SK17092001A3 - Corrosion-resistant special steel canister for propellant-operated dosing aerosols, a container, method for production thereof and its use - Google Patents

Abstract

A canister for a propellant-operated dosage aerosol comprises an alloy container fitted with a valve holder containing an embedded valve. The container is made from an alloy comprising 19-21 % Cr, 24-26 % Ni, 4.5-5 % Mo, 1-2 % Cu, 2 % Mn (maximum), 0.5 % Si (maximum), 0.02 % C (maximum) and Fe (remainder). Independent claims are also included for: (a) a canister in which the container is made from an alloy comprising 16.5-18.5 % Cr, 11-14 % Ni, 2-2.5 % Mo, 0.03 % C (maximum) and Fe (remainder); (b) the container component of the canister; and (c) the production of the canister and the container using an alloy comprising the specified elements.

Description

Technical field

The present invention relates to corrosion resistant stainless steel canisters for propellant-containing aerosol formulations for use in propellant-driven inhalers.

BACKGROUND OF THE INVENTION

In propellant-driven inhalers, the active ingredients with the propellant are stored together in cartridge-like canisters. These canisters generally consist of an aluminum container which is closed by an aluminum valve plate into which the valve is inserted. Such a canister can then be inserted into the inhaler as a cartridge and then either permanently stayed or replaced with a new cartridge after use. Since the use of fluorochlorocarbons (FCKW, CFC) worldwide for their ozone-depleting properties has been rejected worldwide at the Rio de Janeiro Conference in the early 1990s, it has been moving towards the use of fluorocarbons (FKW, HFA) as alternatives to propellant-driven inhalers. The current promising representatives are TG 134a (1,1,2,2-tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane). Accordingly, existing inhalation therapy delivery systems need to be converted to FCKW-free propellants and new delivery systems and drug formulations have to be developed.

Surprisingly, it has been found that aluminum cans are not always resistant to fluorocarbon-containing drug formulations as propellant, but, depending on the formulation of the formulation, exhibit a high risk of corrosion. This is particularly true for formulations containing electrolytes and / or free ions, especially free halides. In these cases, the aluminum is attacked so that it is not possible to use aluminum as a canister sheath material. Similar instabilities in aluminum cans when using fluorocarbons as a propellant are observed when

The formulations contain acidic or basic components, for example in the form of active ingredients, additives such as stabilizers, surfactants, flavor enhancers, antioxidants, etc.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a propellant-driven canister for inhalers that is corrosion resistant in the presence of inhaled drug formulations containing a fluorocarbon propellant and having sufficient resistance to pressure and breaking strength for processing and use, and which guarantees the quality of stored formulations and which overcomes other disadvantages known in the art.

It is a further object of the invention to provide a canister for propellant-driven inhalers whose reservoir is of a single, homogeneous material.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that a canister consisting of a reservoir and a valve plate with a valve in which at least the reservoir is of a particular stainless steel alloy solves the task of the invention.

This alloy contains 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). Preferred containers are comprised of one of the alloys described below.

Accordingly, the present invention provides a propellant-propelled aerosol canister comprising a reservoir and a valve plate with an interposed valve, the reservoir being an alloy with an iron content of 40.0 to 53.0%, a nickel of 23.0 to 28.0% , chromium from 19.0 to 23.0%, molybdenum from 4.0 to 5.0%, manganese from 0.0 to 2.0%, copper from 1.0 to 2.0%, silicon from 0.0 % to 1.0%, phosphorus from 0.0 to 0.045%, sulfur from 0.0 to 0.035% and carbon from 0.0 to 0.020%.

The invention further relates to the use of such containers or canisters composed of a container and a valve-valve plate in metered-dose aerosols driven by propellant (inhalers) and to a method for their manufacture.

In the following, the invention will be illustrated in more detail by means of the figures.

-3Overview of drawings

Figure 1 shows a canister composed of a cartridge (2), a valve plate (8) and a valve (9) in cross-section.

Figure 2 shows another embodiment of the valve plate (8) and the valve (9) in cross-section.

DETAILED DESCRIPTION OF THE INVENTION

Figure 1 shows a canister 1 according to the invention in cross-section. The canister 1 is comprised of a cartridge 2 for accommodating the drug formulation and a valve plate 8 with a valve 9. The canister shape and dimensions correspond to aluminum canisters known in the art.

