CA2373094C - Stainless steel canister for propellant-driven metering aerosols - Google Patents
Stainless steel canister for propellant-driven metering aerosols Download PDFInfo
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- CA2373094C CA2373094C CA2373094A CA2373094A CA2373094C CA 2373094 C CA2373094 C CA 2373094C CA 2373094 A CA2373094 A CA 2373094A CA 2373094 A CA2373094 A CA 2373094A CA 2373094 C CA2373094 C CA 2373094C
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- container
- valve
- canister
- canister according
- gasket
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- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22C—ALLOYS
- C22C38/00—Ferrous alloys, e.g. steel alloys
- C22C38/18—Ferrous alloys, e.g. steel alloys containing chromium
- C22C38/40—Ferrous alloys, e.g. steel alloys containing chromium with nickel
- C22C38/44—Ferrous alloys, e.g. steel alloys containing chromium with nickel with molybdenum or tungsten
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D83/00—Containers or packages with special means for dispensing contents
- B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
- B65D83/38—Details of the container body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22C—ALLOYS
- C22C38/00—Ferrous alloys, e.g. steel alloys
- C22C38/18—Ferrous alloys, e.g. steel alloys containing chromium
- C22C38/40—Ferrous alloys, e.g. steel alloys containing chromium with nickel
- C22C38/42—Ferrous alloys, e.g. steel alloys containing chromium with nickel with copper
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Metallurgy (AREA)
- Materials Engineering (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Anesthesiology (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Nozzles (AREA)
- Filling Or Discharging Of Gas Storage Vessels (AREA)
- Safety Valves (AREA)
Abstract
The present invention relates to corrosion resistant stainless steel canisters for propellant-containing aerosol formulations for use in propellant gas-operated inhalers.
Description
CA 02373094 2001-11-05 4T_a j f t Q
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 1/1089 PCT - 2 - Boehringer Ingelheim Pharma KG
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.
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.
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 (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.
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, 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.
1/1089 PCT - 5 - Boehringer Ingelheim Pharma KG
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.
1/1089 PCT - 6 - Boehringer Ingelheim Pharma KG
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).
1/1089 PCT - 7 - Boehringer Ingelheim Pharma KG
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 1/1089 PCT - 8 - Boehringer Ingelheim Pharma KG
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 1/1089 PCT - 9 - Boehringer Ingelheim Pharma KG
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 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 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 1/1089 PCT - 11 - Boehringer Ingeiheim Pharma KG
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.
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 1/1089 PCT - 2 - Boehringer Ingelheim Pharma KG
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.
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.
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 (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.
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, 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.
1/1089 PCT - 5 - Boehringer Ingelheim Pharma KG
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.
1/1089 PCT - 6 - Boehringer Ingelheim Pharma KG
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).
1/1089 PCT - 7 - Boehringer Ingelheim Pharma KG
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 1/1089 PCT - 8 - Boehringer Ingelheim Pharma KG
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 1/1089 PCT - 9 - Boehringer Ingelheim Pharma KG
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 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 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 1/1089 PCT - 11 - Boehringer Ingeiheim Pharma KG
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.
Claims (20)
1. 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.
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.
2. Canister according to claim 1, wherein the valve cup consists of aluminium and is sealed with a gasket relative to the interior of the container.
3. Canister according to claim 1 or 2, wherein the valve contains one or more stainless steel springs, a valve stem, a metering chamber and a valve body, at least one of the valve stem, the metering chamber and the valve body being made of at least one of steel, the alloy as defined in claim 1 and a plastic.
4. Canister according to claim 3, wherein the one or more stainless steel springs consist of a stainless steel and the valve stem, the metering chamber and the body of the valve consist of polybutylene terephthalate.
5. Canister according to claim 3 or 4, wherein the valve stem is sealed off from the valve cup by a gasket.
6. Canister according to claim 2 or 5, wherein the gasket consists of an ethylene/propylene/diene terpolymer.
7. Canister according to any one of claims 1 to 6, wherein the valve cup consists of the same alloy as the container.
8. Canister according to any one of claims 1 to 7, wherein the container withstands a bursting pressure of more than 30,000 hPa.
