publication number: AU772768B2
Application number: AU58092/00A
Authority: AU
Inventors: Hubert Hoelz; Richard Thomas Lostritto; Juergen Nagel; Julio Cesar Vega
Original assignee: BOEHRINGER INGELHEIM PHARMA
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1999-05-26
Filing date: 2000-05-24
Publication date: 2004-05-06
Anticipated expiration: 2020-05-24
Also published as: UY26165A1; ATE289276T1; TR200103410T2; KR100715138B1; EE04394B1; EP1413528A3; HK1045973B; YU83301A; IL146713A; PL205866B1; BR0011546A; PE20010107A1; UA74338C2; ES2238292T3; WO2000073170A1; KR20020015330A; SK286477B6; CO5271757A1; CZ305422B6; EP1413528A2

Description

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 (1,1,1,2,3,3,3heptafluoropropane). 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 P:\OPERUgc%58092-00 claims.doc-033/04 -2which 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.

It follows there is a need for a canister for propellantdriven 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.

S It would also be useful to provide a canister for propellant- S: driven inhalers, the container of which consists of a single inherently homogenous material.

1C P:\OPERUgc58092-0 cllims.doc3030304 -2A- Description of the Invention 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 may solve or at least in part ameliorate some of the disadvantages of the prior art. These alloys contain as components chromium nickel molybdenum iron (Fe) and carbon Such alloys may additionally contain copper manganese (Mn) and silicon The container preferably consists of one of the alloys described below.

o 0* go* *o* o* oo e* o oooo *oo **go 1/1089 PCT 3 Boehringer Ingelheim Pharma KG 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 valve cup and the valve in cross-section.

Fig. 2 shows another embodiment of the valve cup and the valve in cross-section.

Figure 1 shows the canister according to the invention in cross-section. The canister consists of a container for holding the pharmaceutical formulation and a valve cup with valve The shape and dimensions of the canister correspond to those of the aluminium canisters known from the prior art.

The container 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, 5.0% molybdenum, 0.0 2.0% manganese, 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.

1/1089 PCT 4 Boehringer Ingelheim Pharma KG 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, 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 In an alternative embodiment the container 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, 13.0% nickel, 17.0 21.0% chromium, 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, 2.5% molybdenum, maximum 0.03% carbon, the remainder being iron.

1/1089 PCT 5 Boehringer Ingelheim Pharma KG The alloys mentioned above are such that they are corrosion-resistant to various liquefied fluorohydrocarbons 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 is formed from a casing made of one of the alloys described above. The container has four different zones: the flat or concave, inwardly domed base a cylindrical portion which merges into the tapering neck in its upper third and finally ends in the bead which encircles the opening of the container.

The wall thickness of the container is between 0.1 and 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 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 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 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.

1/1089 PCT 6 Boehringer Ingelheim Pharma KG In the sealed state the container is tightly sealed by means of the valve cup after being filled with the pharmaceutical formulation and the propellant.

In one embodiment the valve cup 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 consists of aluminium. In this case the seal (10) and/or the valve are constructed so that the valve cup itself cannot come into contact with the liquid inside the container.

A preferred embodiment of the valve cup 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 is crimped around the container at its bead In preferred embodiments a seal or gasket (10) seals the valve cup relative to the bead 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).

1/1089 PCT 7 Boehringer Ingelheim Pharma KG On the side of the valve cup facing the inside of the container, a valve is constructed so that the valve stem (12) passes through the valve cup to the other side. The valve sits in the central opening of the gasket (10) to form a seal. The gasket (10) and valve (9) together seal the valve cup from the inside of the container, so that it cannot come into contact with the liquid in the container (2) The valve is constructed so that every element which is capable of coming into contact with the liquid inside the container 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 which projects from the inside to the outside through the opening (17) in the valve cup the metering chamber (13) and the valve body The spring (11) consists of steel, preferably a stainless steel. The other elements of the valve may consist, for example, of steel, the alloy described above and/or a plastic. The elements (13) and (14) preferably consist of a plastic, particularly a polyester, most preferably polybutylene terephthalate.

As shown in Figure one or more other gaskets or seals, e.g. the gaskets (15) and/or 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 The gasket (16) seals the valve stem (12) inside the valve relative to the valve 1/1089 PCT 8 Boehringer Ingelheim Pharma KG body (14) and/or the metering chamber 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 preferably an ethylene/propylene/diene terpolymer.