The container 2 according to the invention is composed of an alloy with proportions: iron from 40.0 to 53.0%, nickel from 23.0 to 28.0%, chromium from 19.0 to 23.0%, molybdenum from 4.0 to 5.0%, manganese from 0.0 to 2.0%, copper from 1.0 to 2.0%, silicon from 0.0 to 1.0%, phosphorus from 0.0 to 0.045%, sulfur from 0 0 to 0.035% and carbon from 0.0 to 0.020%.

This alloy is an alloy according to material number 1.4539 from the list of steels of the Association of German Metallurgy.

A preferred alloy of this type has the following composition: chromium from 19.0 to 21.0%, nickel from 24.0 to 26.0%, molybdenum from 4.0 to 5.0%, copper from 1.0 to 2.0 %, manganese up to 2,0%,

-4 silicon up to 0.5% and carbon up to 0.02%, the remaining part being iron.

In another nearly identical alternative alloy, the molybdenum fraction is limited to 4.5 to 5%.

In an alternative embodiment, the container 2 according to the invention is composed of an alloy according to the material number 1.4404 of the list of steels of the German Metallurgical Association.

The alloy composition is: iron from 60.0 to 72.0% nickel from 9.0 to 13.0%, chromium from 17.0 to 21.0%, molybdenum from 2.0 to 3.0%, manganese from 0 0 to 1.5%, silicon from 0.0 to 1.5% phosphorus from 0.0 to 0.04%, sulfur from 0.0 to 0.04% and carbon from 0.0 to 0.03% .

Another embodiment of the container consists of an alloy with the following composition: chromium from 16.5 to 18.5%, nickel from 11.0 to 14.0%, molybdenum from 2.0 to 2.5%, carbon maximum 0.03% and iron as the remainder.

The alloys are of a type that are corrosion resistant in the presence of various liquefied fluorocarbons such as TG 134a (1,1,1,3-tetrafluorocarbon) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane) ). This includes propellant-containing formulations with active ingredients, surfactants, cosolvents, stabilizers, complexing agents, taste correctors, antioxidants, salts, acids, bases or electrolytes suitable for inhalation therapy, such as hydroxide ions, cyanide ions and / or ions such as fluoride, chloride, bromide or iodide.

The container 2 is formed from a shell which is composed of one of the above-described alloy. The cartridge 2 has four different zones: a straight or concave inwardly curved bottom 3, a cylindrical shaped region 4 that passes in the upper third into

5 of the tapered neck 5 and then ends in the thickened edge 6 which surrounds the opening 7 of the cartridge.

The wall thickness of the cartridge 2 is preferably from 0.1 to 0.5 mm, more preferably from 0.15 to 0.35 mm, most preferably from about 0.19 to 0.3 mm.

In a preferred embodiment, the container 2 resists an excess pressure of greater than 30000 hPa, more preferably greater than 100000 hPa, most preferably greater than 200000 hPa. The weight of container 2 is in one preferred embodiment from 5 to 15 g, in another preferred embodiment from 7 to 10 g, and in yet another preferred embodiment from 7.9 to 8.7 g. In one equally preferred embodiment, the reservoir 2 has a volume of from 5 to 50 ml. Other containers have volumes from 10 to 20 ml and again others from about 15 to 18 ml.

In the closed state, the cartridge 2 is sealed by the valve disk 8 after filling with the drug formulation and the propellant.

In one embodiment, the valve plate 8 is also made of a corrosion resistant material. It is preferred that the container is an alloy described above and / or plastic materials of a quality suitable for pharmaceutical purposes.

In another embodiment, the valve plate 8 is made of aluminum. In this case, the seal 10 and / or the valve 9 are designed in such a way that the valve disk 8 cannot come into contact with the liquid inside the container itself.

A preferred embodiment of the valve disk 8 relates to an embodiment according to GB 2324121, which is fully considered here.