9. Canister according to any one of claims 1 to 7, wherein the container withstands a bursting pressure of more than 100,000 hPa.
10. Canister according to any one of claims 1 to 9, wherein the container withstands a bursting pressure of more than 200,000 hPa.
11. Canister according to any one of claims 1 to 10, wherein the container has a wall thickness of 0.1 to 0.5 mm.
12. Canister according to any one of claims 1 to 10, wherein the container has a wall thickness of 0.15 to 0.35 mm.
13. Canister according to any one of claims 1 to 10, wherein the container has a wall thickness of 0.19 to 3.0 mm.
14. Canister according to any one of claims 1 to 13, wherein the active substance formulation has a pH of 2.0 to 5Ø
15. Canister according to any one of claims 1 to 14, wherein the active substance formulation contains electrolytes.
16. Canister according to claim 15, wherein the electrolytes are selected from among the hydroxide ions, cyanide ions and/or halide anions.
17. Canister according to claim 16, wherein the electrolytes are fluoride, chloride, bromide or iodide.
18. Canister according to any one of claims 1 to 17, wherein the active substance formulation contains ethanol as cosolvent and ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or fenoterol as active substance.
19. Container for a canister as defined in any one of claims 1 to 18.
20. Use of a canister or container according to claim 18 or 19 in an inhaler and/or for storing active substances.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19924098.1 | 1999-05-26 | ||
| DE19924098A DE19924098A1 (en) | 1999-05-26 | 1999-05-26 | Stainless steel canister for propellant-powered MDIs |
| PCT/EP2000/004662 WO2000073170A1 (en) | 1999-05-26 | 2000-05-24 | Special steel canister for propellant-operated dosing aerosols |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2373094A1 CA2373094A1 (en) | 2000-12-07 |
| CA2373094C true CA2373094C (en) | 2012-07-17 |
Family
ID=7909229
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2373094A Expired - Lifetime CA2373094C (en) | 1999-05-26 | 2000-05-24 | Stainless steel canister for propellant-driven metering aerosols |
Country Status (37)
| Country | Link |
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| EP (2) | EP1198395B1 (en) |
| JP (1) | JP4048027B2 (en) |
| KR (1) | KR100715138B1 (en) |
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| CZ (1) | CZ305422B6 (en) |
| DE (2) | DE19924098A1 (en) |
| EA (1) | EA003690B1 (en) |
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| ES (1) | ES2238292T3 (en) |
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| TR (1) | TR200103410T2 (en) |
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| UA (1) | UA74338C2 (en) |
| UY (1) | UY26165A1 (en) |
| WO (1) | WO2000073170A1 (en) |
| ZA (1) | ZA200109597B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9616237D0 (en) | 1996-08-01 | 1996-09-11 | Norton Healthcare Ltd | Aerosol formulations |
| US6739333B1 (en) | 1999-05-26 | 2004-05-25 | Boehringer Ingelheim Pharma Kg | Stainless steel canister for propellant-driven metering aerosols |
| GB0106046D0 (en) | 2001-03-12 | 2001-05-02 | Glaxo Group Ltd | Canister |
| DE20218974U1 (en) * | 2002-12-07 | 2003-07-10 | Boehringer Ingelheim Pharma KG, 55218 Ingelheim | Atomizers for liquids |
