SK286477B6 - Corrosion-resistant special steel canister for propellant- operated dosing aerosols, a container, method for production thereof and its use - Google Patents

Abstract

Canister (1) for propellant operated metering aerosols consisting of a container (2) and a valve cup (8) with valve (9) embedded therein to corrosion resistant stainless steel for propellant-containing aerosol formulations for use in propellant gas-operated inhalers.

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 have a high risk of corrosion depending on the formulation composition. 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 of aluminum cans 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 inhaler canister which is resistant to corrosion in the presence of inhalation therapy active ingredient formulations containing a fluorocarbon propellant having sufficient pressure and strength strength for processing and use to guarantee the quality of the stored formulations, and which overcomes other disadvantages known in the art.

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

SUMMARY OF THE INVENTION

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 described alloys.

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.

BRIEF DESCRIPTION OF THE 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 cartridge 2 according to the invention is composed of an alloy with fractions;

irons 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%, S 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:

chrome 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%, silicon up to 0.5% and carbon up to 0.02%, the remainder being iron.

from 60.0 to 72.0% from 9.0 to 13.0%, from 17.0 to 21.0%, from 2.0 to 3.0%, from 0.0 to 1.5%, from 0.0 to 1.5%, from 0.0 to 0.04%, from 0.0 to 0.04%, and from 0.0 to 0.03%.

from 16.5 to 18.5%, from 11.0 to 14.0%, from 2.0 to 2.5%, maximum 0.03% and iron as the remainder.

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 nickel chromium molybdenum manganese silicon phosphorus sulfur carbon

Another embodiment of the container consists of an alloy with the following composition: chromium nickel molybdenum carbon

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-tetrafluoro-hydrocarbon) and TG 227 (1,1,1,2,3,3,3) heptafluoropropane). This includes propellant-containing formulations with active ingredients, surfactants, co-solvents, stabilizers, complexing agents, taste correctors, antioxidants, salts, acids, bases or electrolytes suitable for inhalation therapy, such as hydroxide ions, cyanide ions and / or halides ions such as fluoride, chloride, bromide or iodide.

The container 2 is made of a shell which is composed of one of the described alloys. The cartridge 2 has four different zones: a straight or concave inwardly curved bottom 3, a cylindrical shaped region 4 that extends in the upper third into the tapered neck 5 and then ends in a 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 reservoir 2 resists an overpressure of greater than 30,000 hPa, more preferably greater than 100,000 hPa, most preferably greater than 200,000 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. Advantageously, the container alloy and / or plastic materials described herein are 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 inside 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 within the container 2 is made of a material resistant to corrosion in the liquid. These elements include, for example, a tongue or tongues 11, a valve stem 12 which protrudes outwardly from the valve disc opening 17, a metering chamber 13 and a valve body 14. The tongue 11 consists of steel, preferably stainless steel. The other elements of the valve 9 may be made, for example, of steel, the alloy and / or plastic described above. 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 such that the liquid inside the reservoir comes into contact with the reservoir housing and the valve only 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 inside the valve. These seals 15 and 16 prevent liquid or gas from escaping from inside the container along the outer sheath of the valve stem out of the canister, or come in contact with the valve plate in this way. The gaskets 15 and 16 may be made of the same material as the gasket 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 described corrosion resistant materials, it is not necessary for the seal 10 together with the valve 9 to completely isolate the valve plate from the contents of the container. 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 this 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 thickened edge 6 of the cartridge. 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 summed 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 extends 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 the methods known, inter alia, from the prior art on 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 molded from a sheet of the 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 the hydrohalogenic 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 active compound salts, those acids whose anion is identical to the anion of the active compound salt are preferred. 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 is preferred. 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.

Example 1 ipatropium bromide monohydrate ethanol, absolute

TG 134a inorganic acid water

Example 2 ipatropium bromide ethanol monohydrate, absolute

TG 134a ascorbic acid (purified)

Example 3 ipatropium bromide monohydrate ethanol, absolute

TG 134a citric acid water (purified) total

Example 4 ipatropium bromide ethanol monohydrate, absolute

TG 134a citric acid water (purified) total

Example 5 ipatropium bromide monohydrate ethanol, absolute

TG 134a citric acid water (purified) total

Example 6 phenoterol hydrobromide ethanol, absolute 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.

0.0040 wt.

0.5000 wt.

100.0000 wt.

0.0374 wt. 15.0000 wt. 84.4586 wt.