In one embodiment in which the valve cup 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 to isolate the valve cup completely from the inside of the container.

Therefore, it is not necessary in this case for the gasket and valve to be in sealing contact with one another. There may be a gap between the gasket (10) and the valve In such a case the gasket (10) sits directly on the underside of the valve cup for example, and seals the edge of the valve cup relative to the bead on the container. The gasket (15) then seals the opening (17) in the valve cup from the interior of the container.

Figure 2 shows another embodiment of the valve cup (8) with embedded valve 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 The gasket (18) encloses the underside of the valve plate 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 The opening (19) is of such dimensions as to seal the valve stem (12) relative to the valve cup The sealing 1/1089 PCT 9 Boehringer Ingelheim Pharma KG material for the gasket (18) is identical to that described for the gasket The container 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 is stamped out of a sheet of the above-mentioned alloys of chromium nickel (Ni), molybdenum iron (Fe) and carbon or from an alloy which additionally contains copper manganese (Mn) and silicon (Si).

The container or canister consisting of container (2) and valve cup with valve 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 1/1089 PCT 10 Boehringer Ingelheim Pharma KG 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 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: Example 1 Ipatropium bromide monohydrate Absolute ethanol TG 134a Inorganic acid Water Example 2 Ipatropium bromide monohydrate Absolute ethanol TG 134a Ascorbic acid Purified water 0.001 2.5% by weight 0.001 50% by weight 50.0 99.0% by weight 0.01 0.00002 normal 0.0 5.0% by weight 0.001 2.5% by weight 0.001 50% by weight 50.0 99.0% by weight 0.00015 5.0 mg/ml 0.0 5.0% by weight 1/1089 PCT 11 Boehringer Ingelheim Pharma KG Example 3 Ipatropium bromide monohydrate Absolute ethanol TG 134a Citric acid Purified water Total Example 4 Ipatropium bromide monohydrate Absolute ethanol TG 134a Citric acid Purified water Total Example Ipatropium bromide monohydrate Absolute ethanol TG 134a Citric acid Purified water Total Example 6 Fenoterol hydrobromide Absolute ethanol TG 134a Citric acid Purified water Total 0.0187% by weight 15.0000% by weight 84.47730% by weight 0.0040% by weight 0.5000% by weight 100.0000% by weight 0.0374% by weight 15.0000% by weight 84.4586% by weight 0.0040% by weight 0.5000% by weight 100.0000% by weight 0.0748% by weight 15.0000% by weight 84.4212% by weight 0.0040% by weight 0.5000% by weight 100.0000% by weight 0.192% by weight 30.000% by weight 67.806% by weight 0.002% by weight 2.000% by weight 100.0000% 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.

P\OPERUgc\58092-00 claims doc-04/03/04 -11A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.