In the closed state of the canister, the valve disk 8 of the cartridge 2 is pressed against its thickened edge 6. In preferred embodiments, the valve disk 8 seals from the thickened edge 6 of the seal 10. The seal may be annular or disc-shaped. A disk shape is preferred. It can be made of materials known in the art which are suitable for use in drug formulations containing fluorocarbons as propellant. Thermoplastics, elastomers, materials such as neoprene, isobutylene, isoprene, butyl rubber, buna-rubber, nitrile rubber, copolymers of ethylene and propylene, terpolymers of ethylene, propylene and one diene, for example butadiene, or fluorinated polymers are suitable for this purpose. Preferred materials are ethylene / propylene-diene terpolymers (EPDM).

On the side of the valve plate 8 facing the interior of the cartridge, the valve 9 is so formed that the valve stem 12 passes through the valve plate 8 to the other side. The valve 9 is tightly seated in the central opening of the seal 10. The seal 10 and the valve 9 together seal the valve disk 8 from the contents of the reservoir so that it cannot come into contact with the liquid in the reservoir 2.

The valve 9 is formed in such a way that each element that can come into contact with the liquid inside the container 2 is made of a material resistant to corrosion in the liquid. These elements include, for example, the tongue (s) 11, the valve stem 12 which extends outwardly from the valve disc opening 17, the metering chamber 13 and the valve body 14. The tongue 11 consists of steel, more preferably stainless steel. The other elements of the valve 9 may be made, for example, of steel, of the above-described alloy and / or plastic. The elements 12, 13, and 14 are preferably made of plastic, particularly preferably of polyester, most preferably of polybutylene terephthalate.

As shown in Figure 1, one or more additional seals, such as seals 15 and / or 16, may be used to prevent liquid or gas leakage from inside the container to the outside. The seal (s) can also be arranged in such a way that the liquid inside the reservoir only comes into contact with the reservoir shell and the valve in addition to the seal (s).

The side seal 15 seals an optionally vertically movable valve stem that passes through the valve plate 8. The seal 16 seals the valve stem 12 from the valve body 14 and / or the metering chamber 13 within the valve. These seals 15 and 16 prevent liquid or gas from being able to escape from the interior of the container along the outer sheath of the valve stem out of the canister, or come into contact with the valve plate in this way. The seals 15 and 16 may be made of the same material as the seal 10, more preferably an ethylene / propylene-diene terpolymer.

In one embodiment, in which the valve plate 8 is not made of aluminum but consists of one of the corrosion resistant materials described above, it is not necessary for the seal 10 together with the valve 9 to completely isolate the valve plate from the contents of the cartridge. Therefore, it is not necessary in this case that the seal 10 and the valve 9 touch each other sealingly. Optionally, there is a gap between the seal 10 and the valve 9. In such a case, the seal 10 abuts, for example, directly on the underside of the valve disk 8 and seals the edge of the valve disk 8 from the reinforced edge 6 ' - r r r r i · r • - r r i · r

-7zásobníka. The seal 15 then seals the opening 17 in the valve plate 8 from the interior of the cartridge.

Figure 2 shows another embodiment of the valve plate 8 with the valve 9 inserted. This embodiment is substantially identical to the embodiment shown in Figure 1. The essential difference is that the gasket 10 and the gasket 16 of the embodiment of Figure 2 are combined into one gasket 18. The gasket 18 covers the underside of the valve plate 8. They are arranged such that the valve body 14 is inserted into the seal. The valve stem 12 passes through the seal through an opening 19 that lies directly below the valve plate opening 8. This opening 19 is sized to seal the valve stem 12 from the valve plate 8. The sealing material of the gasket 18 is identical to the material described for the gasket 10.

The manufacture of the container 2 according to the invention is carried out in an analogous manner to those known in the art for aluminum cans, in which the containers are pressed from a sheet of a corresponding material, for example a corresponding alloy. In the present invention, the container 2 is pressed from a sheet of the above-described alloy containing chromium (Cr), nickel (Ni), molybdenum (Mo), iron (Fe) and carbon (C), or an alloy containing additionally copper (Cu), manganese (Mn) and silicon (Si).