| DE102005002444A1 (en) * | 2005-01-19 | 2006-07-27 | Wella Ag | Container with a valve |
| EP1914027B1 (en) | 2005-08-12 | 2017-07-19 | JFE Steel Corporation | Two-piece can, process for producing the same and steel sheet for two-piece can |
| CN100447283C (en) * | 2006-01-13 | 2008-12-31 | 宝山钢铁股份有限公司 | Stainless teel casting material for anti-high temp, sulfide, ammonium salt corrosion and mfg. process thereof |
| WO2007107174A1 (en) * | 2006-03-21 | 2007-09-27 | Coster Tecnologie Speciali S.P.A. | Structural unit for a dispensing valve for dispensing pressurized fluids, and container having a structural unit of this type |
| JP4972771B2 (en) | 2006-12-05 | 2012-07-11 | Ｊｆｅスチール株式会社 | Method for producing aerosol drawn can and aerosol drawn can |
| EP2201934A1 (en) | 2008-12-23 | 2010-06-30 | CHIESI FARMACEUTICI S.p.A. | Tiotropium aerosol formulation products with improved chemical stability |
| GB201205243D0 (en) | 2012-03-26 | 2012-05-09 | Kraft Foods R & D Inc | Packaging and method of opening |
| KR20150099602A (en) * | 2012-12-24 | 2015-08-31 | 페타팍 아이피 리미티드 | Mounting cup and collar assembly for plastics aerosol container |
| GB2511560B (en) | 2013-03-07 | 2018-11-14 | Mondelez Uk R&D Ltd | Improved Packaging and Method of Forming Packaging |
| GB2511559B (en) | 2013-03-07 | 2018-11-14 | Mondelez Uk R&D Ltd | Improved Packaging and Method of Forming Packaging |
| FR3065176B1 (en) * | 2017-04-13 | 2019-06-07 | Aptar France Sas | DOSING VALVE FOR FLUID PRODUCT DISPENSER |
| CN113768906B (en) * | 2021-10-25 | 2023-05-09 | 上海方予健康医药科技有限公司 | Novel glucocorticoid inhalation aerosol and pharmaceutical assembly |
| CN114293103B (en) * | 2021-12-31 | 2022-07-29 | 台州绿创包装容器股份有限公司 | Metal aerosol can |
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| GB872052A (en) * | 1956-10-19 | 1961-07-05 | United States Steel Corp | Stainless steel resistant to nitric acid corrosion |
| FR2231766B1 (en) * | 1973-06-04 | 1976-09-17 | Creusot Loire | |
| FR2394618A1 (en) * | 1977-06-13 | 1979-01-12 | Commissariat Energie Atomique | AUSTENITIC STAINLESS STEEL |
| DE3724629A1 (en) * | 1987-07-22 | 1989-02-02 | Siemens Ag | PIEZOELECTRICALLY REQUIRED RESONANCE SYSTEM |
| DE3736579C3 (en) * | 1987-10-26 | 1996-10-17 | Mannesmann Ag | Pressure tank for storing gases of high purity |
| JPH02195543A (en) * | 1989-01-24 | 1990-08-02 | Sumitomo Metal Mining Co Ltd | Magneto-optical disk |
| US5340838A (en) * | 1990-05-04 | 1994-08-23 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with 2-phenylcyclopropylamines |
| JP3001614B2 (en) * | 1990-07-11 | 2000-01-24 | 日新製鋼株式会社 | Extremely soft austenitic stainless steel |
| DE4112303A1 (en) * | 1991-04-15 | 1992-10-22 | Minnesota Mining & Mfg | Nitroglycerin, propellant gas-free spray prepn. - stored in container in which the steel parts are made of V4A series steels to inhibit nitroglycerin decomposition |
| JPH0539545A (en) * | 1991-08-03 | 1993-02-19 | Nippon Steel Corp | Stainless steel for ultrahigh vacuum equipment excellent in corrosion resistance and production of ultrahigh vacuum vessel |
| ATE204743T1 (en) * | 1991-12-18 | 2001-09-15 | Minnesota Mining & Mfg | AEROSOL COMPOSITIONS FOR MEDICINAL SUSPENSIONS |