*o ft *r

Claims

1. Canister for propellant operated metering aerosols comprising a container and a valve cup with valve embedded therein, and which includes a fluorohydrocarbon as propellant and an active substance selected from ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or fenoterol, the container consisting 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 copper, 0.0 1.0% silicon, 0.0 0.045% of phosphorus, 0.0 0.035% sulphur and 0.0 0.020% carbon. o* 2. Canister for propellant operated metering aerosols 15 comprising a container and a valve cup with valve embedded therein, and which includes a fluorohydrocarbon as propellant and an active substance selected from ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or fenoterol, wherein the container consists of an alloy having 20 the following composition: 19.0 21.0% chromium, 24.0 26.0% nickel, 4.0 5.0% molybdenum, 1.0 2.0% copper, 0.0 2.0% manganese, 0.0 0.5% silicon and 0.0 0.02% carbon, with iron substantially as the remaining ingredient. 3. Canister for propellant operated metering aerosols comprising a container and a valve cup with valve embedded therein, and which includes a fluorohydrocarbon as propellant and an active substance selected from ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or fenoterol, wherein the container consists of an alloy having the following composition: 60.0 72.0% iron, 9.0 13.0% nickel, 17.0 21.0% chromium, 2.0 3.0% molybdenum, 0.0 P:\OPERUgc58092-00 claims.doc-09A)3104 -13- manganese, 0.0 1.5% silicon, 0.0 0.04% phosphorus, 0.0 0.04% sulphur and 0.0 0.03% carbon. 4. Canister for propellant operated metering aerosols comprising a container and a valve cup with valve embedded therein, and which includes a fluorohydrocarbon as propellant and an active substance selected from ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or fenoterol, wherein 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, and 0.0 0.03% carbon, with iron making up the remainder. 5. Canister according to any one of claims 1 to 4, wherein 0: 0.0. 15 the propellant composition comprises an acid and the propellant composition has a pH of 1.0 6. Canister according to claim 5, wherein the propellant composition has a pH of 2.0 7. Canister according to claim 5 or 6, wherein the acid is sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, ascorbic acid or citric acid. 25 8. Canister according to claim 7, wherein the acid is citric acid. 9. Canister according to any one of claims 1 to 8, wherein the propellant is 1,1,2,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoropropane. P:\OPERUgc 8092-00 claims.doc-09103/04 -14- Canister according to any one of claims 1 to 9, wherein the propellant composition comprises ethanol as a co-solvent. 11. Canister according to any one of claims 1 to 10, wherein the valve cup consists of aluminium and is sealed with a gasket and/or relative to the interior of the container. 12. Canister according to any one of claims 1 to 11, wherein the valve contains one or more stainless steel springs, a valve stem, the metering chamber and a valve body, the valve stem, the metering chamber and/or the valve body being made of steel, the alloy recited in any one of claims 1 to 4 and/or a plastic. 13. Canister according to one of claims 1 to 12, wherein the spring(s) consist(s) of a stainless steel and the valve stem, the metering chamber and the body of the valve consist of polybutylene terephthalate. 20 14. Canister according to one of claims 1 to 13, wherein the valve stem is sealed off from the valve cup by a gasket. Canister according to any one of claims 1 to 14, wherein the gasket consist or consists of an ethylene/propylene/diene 25 terpolymer. 16. Canister according to any one of claims 1 to 15, wherein the valve cup consists of the same alloy as the container. 17. Canister according to one of claims 1 to 16, wherein the container withstands a bursting pressure of more than 30,000 hPa. P:\OPERUgcU8092-00 climis.do-0403/04 18. Canister the container 100,000 hPa. 19. Canister the container 200,000 hPa. Canister the container 21. Canister the container according to any one of claims 1 to 17, wherein withstands a bursting pressure of more than according to any one of claims 1 to 18, wherein withstands a bursting pressure of more than according to any one of claims 1 to 19, wherein has a wall thickness of 0.1 to 0.5 mm. according to any one of claims 1 to 20, wherein has a wall thickness of 0.15 to 0.35 mm. oo o oe eo *o o oeoo ooeo *eo 15 22. Container for use in propellant-operated metering aerosols, and which exhibits corrosion resistance in the presence of active substance formulations for inhalation therapy containing fluorohydrocarbon propellants, the container consisting of an alloy recited in any one of claims 20 1 to 4. 23. Container according to claim 22, wherein the container withstands a bursting pressure of more than 30,000 hPa. 24. Container according to claim 22 or 23, wherein the container withstands a bursting pressure of more than 100,000 hPa. Container according to any one of claims 22 to 24, wherein the container withstands a bursting pressure of more than 200,000 hPa. P:\OPERUgc\58092-00 claim sdoc-09/03/04 -16- 26. Container according to any one of claims 22 to wherein the container has a wall thickness of 0.1 to 0.5 mm. 27. Container according to any one of claims 22 to 26, wherein the container has a wall thickness of 0.15 to 0.35 mm. 28. Use of a container according to any one of claims 1 to 21 in an inhaler and/or for storing active substance formulations. 29. Use of a container according to any one of claims 22 to 27 in an inhaler and/or for storing active substance formulations. 15 30. Process for the manufacture of a container according to any one of claims 22 to 27 or a canister according to any one of claims 1 to 21, wherein the container is stamped out from oO* o a sheet which consists of an alloy recited in any one of claims 1 to 4. S. 31. A canister for propellant operated aerosols substantially as herein described and with reference to the Figures. 25 32. A container for a canister for propellant operated aerosols substantially as herein described and with reference to the Figures. DATED this 9 th day of March, 2004 Boehringer Ingelheiim Pharma KG by DAVIES COLLISON CAVE Patent Attorneys for the Applicant