The cartridge 2 according to the invention or the canister composed of the cartridge 2 and the valve plate 8 with the valve 9 is particularly suitable for use in formulations containing fluorocarbons as propellant. Propellant-containing formulations which can be used particularly in conjunction with the invention are disclosed in WO 94/13262, which is incorporated herein by reference in its entirety. Of this, acid stabilized and / or ethanol formulations containing propellant with 1,1,2,2-tetrafluoroethane (TG 134a) and / or 1,1,1,2,3,3,3-heptafluoropropane (TG 227) are particularly preferred ) as propellant, in particular those containing ipatropium bromide, oxitropium bromide, albuterol, tiotropium bromide or phenoterol as the active substance.

Depending on the type of active substance, inorganic or organic acids are suitable for stabilization. Examples of inorganic acids include, in addition to hydrohalic acids and other mineral acids: sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid, as examples of organic acids ascorbic acid or citric acid. In the case of salts

The active compounds are those acids whose anion is identical to that of the salt of the active compound. Citric acid, and most preferably, is generally suitable for all active ingredients and active ingredient salts.

The acid content is such that the pH of the formulation is in the range of 1.0 to 7.0, more preferably 2.0 to 5.0, and most preferably about 3.5.

In the case of inorganic acids, an acid content in the range of about 0.00002 to 0.01 N is preferred. In the case of ascorbic acid, a content in the range of about 0.0045 to 5.0 mg / ml and in the case of citric acid in the range of 0 0039 to 27.7 mg / ml.

The formulations may additionally contain ethanol as a co-solvent. The preferred amount is from 1.0 to 50.0 wt. formulation.

The following are examples of preferred formulations that can be stored in a canister or container of the type described above:

Example 1 ipatropium bromide ethanol monohydrate, absolute TG 134a inorganic acid water

Example 2 ipatropium bromide ethanol monohydrate, absolute TG 134a ascorbic acid water (purified)

Example 3 ipatropium bromide ethanol monohydrate, absolute TG 134a from 0.001 to 2.5 wt. from 0.001 to 50 wt. % from 50.0 to 99.0 wt. % from 0.01 to 0.00002 N from 0.0 to 5.0 wt.

from 0.001 to 2.5 wt. from 0.001 to 50 wt. % from 50.0 to 99.0 wt. from 0.00015 to 5.0 mg / ml from 0.0 to 5.0 wt.

0.0187 wt. 15.0000 wt. 84.4773 wt.

citric acid water (purified) pretty 0.0040 wt. 0.5000 wt. 100.0000 wt. Example 4 ipatropium bromide monohydrate 0.0374 wt. ethanol, absolute 15.0000 wt. TG 134a 84.4586 wt. citric acid 0.0040 wt. water (purified) 0.5000 wt. pretty 100.0000 wt. Example 5 ipatropium bromide monohydrate 0.0748 wt. ethanol, absolute 15.0000 wt. TG 134a 84.4212 wt. citric acid 0.0040 wt. water (purified) 0.5000 wt. pretty 100.0000 wt. Example 6 phenoterol hydrobromide 0.192 wt. ethanol, absolute 30,000 wt. TG 134a 67.806 wt. citric acid 0.002 wt. water (purified) 2,000 wt. pretty 100,000 wt.

The canister filling method with the corresponding formulation may be, for example, the "Dual Stage Pressure Fill Method", the "Single Stage Cold Fill Method" or the "Single Stage Pressure Fill" Method.

Claims (25)