0.0040 wt.

0.5000 wt.

100.0000 wt.

0.0748 wt. 15.0000 wt. 84.4212 wt.

0.0040 wt.

0.5000 wt.

100.0000 wt.

0.192 wt.

30,000 wt.

TG 134a citric acid water (purified) total

67.806 wt.

0.002 wt.

2,000 wt.

100,000 wt.

The canister filling method with the appropriate 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 (28)

PATENT CLAIMS A canister (1) comprising an active ingredient formulation comprising a salt, acid, base or electrolyte with TG 134a and / or TG 227 as propellant for inhalation therapy, consisting of a reservoir (2) and a valve disc (8) with an insert Valve (9), characterized in that the container (2) is made of an alloy with an iron content of 40.0 to 53.0%, a nickel of 23.0 to 28.0%, a chromium of 19.0 to 23.0%. 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 (2) 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 to 5.0%, copper from 1.0 to 2.0%, manganese to 2.0%, silicon to 0.5%, carbon to 0.02%, and iron is essentially the remainder. Canister according to any one of claims 1 to 2, 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 (2). Canister according to any one of claims 1 to 3, 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 (14) wherein the valve stem (12), the metering chamber (13) and / or the valve body (14) are of steel, alloy and / or plastic. A canister according to any one of claims 1 to 4, 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 5, 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 6, characterized in that the seal (10) and / or the seal (15) and / or the seal (18) are made of ethylene ^; propylene-diene terpolymer. Canister according to any one of claims 1 to 7, characterized in that the valve plate (8) is of the same alloy as the container (2). Container according to any one of claims 1 to 8, characterized in that the container (2) is resistant to an overpressure of greater than 30,000 hPa, more preferably greater than 100,000 hPa. Container according to any one of claims 1 to 9, characterized in that the container (2) is resistant to an overpressure of more than 200,000 hPa. Container according to any one of claims 1 to 10, characterized in that the container (2) has a wall thickness of from 0.1 to 0.5 mm, preferably from 0.15 to 0.35 mm. Container according to any one of claims 1 to 10, characterized in that the container (2) has a wall thickness of 0.19 to 3.0 mm. Canister according to any one of claims 1 to 11, characterized in that the formulation has a pH of 2.0 to 5.0. Canister according to any one of claims 1 to 13, characterized in that the active substance formulation contains electrolytes, which are preferably selected from hydroxide ions, cyanide ions and / or halide ions. The canister of claim 14, wherein the electrolytes are selected from fluoride, chloride, bromide or iodide. Container (2) comprising an active ingredient formulation comprising a salt, acid, base or electrolyte with TG 134a and / or TG 227 as propellant for inhalation therapy, characterized in that the reservoir (2) is of an alloy according to any one of claims 1 and 2. A container according to claim 16, characterized in that the container (2) is resistant to an overpressure of greater than 30,000 hPa, more preferably greater than 100,000 hPa. Container according to claim 16, characterized in that the container (2) is resistant to an overpressure of more than 200,000 hPa. A container according to any one of claims 16 to 18, characterized in that the container (2) has a wall thickness of from 0.1 to 0.5 mm, preferably from 0.15 to 0.35 mm. A container according to any one of claims 16 to 18, characterized in that the container (2) has a wall thickness of from 0.19 to 3.0 mm. A container according to any one of claims 16 to 20, wherein the formulation has a pH of 2.0 to 5.0. Container according to any one of claims 16 to 21, characterized in that the active substance formulation contains electrolytes which are preferably selected from hydroxide ions, cyanide ions and / or halide ions. 23. The container of claim 22, wherein the electrolytes are selected from fluoride, chloride, bromide or iodide. Use of a canister according to any one of claims 1 to 15 or a container according to any one of claims 16 to 23 in an inhaler and / or for the storage of active agent formulations, characterized in that the active agent formulation comprises ethanol as a cosolvent and ipatropium bromide, oxitropium bromide, tiotTopium bromide, albuterol or phenoterol as the active substance. Use according to claim 24, characterized in that the active substance formulation contains ethanol and ipatropium bromide, oxitropium bromide or tiotropium bromide as the active substance. Use according to claim 24 or 25, characterized in that the formulation comprises citric acid. Use according to claim 24 or 25, characterized by a mineral acid. Use according to claim 24 or 25, characterized by hydrochloric acid. characterized in that the formulation contains mines and that the formulation contains