| JPH05340838A (en) * | 1992-06-04 | 1993-12-24 | Ricoh Co Ltd | Method and instrument for measuring eccentricity of aspherical lens |
| FR2711674B1 (en) * | 1993-10-21 | 1996-01-12 | Creusot Loire | Austenitic stainless steel with high characteristics having great structural stability and uses. |
| AU680530B2 (en) * | 1993-07-15 | 1997-07-31 | Minnesota Mining And Manufacturing Company | Seals for use in an aerosol delivery device |
| US5421492A (en) * | 1993-11-02 | 1995-06-06 | Glaxo Inc. | Metered aerosol dispensing apparatus and method of use thereof |
| US5513767A (en) * | 1994-01-03 | 1996-05-07 | Materials Engineering Inc. | Pressurized container |
| DE19504502A1 (en) * | 1995-02-13 | 1996-08-14 | Henkel Kgaa | Corrosive agent and dispenser |
| JP3514889B2 (en) * | 1995-10-04 | 2004-03-31 | 株式会社日本製鋼所 | Austenitic stainless clad steel sheet with excellent corrosion resistance and method for producing the same |
-
1999
- 1999-05-26 DE DE19924098A patent/DE19924098A1/en not_active Ceased
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2000
- 2000-05-24 CA CA2373094A patent/CA2373094C/en not_active Expired - Lifetime
- 2000-05-24 AT AT00943730T patent/ATE289276T1/en active
- 2000-05-24 CO CO00038310A patent/CO5271757A1/en active IP Right Grant
- 2000-05-24 RS YUP-833/01A patent/RS49749B/en unknown
- 2000-05-24 PE PE2000000495A patent/PE20010107A1/en active IP Right Grant
- 2000-05-24 DE DE50009558T patent/DE50009558D1/en not_active Expired - Lifetime
- 2000-05-24 ME MEP-2001-833A patent/ME01657B/en unknown
- 2000-05-24 JP JP2000621251A patent/JP4048027B2/en not_active Expired - Lifetime
- 2000-05-24 IL IL14671300A patent/IL146713A0/en active IP Right Grant
- 2000-05-24 SK SK1709-2001A patent/SK286477B6/en not_active IP Right Cessation
- 2000-05-24 TR TR2001/03410T patent/TR200103410T2/en unknown
- 2000-05-24 NZ NZ516317A patent/NZ516317A/en not_active IP Right Cessation
- 2000-05-24 CN CN00808003A patent/CN1106999C/en not_active Expired - Lifetime
- 2000-05-24 EE EEP200100620A patent/EE04394B1/en unknown
- 2000-05-24 EP EP00943730A patent/EP1198395B1/en not_active Expired - Lifetime
- 2000-05-24 EA EA200101158A patent/EA003690B1/en not_active IP Right Cessation
- 2000-05-24 BR BR0011546-0A patent/BR0011546A/en active Pending
- 2000-05-24 AU AU58092/00A patent/AU772768B2/en not_active Expired
- 2000-05-24 ES ES00943730T patent/ES2238292T3/en not_active Expired - Lifetime
- 2000-05-24 PT PT00943730T patent/PT1198395E/en unknown
- 2000-05-24 PL PL352052A patent/PL205866B1/en unknown
- 2000-05-24 KR KR1020017014997A patent/KR100715138B1/en active IP Right Grant
- 2000-05-24 MY MYPI20002274A patent/MY128067A/en unknown
- 2000-05-24 UA UA2001129044A patent/UA74338C2/en unknown
- 2000-05-24 MX MXPA01011839A patent/MXPA01011839A/en active IP Right Grant
- 2000-05-24 EG EG20000668A patent/EG22571A/en active
- 2000-05-24 WO PCT/EP2000/004662 patent/WO2000073170A1/en active IP Right Grant
- 2000-05-24 HU HU0201330A patent/HU224648B1/en active IP Right Grant
- 2000-05-24 EP EP03027354A patent/EP1413528A3/en not_active Withdrawn
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- 2000-05-25 UY UY26165A patent/UY26165A1/en not_active IP Right Cessation
- 2000-05-26 AR ARP000102576A patent/AR024113A1/en active Pending
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