PATENT CLAIMS A propellant-propelled aerosol dispenser (1) comprising a container (2) and a valve plate (8) with an interposed valve (9), characterized in that the container is an alloy with an iron content of 40.0 up to 53.0%, nickel from 23.0 to 28.0%, chromium from 19.0 to 23.0%, molybdenum from 4.0 to 5.0%, manganese from 0.0 to 2.0%, copper from 1.0 to 2.0%, silicon from 0.0 to 1.0%, phosphorus from 0.0 to 0.045%, sulfur from 0.0 to 0.035% and carbon from 0.0 to 0.020%. Canister according to claim 1, characterized in that the container is made of an alloy having the following composition: chromium from 19.0 to 21.0%, nickel from 24.0 to 26.0%, molybdenum from 4.0 up to 5.0%, copper from 1.0 to 2.0%, manganese to 2.0%, silicon to 0.5%, and carbon to 0.02%, and iron is essentially the remainder. A propellant-dispensed aerosol canister (1) comprising a reservoir (2) and a valve plate (8) with an interposed valve (9), characterized in that the reservoir is of an alloy having the following composition: iron from 60 , 0 to 72.0%, nickel from 9.0 to 13.0%, chromium from 17.0 to 21.0%, molybdenum from 2.0 to 3.0%, manganese from 0.0 to 1.5 %, silicon from 0.0 to 1.5%, phosphorus from 0.0 to 0.04%, sulfur from 0.0 to 0.04% and carbon from 0.0 to 0.03%. A propellant-dispensed aerosol canister (1) comprising a container (2) and a valve plate (8) with an interposed valve (9), characterized in that the container is an alloy comprised of from 16.5 to 18, 5% chromium, from 11.0 to 14.0% nickel, from 2.0 to 2.5% molybdenum, maximum 0.03% carbon and iron as the remainder. Container according to any one of claims 1 to 4, characterized in that the valve plate (8) is made of aluminum and is closed by a gasket (10) and / or (18) from the interior of the container. -11 Canister according to any one of claims 1 to 5, characterized in that the valve (9) comprises one or more stainless steel tongues (11), one valve stem (12), a metering chamber (13) and a valve body (9). 14), wherein the valve stem (12), the metering chamber (13) and / or the valve body (14) are of steel, an alloy according to any one of claims 1 to 3 and / or plastic. Canister according to any one of claims 1 to 6, characterized in that the tongue (s) (11) are made of stainless steel and the valve stem (12), the metering chamber (13) and the valve body (14) are made of polybutylene terephthalate. . Canister according to any one of claims 1 to 7, characterized in that the valve stem (12) is hermetically sealed by a seal (15) or (18) from the valve plate (8). Container according to any one of claims 1 to 8, characterized in that the seal (10) and / or the seal (15) and / or the seal (18) are made of an ethylene / propylene-diene terpolymer. A container according to any one of claims 1 to 9, characterized in that the valve plate (8) is of the same alloy as the container (2). A container according to any one of claims 1 to 10, characterized in that the container can withstand an overpressure of greater than 30000 hPa, more preferably greater than 100000 hPa. Canister according to any one of claims 1 to 11, characterized in that the container can withstand an overpressure greater than 200,000 hPa. A container according to any one of claims 1 to 12, characterized in that the container has a wall thickness of from 0.1 to 0.5 mm, preferably from 0.15 to 0.35 mm. -1214. Container according to any one of claims 1 to 13, characterized in that the container has a wall thickness of 0.19 to 3.0 mm. A container for a propellant-dispensed aerosol canister (1), characterized in that the container is an alloy according to any one of claims 1 to 4. A container according to claim 15, characterized in that the container can withstand an overpressure of greater than 30000 hPa, more preferably greater than 100000 hPa. A container according to claim 15, characterized in that the container can withstand an overpressure greater than 200,000 hPa. A container according to any one of claims 15 to 17, characterized in that the container has a wall thickness of from 0.1 to 0.5 mm, more preferably from 0.15 to 0.35 mm. A container according to any one of claims 15 to 18, wherein the container has a wall thickness of from 0.19 to 3.0 mm. Use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 in an inhaler and / or for the storage of active substance formulations containing 1,1,2,2-tetrafluoroethane and / or 1 as a propellant, 1,1,2,3,3,3-heptafluoropropane. The use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 according to claim 20, wherein the formulation comprises for stabilization an acid, ethanol as a cosolvent and ipatropium bromide, oxitropium bromide, tiotropium bromide, albuterol or phenoterol as active ingredient. Use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 according to claims 20 and 21, wherein the formulation 13 contains for stabilization acid, ethanol and ipatropium bromide, oxitropium bromide or tiotropium bromide as the active substance. Use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 according to claim 20, 21 or 22, wherein the formulation comprises citric acid. Use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 according to claim 20, 21 or 22, wherein the formulation comprises a mineral acid. Use of a canister according to any one of claims 1 to 14 or a container according to any one of claims 15 to 19 according to claim 20, 21 or 22, wherein the formulation comprises hydrochloric acid. A method of manufacturing a cartridge (2) or canister (1) comprised of a cartridge (2) and a valve plate (8) with an insertion valve (9) for dispensed aerosols driven by a propellant, characterized in that the cartridge (2) is molded from a sheet comprising an alloy according to any one of claims 1 to 4.